Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8]C([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.S(O)(O)(=O)=O.[CH3:17][NH:18][C:19](=[NH:21])[SH:20].[C:22](=[O:25])(O)[O-:23].[Na+].O>C(Cl)Cl>[C:4]([O:23][C:22]([N:18]([CH3:17])[C:19](=[N:21][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:8])[SH:20])=[O:25])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CNC(=N)S
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C(S)=NC(=O)OC(C)(C)C
Yield: 69.2 %

Procedure:
58.1 g of tert-butyl dicarbonate, 25.3 g of methyl thioisourea sulfate, 50 g of sodium bicarbonate, 500 ml of water and 500 ml of methylene chloride were stirred for 48 hours at 20° C. and after decanting, followed by extraction with methylene chloride and evaporation to dryness, 27 g of the expected product melting at 118° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:27])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)=O)(=[O:10])=[O:9]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:27])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH2:16][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)(=[O:10])=[O:9]
Reactant: COc1cccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Solvent: C1CCOC1
Product: COc1cccc(NCc2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 11.6 %

Procedure:
BH3 -THF (15 ml, 1 M in THF) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (Example 22) (1.0 g, 2.12 mmol) in dry THF (15 ml). The mixture was refluxed for 8 hours and cooled. THF was evaporated on a rotavap and MeOH was added to the residue. The resulting solution was concentrated. The final residue was purified by HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)aminomethyl]thiophene-3-sulfonamide (113 mg., 12% yield) as a grey powder, m.p. 70-73° C.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[F:7][C@@H:8]1[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][C:23](=[O:26])[CH:24]=2)[C:19]2[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH:18]=2)([CH3:16])[C:14](=[O:28])[CH2:13][CH2:12]3)[CH2:9]1>C1COCC1>[C:1]([C@:14]1([OH:28])[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C:19](=[CH:18][CH2:17][C@:15]12[CH3:16])[C@:20]1([CH3:27])[C:25]([CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)=[C:8]([F:7])[CH2:9]3)#[CH:2]
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CCC(=O)C=C1[C@@H](F)C[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [K+]
Solvent: C1CCOC1
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CC(F)=C4CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reaction time: 0.67 h

Procedure:
Potassium t-butoxide (as a 20% solution in THF, 1.6 ml) is added to THF (10 ml) containing 6α-fluoro-androst-4,9(11)-diene-3,17-dione (V, Example 4, 350 mg), previously cooled to -10°. After stirring at -10° for 40 min, acetylene is slowly bubbled in over 2 hrs. The solution is then allowed to warm to 20°-25°, quenched with aqueous ammonium chloride and extracted with ethyl acetate which is then back extracted with water, dried over sodium sulfate, the solvent removed under reduced pressure to give the title compound Rf (ethyl acetate/hexane, 1/1)=0.6; NMR (CDCl3 +CD3OD) 0.9, 1.4, 2.6 and 5.7 δ.
Reaction SMILES: C([O:8][C:9](=[O:34])[C@H:10]([N:20]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:32]([O:31][C:29]([CH2:28][N:20]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[C@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:9]([OH:34])=[O:8])=[O:30])[CH3:33]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)O
Yield: 86.5 %

