Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[C:9]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:10][NH:11][C:12]=2[C:13]([O:15]CC)=O)=[O:7])=[C:4]([NH2:28])[CH:3]=1.CN1CCCC1=O.C([O-])(=O)C.[NH4+]>O>[C:18]([C:9]1[C:8]2[C:6](=[O:7])[C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[NH:28][C:13](=[O:15])[C:12]=2[NH:11][N:10]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1[nH]nc(C(=O)c2ccccc2)c1C(=O)c1ccc(Cl)cc1N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 160 °C
Yield: 5.6 %

Procedure:
A solution of ethyl 4-(4-chloro-2-aminobenzoyl)-3-benzoyl-1H-pyrazole-5-carboxylate (620 mg, 1.56 mmol), 1-methyl-2-pyrrolidinone (4 mL) and ammonium acetate (120 mg, 1.56 mmol) was heated at 146° C. for 16.5 hours. The temperature was increased to 160° C. for 1 hour. The solution was allowed to cool to room temperature and water (60 mL) was added. The insoluble material (468 mg) was filtered, dried, and twice subjected to flash chromatography eluting with hexanes:ethyl acetate (90:10-50:50) to give impure product. The crude solid was triturated with ethanol (15 mL), washed with ethanol (3×10 mL) and dried to give the title compound (30.5 mg, 5.6% yield m.p. 370-373° C. dec.).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.Cl>CCOCC>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:11][CH:13]2[O:15][CH2:14]2)=[CH:4][CH:5]=1)[CH3:10]
Reactant: CCc1ccc(Br)cc1
Reactant: ClCC1CO1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCc1ccc(CC2CO2)cc1
Temperature: 20 °C

Procedure:
A Grignard solution freshly prepared from 12.15 g (0.50 g atom) magnesium chips and 92.5 g (0.50 mole) 1-bromo-4-ethylbenzene in 400 ml dry ether is dripped with agitation into a precooled solution of 92.5 g (1.00 mole) of epichlorohydrin in 100 ml of dry ether, so that the temperature does not exceed -40° C. After addition is complete, the solution is heated slowly to 20° C. and is hydrolyzed after another three hours by the addition of ice water and dilute hydrochloric acid. The ether phase is separated, washed twice with water and dried over sodium sulfate. Following the removal of the ether, the bath temperature is raised to 70° C. and the volatile components carefully removed at 0.1 mbar. The residue is taken up in 185 ml of methanol and a freshly prepared solution of 6.90 g (0.30 g atom) sodium in methanol added at room temperature. After three hours the sodium chloride precipitate is separated, the filtrate concentrated in vacuum and the yellow, oily residue used without purification for further conversion.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.CCN(C(C)C)C(C)C.[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)COc1cccc(F)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1cccc(F)c1)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
To a stirred mixture of 2-(3-fluorophenoxy)acetic acid (252 mg, 0.893 mmol) in DCM (5 mL) was added DIEA (173 mg, 1.34 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (183 mg, 0.893 mmol), and Bop-Cl (273 mg, 1.07 mmol). The mixture was stirred at 25° C. for 16 hours then quenched with water (20 mL), extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was then purified by prep-HPLC to afford the product (18 mg, Yield 5.6%). 1H NMR (400 MHz, METHANOL-d4) δ=7.26-7.29 (m, 1H), 7.13-7.02 (m, 4H), 6.76-6.69 (m, 3H), 4.55 (s, 2H), 4.06-4.00 (m, 1H), 3.71 (s, 1H), 3.47-3.31 (m, 2H), 2.91-2.90 (m, 2H), 2.86-2.77 (m, 2H), 2.61 (d, J=6.0 Hz, 2H). LCMS (m/z): 359.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([CH3:26])[N:19]=1)=[O:16])(=[O:13])=[O:12].[H][H]>C(OCC)(=O)C.[Pd]>[F:27][C:2]([F:1])([F:28])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([CH3:26])[N:19]=1)=[O:16])(=[O:12])=[O:13]
Reactant: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CC(F)(F)F)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2CCC(F)(F)F)n1

