Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9]2=[O:16].C(=O)([O-])[O-].[K+].[K+].CCC(=O)CC.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>O>[CH3:38][O:37][C:35](=[O:36])[CH2:34][N:10]1[C:9](=[O:16])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([O:5][C:4]3[CH:17]=[CH:18][C:19]([F:20])=[C:2]([F:1])[CH:3]=3)[CH:7]=2)[C:11]1=[O:15]
Reactant: COC(=O)CBr
Reactant: O=C1NC(=O)c2cc(Oc3ccc(F)c(F)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(=O)CC
Product: COC(=O)CN1C(=O)c2ccc(Oc3ccc(F)c(F)c3)cc2C1=O
Temperature: 105 °C

Procedure:
To a pressure tube was added 5-(3,4-difluoro-phenoxy)-isoindole-1,3-dione (680 mg), potassium carbonate (1 g), 3-pentanone (20 ml), and methyl bromoacetate (295 μL). The resulting mixture was heated to 105° C. for 17 h. The reaction was diluted with 20 ml water and extracted with ethyl acetate (2×). The organic layer was dried and concentrated. The mixture was purified through silica gel chromatography with 4:1 hexanes/ethyl acetate and 3:1 hexanes/ethyl acetate to give 657 mg of the title compound. ): 1H NMR (200 MHz, DMSO) δ 7.95 (d, J=9.0 Hz, 1H), 7.64-7.41 (m, 4H), 7.15-7.08 (m, 1H), 4.44 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30](=[O:32])[NH2:31])[CH:28]=4)[N:23](C(OC(C)(C)C)=O)[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH2:31])=[O:32])[CH:28]=4)[NH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(C(N)=O)cc34)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc2[nH]cc(-c3cncc(N4CCC(N)CC4)n3)c2c1
Temperature: 50 °C
Yield: 20.1 %

Procedure:
To a mixture of tert-butyl 3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-carbamoyl-1H-indole-1-carboxylate (200 mg, 0.37 mmol) in chloroform was added TFA at 0° C. The reaction mixture was heated at 50° C. for 12 h. After removal of TFA the crude product was purified by preparative HPLC to obtain title compound (25 mg, 20%) as a brown solid. MS (ESI, pos. ion) m/z: 337.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:13]([O:20][C:21](=[O:38])[CH:22](Br)[CH2:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC#N>[CH2:13]([O:20][C:21](=[O:38])[CH:22]([N:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH2:23][CH2:24][CH2:25][N:26]1[C:27](=[O:36])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]1=[O:35])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1CNCCNCCNCCN1
Reactant: O=C(OCc1ccccc1)C(Br)CCCN1C(=O)c2ccccc2C1=O
Solvent: CC#N
Product: O=C(OCc1ccccc1)C(CCCN1C(=O)c2ccccc2C1=O)N1CCNCCNCCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
55 g of cyclen base (320 mmol) are dissolved in 550 ml of CH3CN, to which 119.8 g of brominated derivative (2-bromo-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid benzyl ester, 288 mmol) dissolved in 550 ml of CH3CN are added dropwise. The medium is stirred at ambient temperature overnight. The precipitate is filtered off and washed thoroughly with acetonitrile. 138 g of product are obtained in the form of a white powder (corrected yield 81.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[SH:9][CH2:10][C:11](O)=[O:12]>Cl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:11](=[O:12])[CH2:10][SH:9])=[CH:3][CH:4]=1
Reactant: O=C(O)CS
Reactant: Nc1ccc(O)cc1
Agent: Cl
Product: O=C(CS)Nc1ccc(O)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-aminophenol (4.0 g, 36.7 mmol) and mercaptoacetic acid (2.93 g, 38.5 mmol) under an atmosphere of carbon dioxide was heated to reflux (oil bath temperature ˜120° C.) for 4 hours. The mixture was cooled and diluted with 2 N hydrochloric acid (˜100 mL). A purple solid, 1.3 g, was collected by filtration and washed with water. The product was purified by flash chromatography, on silica gel, eluted with 5 to 10% methanol in DCM, to give a colorless solid, 1.03 g (15%). MS m/z 184 (MH+). 1H NMR(DMSO-d6) δ 2.08 (t, 1H), 3.24 (s, 2H), 6.70 (d, 2H), 7.35 (d, 2H), 9.21 (br s, 1H) and 9.83 (s, 1H). Anal. calcd for C8H9NO2S: C, 52.44; H, 4.95; N, 7.64. Found: C, 52.57; H, 4.95; N, 7.40.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].CC(C)=O.O.[Cl:15][C:16]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:16]=2[Cl:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a solution of 3,4-dichloroaniline (2.6 g; 2 eq.) in a 1/1 acetone/water mixture (30 ml) is added dropwise at 0° C. a solution of 2-chloro-3-nitro-5-trifluoromethylbenzoyl chloride (2.3 g; 1 eq.) in acetone (10 ml). After 18 hours at room temperature, 20 ml of water are added. The resulting solid is filtered off by suction, washed with water and dried. 3.1 g of N-(3,4-dichlorophenyl)-2-chloro-3-nitro-5-trifluoromethylbenzamide are obtained (m.p.=202° C.).
Reaction SMILES: O.O.O.[O-:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccccc2)c([N+](=O)[O-])c1