Procedure:
N-Ethoxycarbonylmethyl-N-tert.-butoxycarbonyl-2-(R)-amino-3-(4-methoxyphenyl)-propionic acid benzyl ester (1.50 g) were dissolved in 40 mL of methanol and hydrogenated for 4 h at room temperature using 0.3 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 1.05 g (87%) of the title compound as a colorless oil. (−)-APCI-MS: 381 ([M-H]−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH:36]([CH2:39][OH:40])[CH2:37][OH:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH:36]([CH2:39][OH:40])[CH2:37][OH:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NC(CO)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: O=C(NC(CO)CO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-amino-1,3-propanediol using methods similar to Example 563 to provide a white solid: ES+ MS: 513 (M+H+).
Reaction SMILES: C[C:2]([O-:5])([CH3:4])C.[K+].[C:7]([O:11][C:12](=[O:24])[NH:13][C@H:14]([C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)[C@H:15]([CH3:18])[CH:16]=O)([CH3:10])([CH3:9])[CH3:8].C1C[O:28][CH2:27][CH2:26]1>>[CH2:27]([O:28][C:2](=[O:5])[CH:4]=[CH:16][C@@H:15]([CH3:18])[C@H:14]([NH:13][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:24])[C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)[CH3:26]
Reactant: C[C@H](C=O)[C@H](NC(=O)OC(C)(C)C)c1ccco1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)C=C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of ethyl 2-triethylphosphono-acetate (2.2 mL, 11 mmol) in THF (30 mL) at 0° C. was added KOtBu (1.01 g, 9.02 mmol) and stirred for 1 hour at room temperature. The mixture was cooled to −78° C. To the mixture was added slowly a solution of 2.12a (0.993 g, 3.92 mmol) in THF (10 mL. The reaction mixture was poured onto a mixture of ice-cold water/Et2O (10 mL/600 mL), washed with brine twice, dried over MgSO4 and concentrated. Purification by silica gel column chromatography (0-50%, EtOAc/heptane) to give 2.12b (1.14 g, 90% yield). MS m/z (M+23) 346.2. 1H NMR (E, major isomer) (400 MHz, CDCl3) δ ppm 1.05 (d, J=6.90 Hz, 2H) 1.07-1.18 (m, 1H) 1.19-1.32 (m, 2H) 1.36-1.46 (m, 2H) 1.44 (s, 4H) 1.55-1.57 (m, 1H) 4.14-4.22 (m, 1H) 5.74-5.85 (m, 1H) 6.14-6.19 (m, 1H) 6.27-6.33 (m, 1H) 6.86 (dd, J=15.70, 8.17 Hz, 1H) 7.26 (s, 1H) 7.31-7.37 (m, 1H).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][O:30][CH2:31][C@H]1CC[C@H](N)CC1.C(=O)CC(C)C.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:29][O:30][CH2:31][C@H:4]1[CH2:5][CH2:6][C@H:1]([N:7]([CH2:21][CH2:22][CH:23]([CH3:28])[CH3:24])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: COC[C@H]1CC[C@H](N)CC1
Agent: CC(C)CC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COC[C@H]1CC[C@H](N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
{2-[3-(trans-4-Methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid was prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethylureido)-thiazol-5-ylsulfanyl]-acetic acid using, trans-4-methoxymethyl-cyclohexylamine, isovaleraldehyde and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[S:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[N+:15]([C:12]1[S:11][C:10]([NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[N:14][CH:13]=1)([O-:17])=[O:16]
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)CCCC(=O)Nc1ncc([N+](=O)[O-])s1
Reaction time: 18 h
Yield: 49.5 %

Procedure:
Glutaric anhydride (1.0 g, 8.8 mmol), TEA (1.35 ml, 9.6 mmol) and cat. DMAP were dissolved in CH2Cl2 (7 mL). 2-Amino-5-nitrothiazole (1.4 g, 9.64 mmol) was then added and the solution was held at ambient temperature. After 18 hours, the solution was diluted with EtOAc (50 mL) and extracted with 1M NaOH (3×30 mL). The combined aqueous layers were washed with EtOAc (20 mL) then acidified with 12M HCl and subsequently extracted with EtOAc (5×20 mL). The combined organics were washed with brine (2×20 mL), dried (MgSO4), filtered and concentrated to dryness to yield 5-(5-nitrothiazol-2-ylamino)-5-oxopentanoic acid (1.13 g, 54%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 12.59 (bs, 1H), 8.59 (s, 1H), 2.57 (t, J=7.4 Hz, 2H), 2.28 (t, J=7.3 Hz, 2H), 1.82 (quint., J=7.3 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 174.0, 172.8, 161.8, 142.8, 141.7, 34.1, 32.7, 19.6; HRMS (ESI) calcd for [C8H9N3O5S+H]+ 260.0336. found 260.0344. Method B with 5-(5-nitrothiazol-2-ylamino)-5-oxopentanoic acid (30 mg, 0.12 mmol) afforded the title compound VPC161276 (23 mg, 46%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 2H), 2.61 (t, J=7.2 Hz, 4H), 1.97 (quint., J=7.0 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 172.8, 162.0, 142.8, 141.5, 34.0, 19.3; HRMS (ESI) calcd for [C11H10N6O6S2+H]+ 387.0176. found 387.0185.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:11]=[N:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:18]3)[CH:7]=1.[BH4-].[Na+]>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:28])([F:27])[F:29])[CH2:11][NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2ccc(C(N)=O)nc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2ccc(C(N)=O)nc12)C(F)(F)F
Reaction time: 16 h