Procedure:
2.9 g of N-[2-(3,3,3-trifluoro-1-propenyl)-phenylsulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2yl)-urea are dissolved in 50 ml of ethyl acetate; there are then added 1.5 g of a 5% palladium/charcoal catalyst, and the mixture is shaken for 16 hours at 20°-25° C. in a hydrogen atmosphere. The catalyst is filtered off, and the residue is completely concentrated by evaporation and subsequently crystallised from an acetone-ether mixture to thus obtain 2.2 g of N-[2-(3,3,3-trifluoropropyl)-phenylsulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea, m.p. 157°-158° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH2:2][C:3]#[CH:4].Br[C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:18]=1.CCN(CC)CC>CN(C=O)C.[Cu](I)I.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>[C:19]1([C:17]2[N:18]=[C:14]([C:4]#[C:3][CH2:2][CH2:1][C:5]3[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=3)[C:8]#[N:9])[S:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Brc1nc(-c2ccccc2)cs1
Reactant: C#CCCc1cccc(C#N)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CCC#Cc2nc(-c3ccccc3)cs2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
3-(But-3-yn-1-yl)benzonitrile (462 mg, 2.98 mmol) and 2-bromo-4-phenylthiazole (650 mg, 2.71 mmol) were taken in dry DMF (20 mL) and purged with nitrogen gas for 15 min. Et3N (1.9 mL, 13.5 mmol) was added to the reaction mixture, followed by a catalytic amount of copper iodide (51 mg, 0.27 mmol) and Pd(PPh3)4 (115 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 12 h and then quenched with water. The organic product was extracted with EtOAc, and the combined extracts were concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 15-20% EtOAc in petroleum ether) to get 3-(4-(4-phenylthiazol-2-yl)but-3-yn-1-yl)benzonitrile (430 mg, yield 50%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.92-7.90 (m, 2H), 7.59-7.52 (m, 3H), 7.47-7.33 (m, 5H), 3.04-2.99 (m, 2H), 2.83-2.78 (m, 2H). MS (ESI) m/z: Calculated for C20H14N2S: 314.09. found: 315.2 (M+H)+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(N(CC)CC)C.[CH3:19][Si:20]([CH3:23])([CH3:22])Cl>C(#N)C>[CH3:19][Si:20]([CH3:23])([CH3:22])[N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N1C(=O)c2ccccc2C1=O

Procedure:
250 g (1.7 moles) of phthalimide were suspended in 2.75 liter of acetonitrile and after 250 ml (1.8 moles) of triethylamine were added, the mixture was heated to gentle reflux 250 ml (1.97 moles) of trimethylchlorosilane were added in 10 minutes and the reaction mixture was then concentrated to a thick paste. 2.5 liter of light petroleum (80°-110° C) were added, the triethylammonium hydrochloride was filtered off and washed with 500 ml of light petroleum. The filtrate and washings were combined and concentrated until crystallization started. After cooling in the refrigerator for several hours, N-trimethylsilylphthalimide was isolated by filtration, washed with a small portion of light petroleum (40°-60° C) and dried in vacuo. The compound was further purified by recrystallization from ligroin (80°-100° C).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Br:21])[C:3]=1[NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[C:26]([N+:35]([O-])=O)[CH:25]=1.Cl>C(O)C.O.[Fe]>[NH2:35][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C:23]([NH:22][C:3]1[C:2]([Br:1])=[CH:7][C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:12])([F:13])[F:11])=[CH:5][C:4]=1[Br:21])=[O:38]
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Br)ccc1-n1cncn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of N-[2,6-dibromo-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-phenyl]-3-nitro-4-(1,2,4-triazol-1-yl)benzamide (Example I2) (675 mg, 0.98 mmol) in a mixture of ethanol and water (20 ml and 4 ml, respectively) was added aqueous hydrochloric acid (37% w/v) (0.25 ml) and iron metal powder (5550 mg, 9.8 mmol). The reaction mixture was stirred at 80° C. for 1 hour. The mixture was filtered through a silica gel pad and the filtrate concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1) to give Compound No. B4 of Table B (372 mg, 58% yield).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])([CH3:3])[CH3:2].CO>[C].[Pd].C(OCC)(=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:8]([O:7][CH2:6][CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])=[C:9]([CH:15]=1)[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(C)NCCOc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)NCCOc1ccc(N)cc1NS(C)(=O)=O
Yield: 93.1 %

Procedure:
2′-[2-(Isopropylamino)ethoxy]-5′-nitromethanesulfonanilide (26.1 g) was dissolved into mixed solvents of methanol (200 ml) and ethyl acetate (200 ml) and subjected to hydrogenation reaction with 10% palladium carbon catalyst at ambient pressure. After completion of hydrogenation reaction, catalyst was removed by filtration. Filtrate was concentrated to dryness under vacuum to obtain 5′-amino-2′-[2-(isopropylamino)ethoxy]methanesulfonanilide (22 g) as brownish solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[Cl:40][CH:41]=[CH:42][CH2:43]Cl>CN(C=O)C>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[N:32]([CH2:43][CH:42]=[CH:41][Cl:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37]
Reactant: ClC=CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2c1Br
Temperature: 25 °C
Yield: 94.6 %