Procedure:
A solution of sodium phenoxide trihydrate (5.0 g, 30 mmol) and 4-chloro-3-nitrotoluene (2.65 mL, 30 mmol) was heated in 60 mL of DMF at 100° C. for 5 days with stirring following the procedure from Example 1c. The product was purified by silica gel column chromatography eluting with CH2Cl2 giving the title compound as an orange solid (1.36 g, 30%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.Br[CH2:15][C:16]([CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)=O.O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:15]=[C:16]([CH:18]4[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]4)[N:13]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)CBr)C1
Reactant: Nc1nccnc1N1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2cn3ccnc(N4CCOCC4)c3n2)C1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of compound 1b (2.4 g, 13 mmol) in DMF (20 mL), Na2HPO4 (4.7 g, 33 mmol) was added followed by tert-butyl 3-(2-bromoacetyl)azetidine-1-carboxylate (6.0, 21 mmol). The resulting mixture was stirred at 100° C. for 3 h. The reaction mixture was allowed to cool to rt and water (50 mL) was added. The aqueous layer was extracted with EtOAc (3×25 mL). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0:1-1:0 EtOAc/hexanes) to obtain compound 29a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C18H25N5O3: 360.2 (M+H). found: 360.3.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.C(O)(=O)C.[F:10][C:11]([F:39])([F:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[NH:22][C:23]1[N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[C:27](=[O:33])[CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1.C(=O)(O)[O-].[Na+]>CCOCC>[F:39][C:11]([F:38])([F:10])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=1[NH:22][C:23]1[N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[C:27](=[O:33])[C:26]([Cl:4])=[C:25]([C:34]([F:35])([F:36])[F:37])[N:24]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Sulfuryl chloride (0.011 ml) was added to acetic acid (1.3 ml) solution of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-butyl-6-trifluoromethyl-4(3H)-pyrimidinone (60 mg, 0.13 mmol) which had been synthesized in accordance with the method of Example 24, followed by stirring at room temperature for 1 hour. After completion of the reaction, ether (20 ml) was saturated sodium bicarbonate aqueous solution (20 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ether (10 ml×2). The thus obtained ether layers were combined, washed with sodium bicarbonate aqueous solution (20 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained crude product by a silica gel column chromatography (dichloromethane:hexane=10:3), white solid of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-butyl-5-chloro-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 55] was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:13])[C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH:15]([O:12][C:6]1[C:5]([CH3:13])=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)([CH3:17])[CH3:16]
Reactant: Cc1ccc2ccc(O)c(C)c2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc2ccc(OC(C)C)c(C)c2n1
Yield: 24.1 %

Procedure:
2,8-Dimethylquinolin-7-ol (1.0 g, 2.31 mmol), 2-iodopropane (0.785 g, 4.62 mmol) and potassium carbonate (0.957 g, 6.93 mmol) in acetone (15 mL) were heated to 70° C. in a sealed tube for 18 hours. After cooling, water (20 mL) was added and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-isopropoxy-2,8-dimethylquinoline (120 mg, 24.1% yield) as an oil
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.O=[C:22]1[CH2:27][CH:26]2[CH2:28][CH:23]1[CH2:24][CH:25]2[O:29][C:30](=[O:32])[CH3:31].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:22]3[CH2:27][CH:26]4[CH2:28][CH:23]3[CH2:24][CH:25]4[O:29][C:30](=[O:32])[CH3:31])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CC(=O)OC1CC2CC1CC2=O
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CC(=O)OC1CC2CC1CC2Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-acetic acid 5-oxo-bicyclo[2.2.1]hept-2-yl ester (prepared as in J. Meinwald et al., Tetrahedron 1962, 18, 815-820) using decaborane yielded a mixture of isomers of the title compound as a white foam. MS (ESI): m/z=431.4 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:39])[C@H:10]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[N:11]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])C1C=CC=CC=1.[Li+].[OH-]>O1CCCC1.O>[C:20]([N:11]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[C@H:10]([C:9]([OH:39])=[O:8])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: COc1ccc(C[C@@H](C(=O)OCc2ccccc2)N(C(=O)CCCCCN)C(=O)OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C[C@@H](C(=O)O)N(C(=O)CCCCCN)C(=O)OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of 2.66 g (5 mmol) of the resultant compound of Example 170 in 60 mL of tetrahydrofuran was cooled to 0° C., treated with 0.63 g (15 mmol) of LiOH in 30 mL of H2O and allowed to stir for 2 h. After concentration of the solvent, the mixture was partitioned between H2O and ether, acidified, extracted with ethyl acetate, dried over MgSO4 and concentrated to give 1.55 g (70%) of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(CC(=O)O)cc1