Procedure:
703 mg (1.47 mmol) of 8-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]quinoline-2-carboxylic acid amide in 10 ml of methanol and 5.0 ml of tetrahydrofuran are mixed with 449 mg (11.8 mmol) of sodium borohydride. After 16 hours, the solvent is concentrated by evaporation, the residue is taken up in water and ethyl acetate, extracted with ethyl acetate, and the combined organic phases are dried on sodium sulfate. After removal of the solvent and purification on silica gel with hexane-ethyl acetate (0-50%) as well as dichloromethane-methanol (0-7%), 358 mg (51% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:18]([OH:20])=O)[N:15]([CH3:17])[CH:16]=2)=[O:10])=[CH:4][C:3]=1[F:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:46][O:47][C:48]1[N:53]=[CH:52][C:51]([CH:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:21][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:18]([NH:56][CH:54]([C:51]3[CH:52]=[N:53][C:48]([O:47][CH3:46])=[CH:49][CH:50]=3)[CH3:55])=[O:20])[N:15]([CH3:17])[CH:16]=2)=[O:10])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)Nc2cn(C)c(C(=O)O)n2)cc1F
Reactant: COc1ccc(C(C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C(C)NC(=O)c2nc(NC(=O)Nc3ccc(C)c(F)c3)cn2C)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60 mg (0.2 mmol) of 4-({[(4-methyl-3-fluorophenyl)amino]carbonyl}amino)-1-methyl-1H-imidazole-2-carboxylic acid (Example 18A) are dissolved in 4 ml of DMF and, after addition of 150 mg (0.39 mmol) of HATU and 36 mg (0.3 mmol) of DMAP, stirred at room temperature for 15 minutes. 60 mg (0.39 mmol) of [1-(6-methoxypyridin-3-yl)ethyl]amine are added to this solution and the mixture is stirred overnight. The reaction mixture is purified by preparative HPLC. The correct fractions are evaporated in vacuo.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([S:29][C:30]([F:33])([F:32])[F:31])=[CH:25][C:23]=2[N:24]=1)C.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:34]([C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([S:29][C:30]([F:32])([F:33])[F:31])=[CH:25][C:23]=2[N:24]=1)(=[O:38])=[O:36])[CH3:11]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1ccsc1-c1nc2cc(SC(F)(F)F)ccc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccsc1-c1nc2cc(SC(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.08 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 2.44 g of 2-(3-ethylthiothiophen-2-yl)-5-(trifluoromethylthio)benzoxazole and 20 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 2.6 g of 2-(3-ethylsulfonylthiophen-2-yl)-5-(trifluoromethylthio)benzoxazole (Compound of Present Invention (29)).
Reaction SMILES: CN(C)C=O.[CH3:6][NH:7][C:8]1[CH:9]=[C:10]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:28])=[C:23](F)[C:24]=3[Cl:26])[C:19](=[O:29])[C:18]([C:30]([OH:32])=[O:31])=[CH:17]2)[C:11]([F:15])=[CH:12][C:13]=1[F:14].Cl.Cl.[NH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[CH:36]([O:29][CH:19]([CH3:18])[CH3:20])([CH3:39])[CH3:37].[NH2:35][CH:36]1[CH2:39][N:38]([C:23]2[C:24]([Cl:26])=[C:25]3[C:20]([C:19](=[O:29])[C:18]([C:30]([OH:32])=[O:31])=[CH:17][N:16]3[C:10]3[C:11]([F:15])=[CH:12][C:13]([F:14])=[C:8]([NH:7][CH3:6])[CH:9]=3)=[CH:21][C:22]=2[F:28])[CH2:37]1
Reactant: NC1CNC1
Reactant: CNc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)OC(C)C
Product: CNc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 153.4 %

Procedure:
To 650 mg of N,N-dimethylformamide were added 150 mg of 1-(3-methylamino-4,6-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 110 mg of 3-aminoazetidine dihydrochloride, and 250 mg of N-methylpyrrolidine. The solution was stirred at 90° C. for 1 hour. After 0.5 ml of ethanol was added, the reaction solution was allowed to cool down. The precipitate was collected by filtration and washed with ethanol and then diisopropyl ether to give 130 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[N+:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([O-:22])=[O:21]>ClCCl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
A solution of 4-amino benzoic acid ethyl ester (1.95 g, 11.8 mmol) in dry dichloromethane (20.0 ml) was treated with triethylamine (1.31 g, 13.0 mmol) and cooled to 0° C. 3-Nitrobenzoyl chloride (2.00 g, 10.8 mmol) was added portion wise over 5 min. The mixture was stirred at 0° C. for 5 min, then at room temperature for 10 min. The reaction was quenched by addition of 20 ml of saturated NaHCO3. The organic phase was separated and filtered washing with dichloromethane. Drying of the solid under high vacuum yielded 4-(3-nitro-benzoylamino)-benzoic acid ethyl ester as a white solid (2.52 g, 74%), MS (ISP): m/e=315.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)CC)C>C(#N)C>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:15]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)c1ccc(NC(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.2 %