Procedure:
NaH (107 mg, 2.69 mmol, 60% in oil) was added to a solution of 212 (1.3 g, 2.24 mmol) in DMF (15 mL) at 0° C. 1,3-Dichloropropene (414 mg, 3.36 mmol, mixed isomers) was added and the mixture was allowed to warm to room temperature over 12 h. The DMF was evaporated under reduced pressure and the residue was partitioned between EtOAc and H2O. The EtOAc layer was washed with H2O, brine, then dried and evaporated. The residue was purified by chromatography on silica gel, eluting with petroleum ether/EtOAc (4:1) to give tert-butyl 1-bromo-7-[(dibenzylamino)sulfonyl]-2-naphthyl(3-chloro-2-propen-1-yl)carbamate (213) (1.39 g, 95%) as a yellow foam: 1H NMR (CDCl3) (mixture of rotamers and E and Z forms) δ 8.86 (s, 1H), 7.97-7.91 (m, 1H), 7.89-7.82 (m, 2H), 7.51-7.31, 7.26-7.16 (2 m, 7H), 7.13-7.06 (m, 4H), 6.14-6.01 (m, 2H), 4.64-4.48, 4.02-3.90 (2 m, 2H), 4.43 (s, 4H), 1.56, 1.33 (2 s, 9H). HRMS (FAB) calcd. for C32H3279Br35ClN2O4S (M) 655.1033, found 655.1032.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([OH:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1.[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:19][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: OC1CCCc2ccccc21
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Clc1cncc(OC2CCCc3ccccc32)n1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol) and 1,2,3,4-tetrahydro-1-naphthol (488 mg, 3.30 mmol) and NaH (55% in oil, 144 mg, 3.30 mmol). The crude product (0.86 g) was used directly in the next step. MS m/z 261 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7](O)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([Cl:28])=[O:8]
Reactant: CCCCCCc1ccc(SC)c(C=CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCc1ccc(SC)c(C=CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 25 ml of methylene chloride is added 2-methylthio-5-n-hexylcinnamic acid (1.4 g, 0.005 mmol) with cooling in an ice bath. To this mixture is added DMF (0.365 g, 0.005 mmol) and then oxalyl chloride (0.9 ml, 0.01 mmol) dropwise. The bath is removed and the reaction mixture stirred at room temperature for 2 hours to afford 2-methylthio-5-n-hexylcinnamic acid chloride.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]([C:13]1[CH:17]=[CH:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH:14]=1)=[O:12]>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[CH:17]=[C:16]([Br:8])[N:15]([CH:18]([CH3:20])[CH3:19])[CH:14]=1)=[O:12]
Reactant: COC(=O)c1ccn(C(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)n(C(C)C)c1
Reaction time: 4 h

Procedure:
NBS (36.6 mmol) was added to a mixture of 1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step D5) (37.4 mmol) in CCl4 (250 mL). After 4 h, the reaction mixture was successively washed with a saturated aqueous solution of NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a pale yellow-pink oil. tR: 4.56 min (HPLC 1); ESI-MS: tR=1.13 min, [M+H]+ 246/248 (LC-MS 1); TLC: Rf=0.35 (1:6 EtOAc/heptanes).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:17])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(Trifluoromethyl)benzoic acid (0.8 g, 4.2 mmol) dissolved in DCM (20 ml), cooled to 0° C. and added oxalyl chloride (0.8 g, 6.1 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 4-(trifluoromethyl)benzoyl chloride quantitatively. 2-Amino-5-bromophenol (0.71 g, 3.8 mmol) dissolved in DCM (20 ml) and added Pyridine (0.32 ml, 4.1 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 4-(trifluoromethyl)benzoyl chloride (0.88 g, 4.2 mmol). After continuing stirring at rt for 15 mins, reaction mass diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (0.6 g) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:41]([CH2:43][NH2:44])[OH:42]>CCOC(C)=O.C1COCC1>[OH:42][CH2:41][CH2:43][NH:44][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH:9]=[C:10]2[C:20]([CH:22]1[C:23]([CH3:27])([CH3:28])[C:24]1([CH3:26])[CH3:25])=[O:21])=[O:18]
Reactant: NCCO
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)NCCO)cc23)C1(C)C
Yield: 46 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and ethanolamine (21 μL, 0.34 mmol) in 4 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (51 mg, 0.12 mmol, 46% yield). 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.27 (s, 12H), 1.30-1.45 (m, 4H), 2.05-2.19 (m, 1H), 2.23 (s, 1H), 3.22 (dt, J=11.1, 3.2 Hz, 2H), 3.31-3.39 (m, 2H), 3.52 (q, J=6.0 Hz, 2H), 3.83 (d, 2H), 4.17 (d, J=7.1 Hz, 2H), 4.70 (t, J=5.6 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.74 (dd, J=8.5, 1.7 Hz, 1H), 8.35 (t, J=5.8 Hz, 1H), 8.38 (s, 1H), 8.74 (d, J=1.4 Hz, 1H); MS (DCI/NH3) m/z 427 (M+H)+; Anal. Calculated for C25H34N2O4.0.3H2O: C, 69.51; H, 8.07; N, 6.49. Found: C, 69.36; H, 7.88; N, 6.27.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13](Cl)[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([N:4]([CH2:5][CH3:6])[CH2:1][CH3:2])[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)c1ccc([N+](=O)[O-])c(N2CCN(C(C)=O)CC2)n1
Reaction time: 1.25 h
Yield: 136.1 %