Procedure:
p-Hydroxyphenylacetic acid (5.0 g) is dissolved in 30 ml of dimethyl formamide, 10 ml of allyl bromide and 10 g of anhydrous potassium carbonate are added thereto, and the mixture is heated at 70°-80° C. for six hours with stirring. The reaction solution is diluted with 300 ml of water, extracted with ether, the resulting extract is dissolved in 100 ml of methanol, and the mixture is heated to reflux for one hour with 30 ml of 15% aqueous solution of potassium carbonate. The reaction solution is then concentrated in vacuo, 100 ml of water is added thereto, the mixture is washed with ether, acidified with hydrochloric acid, and extracted with ether to give 5.0 g of p-allyloxyphenylacetic acid, melting point: 61°-62° C.
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH3:23][C:22]([CH3:25])([CH3:24])[C:21](=[O:26])[CH:9]([O:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)C(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)C(Oc1ccccc1)C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Triethylamine (57.35 g, 566 mmol) was added to a stirred solution of N-[2-chloro-4,4,-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline prepared as above (155.9 g, 483 mmol) and phenol (49.9 g, 530 mmol) in dry acetonitrile (1.3 L) under argon. After the addition had been completed, the mixture was heated at reflux for 7 hours. The reaction mixture was then cooled and the solvent was removed under reduced pressure. The residue was dissolved in methanol (300 mL) and allowed to stir at room temperature until crystallization began. After 2 hours, the mixture was cooled in an ice bath for a further 1 hour. The product was removed by filtration, washed with cold methanol, and dried to afford N-[4,4-dimethyl-3-oxo-2-phenoxypentanoyl]-2,4-dichloroaniline (99 g, 54% yield) as a white crystalline solid which melted at 112°-113.5° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[CH3:22][C@:23]12[CH2:39][CH2:38][C@H:37]3[C@@H:28]([CH:29]=[CH:30][C:31]4[C@@H:36]3[CH2:35][CH2:34][C:33](=[O:40])[CH:32]=4)[C@@H:27]1[CH2:26][CH2:25][C:24]2=[O:41].C(O)(=O)C>O1CCCC1.[Cu]I>[CH3:16][Si:15]([CH3:17])([C:18]([CH3:21])([CH3:20])[CH3:19])[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:29]1[CH2:30][C:31]2[C@H:36]([CH2:35][CH2:34][C:33](=[O:40])[CH:32]=2)[C@@H:37]2[C@@H:28]1[C@H:27]1[C@@:23]([CH2:39][CH2:38]2)([CH3:22])[C:24](=[O:41])[CH2:25][CH2:26]1
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCBr
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reaction time: 1 h
Yield: 172 %

Procedure:
7.4 g of magnesium filings is placed into 31 ml of tetrahydrofuran and combined within 1.5 hours with a solution of 113 g of 11-bromoundecyl-tert-butyldimethylsilyl ether in 310 ml of tetrahydrofuran. After one hour at a bath temperature of 100°, the mixture is diluted with 157 ml of tetrahydrofuran, cooled to -30°, mixed with 29.5 g of copper(I) iodide, stirred for 0.2 hour at -30°, a solution of 25 g of 4,6-estradiene-3,17-dione [Kalvoda, J., and Anner, G., Helv. Chim. Acta 50 : 269 (1967)]in 220 ml of tetrahdyrofuran is added dropwise, and the mixture is further stirred for 1.5 hours at -30°. Then, 18.7 ml of glacial acetic acid is added, the mixture is concentrated under vacuum, poured on water, suctioned off through "Celite", rinsed with ethyl acetate, extracted twice with ethyl acetate, washed with water and sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus obtaining 88.6 g of 7α-[11-(dimethyl-tert-butyl-silyloxy)undecyl]-4-estrene-3,17-dione, [α]D =54.4°, as an oil, as well as 55.2 g of 7β-[11-(dimethyl-tert-butylsilyloxy)undecyl]-4-estrene-3,17-dione, mp 65°.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[Br:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([NH2:17])=[CH:11][CH:10]=1>C(O)=O>[Br:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([NH:17][CH:1]=[O:3])=[CH:11][CH:10]=1
Reactant: COc1nc(Br)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COc1nc(Br)ccc1NC=O
Reaction time: 0.42 h