Procedure:
under an N2 atmosphere, 4-aminobenzoic acid (2.50 g, 18.2 mmol) was dissolved in acetonitrile (100 ml) and treated with 2-chlorobenzoyl chloride (2.43 ml, 19.1 mmol). Triethylamine (2.66 ml, 19.1 mmol) was added and the reaction was allowed to stir at room temperature for four hours. The reaction was concentrated in vacuo, and the resulting solid was partitioned between Et2O and 0.5N NaOH. The layers were separated and the organic layer was discarded. The aqueous layer was acidified to pH 2 with HCl and the aqueous layer was extracted with ethyl acetate. The organic layer was dried Na2SO4, filtered and concentrated in vacuo. The resulting solid was triturated with Et2O, and the solid was collected by filtration to afford 4-(2-chlorobenzamido)benzoic acid (2.72 g, 54.2% yield). ESI m/z=276.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24].C(O)(C)C>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:23]([C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH3:18])[CH:21]=2)[OH:24])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: COc1cccc(C=O)c1
Reactant: CCOc1cc(Br)ccc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CCOc1cc(C(O)c2cccc(OC)c2)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (1.88 g, 8.1 mmol) and dry THF (15 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.3 mL, 8.1 mmol) and stirred for 20 min. Then a mixture of 3-methoxy-benzaldehyde (1.01 g, 7.4 mmol) in dry THF (10 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (3.4 mL, 44 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (3-ethoxy-4-methoxy-phenyl)-(3-methoxy-phenyl)-methanol as an oil (1.92 g, 90% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH2CH3), 2.17 (d, J=4 Hz, 1H, OH), 3.79 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.07 (q, J=7 Hz, 2H, CH2CH3), 5.76 (d, J=4 Hz, 1H, CH), 6.78-7.28 (m, 7H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:32]2[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=2[Cl:30])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: Cc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Br)cc2)c(Cl)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-chloro-4-methylphenol: ESMS m/e: 583.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:18])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(C)cccc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(Br)cccc1CBr
Temperature: 80 °C
Yield: 98.6 %

Procedure:
1-Bromo-3-methyl-2-(methyloxy)benzene (30.3 g, 0.15 mol), NBS (28.2 g, 0.16 mol), and BPO (1.83 g, 7.55 mmol) were suspended in 300 mL of CCl4, and the mixture was heated to 80° C. over night. After cooling to room temperature, the solution was filtrated and the solid was washed with CCl4 (30 mL×2). The filtrate was washed with NaHSO3 (aq. 250 mL×2), Na2CO3 (aq. 100 mL×2), brine (100 mL) and dried over Na2SO4. After removing the solvent, 41.4 g of the crude product was obtained (yield: 97.9%).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1.O>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:20][C:9]2[CH:8]=[CH:7][C:6]3[C@@H:5]4[C@H:14]([C@H:15]5[C@@:2]([CH2:3][CH2:4]4)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]5)[CH2:13][CH2:12][C:11]=3[CH:10]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]23)cc1

Procedure:
Oestrone (2 g., 7.4 mmole) in pyridine (10 ml.) was treated at room temperature for 3 days with toluene-p-sulphonyl chloride (2 g., 1.4 equiv.). The stirred mixture was slowly diluted with water (40 ml.). The precipitated oil slowly crystallized on agitation. Recrystallisation from methanol -- methylene cloride gave the title compound plates (2.65 g., 85%), m.p. 143°-145° , [α]D + 105°. (c, 1.00).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:24][O:25][CH2:26]Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.Cl>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH2:24][O:25][CH3:26])[CH:5]=1)[CH3:14]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: COCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(C=O)c(OCOC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
4-Diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol) was placed in a 20 mL reaction vessel, and dissolved in 4.7 mL of dry dichloromethane. To the solution were added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol), 4-dimethylaminopyridine (13 mg, 0.11 mmol), and chloromethyl methyl ether (147 μL, 1.94 mmol). After the reaction mixture was stirred at room temperature overnight, N,N-diisopropylethylamine (0.40 mL, 2.3 mmol), 4-dimethylaminopyridine (13 mg, 0.11 mmol), and chloromethyl methyl ether (147 μL, 1.94 mmol) were added again with additional stirring for 3 h. The resulting mixture was diluted with 100 mL of ethyl acetate and 20 mL of 1N HCl, and extracted. The extract was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a pale yellow oil (324.7 mg, 88%).