Procedure:
A solution of 51.22 g of N-acetylpiperazine in 200 ml of acetonitrile was added over 50 minutes at 0° C. to a mixture of 78 g of 2,6-dichloro-3-nitropyridine, 600 ml of acetonitrile and 66.3 g of potassium carbonate. The mixture was allowed to return to room temperature and was stirred for 75 minutes. The inorganic salts were filtered off and after 180 ml of N,N-diethylamine and 76 g of potassium carbonate were added to the filtrate, the mixture was refluxed for 75 minutes. The inorganic salts were filtered off after cooling and the filtrate was evaporated to dryness under reduced pressure. The 166.9 g of residue were crystallized from 200 ml of ethyl acetate to obtain 87.4 g of the expected product melting at 120° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:13][CH3:14])([CH3:12])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(C(C)C)cccc1C(C)C
Yield: 72.7 %

Procedure:
A mixture of 2,6-diisopropyl phenol (20 g, 0.11 mol), potassium carbonate (62 g, 0.45 mol), acetone (160 ml) and methyl iodide (28 ml, 0.45 mole) is refluxed for three days. The reaction mixture is filtered through celite, evaporated, dissolved in ether, washed twice with 1M sodium hydroxide, dried over magnesium sulphate and concentrated to afford 15.1 g (0.08 mol, 70%) of 2,6-diisopropyl anisole as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:11](=[O:32])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.IC.[Li+].[CH3:36][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:11](=[O:32])[CH:10]([CH3:36])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(CN2C(=O)CC[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CN2C(=O)C(C)C[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one (Example 71, Step A) (140.34 g, 298 mmol) in anhydrous THF (994 mL) was degassed by bubbling argon through the solution for 20 minutes while it cooled to −78° C. Iodomethane (23.32 mL, 373 mmol) was added followed by the addition of LHMDS (328 mL, 328 mmol) over 15 minutes. The reaction mixture was stirred for 15 minutes at −78° C. and then the reaction was removed from the cold bath and stirred at rt for 12 hours. The reaction was quenched by the addition of sat. aq. NH4Cl and the layers were separated. The aqueous layer was extracted with EtOAc (2×500 mL) and the organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide an orange oil. Purification (wet loaded with small amount of DCM) using the Combiflash Companion XL (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) with a 1.5 kg SiO2 column and eluting with 4 L each of 15-20-25-30-35% EtOAc/hexanes provided the title compound as a thick very pale yellow oil and a 3.7:1 mixture of C-3 diastereomers.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1)#[N:2].N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)C>[Si:20]([O:10][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: N#Cc1cc(CO)ccn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(C#N)c1
Reaction time: 1 h

Procedure:
To a solution of 2-cyano-4-hydroxymethylpyridine (step 1, 3.63 g, 27.06 mmol) in DMF (50 ml) were added imidazole (4.42 g, 64.95 mmol) and TBDMSCl (4.89 g, 32.47 mmol) at room temperature. After stirring for 1 h, the mixture was diluted with diethyl ether (300 ml), washed with water (100 ml×4), and dried (MgSO4). Removal of solvent gave the title compound. 1H-NMR (CDCl3) δ: 8.65 (1 H, d, J=5.1 Hz), 7.68 (1 H, s), 7.46 (1 H, d, J=4.9 Hz), 4.78 (2 H, s), 0.96 (9 H, s), 0.13 (6 H, s).
Reaction SMILES: Br[CH:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[N-:23]=[N+:24]=[N-:25].[Na+].CO>CN(C)C=O>[N:23]([C:18]1[C:17](=[O:20])[CH2:16][CH2:15][C@@:14]2([CH3:21])[C:19]=1[CH2:2][CH2:3][C@@H:4]1[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]1[CH2:6][CH2:7][C:8]2=[O:22])=[N+:24]=[N-:25]
Reactant: C[C@]12CCC(=O)C=C1C(Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@]12CCC(=O)C(N=[N+]=[N-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 48.3 %

Procedure:
To a stirred solution of 1.1 g of 6-bromoandrost-4-en-3,17-dione in 57.4 ml of dimethylformamide are added 0.250 g of sodium azide. The resulting mixture is heated at 30°-35° C. for 72 hours, cooled and worked up as described in the example 3. There are obtained 0.476 g of the title compound, m.p. (MeOH) 143°-144° C. (dec.);