Procedure:
Acetic anhydride (203 mL) was added dropwise to formic acid (204 mL) under ice-cooling, and the mixture was stirred at the same temperature for 25 min. 6-bromo-2-methoxypyridine-3-amine power (CAS#89466-18-2, 146 g) was put into the reaction mixture over 10 minutes, and the reaction solution was stirred at the same temperature for 30 minutes. The water bath was removed. tert-Butyl methyl ether (300 mL) and n-heptane (500 mL) were sequentially added dropwise to the reaction solution, and then the reaction solution was stirred for 30 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.[ClH:33]>O1CCOCC1.CCOCC>[ClH:33].[F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2F)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)c(F)c2)cc1
Yield: 88 %

Procedure:
4-({[3-Fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (0.23 g, 88%) was prepared as a white solid from 1,1-dimethylethyl 4-({[3-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarboxylate (Example 64, 0.30 g, 0.65 mmol), 1,4-dioxane (12 mL), ether (9 mL), 4.0M HCl in 1,4-dioxane (9 mL) and 2M HCl in ether (9 mL) in a manner similar to Example 66, Step 1. 1H NMR (400 MHz, CD3OD): δ 7.99 (d, 2H, J=8.5 Hz), 7.84 (d, 2H, J=8.5 Hz), 7.55-7.45 (m, 2H), 7.25-7.20 (m, 1H), 4.04 (d, 2H, J=5.9 Hz), 3.50-3.40 (m, 2H), 3.14 (s, 3H), 3.10-3.00 (m, 2H), 2.30-2.15 (m, 1H), 2.15-2.05 (m, 2H), 1.75-1.60 (m, 2H); LRMS (ESI), m/z 364 (M+H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([C:15]2[C:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:17][NH:18][CH:19]=2)[N:7]=1)[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Cl.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]Cl)[CH2:32][CH2:31]1>CN(C=O)C>[CH2:1]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([C:15]2[C:16]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:17][NH:18][C:19]=2[CH:36]([N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH3:37])[N:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: ClCCN1CCOCC1
Reactant: CC(C)CNc1nc(-c2c[nH]nc2-c2ccc(F)cc2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CNc1nc(-c2c(-c3ccc(F)cc3)n[nH]c2C(C)N2CCOCC2)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 81.9 %

Procedure:
Treat a solution of 2-isobutylamino-3-nitro-6-[3-(4-fluorophenyl)pyrazol-4-yl]pyridine (1.25 g, 3.52 mmol) in dry DMF (15 mL) with 95% NaH (0.36 g, 14.3 mmol) at 0° C. for 15 min. Add morpholinoethylchloride hydrochloride (0.983 g, 5.28 mmol) and slowly warm to RT. Add additional NaH (0.36 g, 14.3 mmol), after 1 h and stir the reaction mixture for 24 h. Quench with MeOH (1 mL) and dilute with water (30 mL). Extract with EtOAc (100 mL), dry with MgSO4, and concentrate. Purify the residue (silica gel chromatography, eluting with hexanes:EtOAc 1:2) to give the title compound (1.35 g, 81%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)[C:3]=1[CH:19]=[O:20].[O:21]1CCC[CH2:22]1.CO.[H-].[Na+]>O>[CH:19]([C:3]1[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)=[N:5][N:6]([CH3:7])[C:2]=1[O:21][CH3:22])=[O:20]
Reactant: Cc1cc(-c2nn(C)c(Cl)c2C=O)ccc1OC(C)C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C=O)c(-c2ccc(OC(C)C)c(C)c2)nn1C
Reaction time: 3 h

Procedure:
At room temperature, to a mixture of 5-chloro-4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole (described in Reference Preparation example 96) 4.8 g and tetrahydrofuran 100 ml was added methanol 0.6 g and 55% sodium hydride 0.8 g, and the resulting mixture was stirred for three hours. To the reaction mixture was added water 50 ml, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole 4.5 g.
Reaction SMILES: Cl[C:2]1[C:3]([N+:30]([O-:32])=[O:31])=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:6].[CH3:33][NH:34][CH3:35].O>CN(C=O)C>[CH3:33][N:34]([CH3:35])[C:2]1[C:3]([N+:30]([O-:32])=[O:31])=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:6]
Reactant: O=C(NC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cccc(C(=O)NC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1[N+](=O)[O-]
Yield: 88.5 %

Procedure:
Step 2): A solution of 3-chloro-2-nitro-N-(1-diphenylmethylpiperidin-4-yl)benzamide (13.5 g, 30 mmol) and 40% dimethylamine (20 ml) in DMF (60 ml) was heated at 130° C. for 15.5 hours in a sealed tube. The mixture was poured into water and extracted with ether. The organic layer was washed with water, dried (MgSO4) and concentrated. The residue was recrystallized (ethyl acetate/hexane) to give 3-dimethylamino-2-nitro-N-(1-diphenylmethyl piperidin-4-yl)benzamide (88.5%): mp 176° C.