Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][S:7]([C:10]1[CH:29]=[CH:28][C:13]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:25]([CH3:26])[C:24]([CH3:27])=[N:23][CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:5])[CH3:4].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N1C=CC=CC=1.O>[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36]([O:1][CH2:2][C:3]([NH:6][S:7]([C:10]2[CH:29]=[CH:28][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH3:26])[C:24]([CH3:27])=[N:23][CH:22]=4)[CH:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])([CH3:5])[CH3:4])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NC(C)(C)CO)cc3)n2)n1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)NS(=O)(=O)c2ccc(Nc3nccc(-c4cnc(C)n4C)n3)cc2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
2-{4-[N-(1-Hydroxy-2-methylprop-2-yl)sulphamoyl]anilino}-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Example 59; 2.36 g, 5.66 mmol) was dissolved in dry pyridine (55 ml) and the solution stirred and cooled to 0° C. under inert gas. Solid p-toluenesulphonyl chloride (5.61 g, 29.4 mmol) was added portionwise over 2 minutes. The reaction was stirred at 0° C. for 10 minutes and then at room temperature for 18 hr. The reaction mixture was diluted with water (200 ml) and the precipitated oil allowed to settle out. The supernatant water layer was decanted off and the residual oil was washed with more water and this was decanted off. This process was repeated and then the oil partitioned between EtOAc (100 ml) and water (50 ml). The layers were separated and the organic layer washed with water (50 ml), dried and the solvent evaporated in vacuo to yield the title compound as a gum (1.94 g, 60%) NMR 1.0 (s, 6H), 2.36 (s, 3H), 2.38 (s, 3H), 3.77 (s, 2H), 3.93 (s, 3H), 7.20 (d, 1H), 7.43 (d, 2H), 7.55 (s, 1H), 7.65 (m, 5H), 7.87 (d, 2H), 8.45 (d, 1H), 9.9 (s, 1H); m/z 571.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C@@H:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10](=[O:12])N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH2:27]>CN(C)C=O>[CH2:19]([N:14]1[C@@H:13]([CH2:17][SH:16])[C@H:9]([C:10]([OH:12])=[O:27])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:15]1=[O:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O
Reactant: NC(=O)[C@H](NCc1ccccc1)[C@@H]1CSC(=O)N1Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)[C@H]1[C@H](CS)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
In 200 ml of N,N-dimethylformamide was dissolved 100 g of (4R)-4-[(1R)-1-(N-benzylamino)-1-carbamoylmethyl]-3-benzylthiazolidin-2-one, and under nitrogen atmosphere, the solution was stirred at 85° C. for 5 hours. At 90° C. to 95° C., 200 ml of 35% hydrochloric acid was added dropwise to the solution, and the mixture was stirred for 1 hour and 15 minutes. Moreover, 100 ml of 35% hydrochloric acid was added dropwise, and the mixture was stirred for 2 hours. Then, 200 ml of water was added dropwise to the mixture at 85° C. The solution was ice-cooled, and precipitated crystal was collected by filtration, washed with water and then dried at 50° C. for 17 hours to give 93.1 g of (4R,5R)-1,3-dibenzyl-2-oxo-5-(mercaptomethyl)-imidazolidin-4-carboxylic acid as colorless crystal.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH3:18])[C:3]=1[O:20][CH2:21][CH3:22].[CH:23]([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH2:18][CH3:23])[C:3]=1[O:20][CH2:21][CH3:22]
Reactant: CCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1c(C(=O)CC)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-109, 1.75 g, 4.81 mmol) in THF (33 mL) at −78° C. was added lithium diisopropylamide (1.5 M in cyclohexane, 3.85 mL, 5.78 mmol). The bath was removed and the mixture was stirred for 2.5 h. The mixture was cooled to −78° C. again and methyl iodide was added. The mixture was stirred at room temperature for 16 h, quenched with saturated ammonium chloride, and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 2% ethyl acetate in hexanes) followed by HPLC (normal phase, 2% ethyl acetate in hexanes) to give the title compound as clear oil.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[O:7][CH:6]=[CH:5][CH:4]=1.[CH2:27]([N:29]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]=O)=[CH:38][CH:37]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH3:28].[O-]CC.[Na+]>C(O)C>[CH2:27]([N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[C:36]1[CH:37]=[CH:38][C:39](/[CH:42]=[CH:2]/[C:3]2[O:7][CH:6]=[CH:5][CH:4]=2)=[CH:40][CH:41]=1)[CH3:28]
Reactant: CCN(CCCCCO)c1ccc(C=O)cc1
Reactant: c1ccc([P+](Cc2ccco2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CCCCCO)c1ccc(/C=C/c2ccco2)cc1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
In a 200 mL flask, 1A (18.47 g, 43.6 mmol) and N-ethyl-N-(4-formyl phenyl)-5-aminopentyl alcohol 1B (10.27 g, 43.6 mmol) were dissolved in anhydrous ethanol (115 mL) under Ar at RT. In a separate flask, sodium ethoxide (2.97 g, 43.6 mmol) was dissolved in anhydrous ethanol (51 mL). The ethanolic sodium ethoxide solution was added by addition funnel to the solution containing the starting reagents. The reaction mixture was then heated to 85° C. and stirred for 4 hours. The reaction mixture was evaporated and the product was extracted into dichloromethane against water. The crude product was purified on silica gel using 1:1 hexane:ethyl acetate. Product 2 was a red viscous liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].CNCCNC.[Na+].[I-:30]>O1CCOCC1.[Cu]I>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([I:30])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)CCN1CCSC(c2ccc(Br)cc2)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCN1CCSC(c2ccc(I)cc2)C1
Temperature: 130 °C
Yield: 77.7 %

Procedure:
To a degassed solution of 3-[2-(4-bromo-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl ester (22.15 g; 57.33 mmol) and N,N′-dimethylethylenediamine (3.05 mL; 28.7 mmol) in 1,4-dioxane (250 mL) was added CuI (1.09 g; 5.73 mmol), and NaI (21.48 g; 143.33 mmol). The resulting mixture was heated at 130° C., for 4 days, in sealed flask. After cooling to RT the mixture was concentrated in vacuol and purified by column chromatography (SiO2, Et2O/hexanes 2:3) to afford 3-[2-(4-iodo-phenyl)-thiomorpholin-4-yl]-propionic acid tert-butyl ester (19.30 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([N+:18]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([NH2:18])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(C)(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A suspension of (4-tert-butyl-3-nitro-phenyl)-carbamic acid tert-butyl ester (3.0 g, 10.19 mol) and 10% Pd—C (1 g) in MeOH (40 mL) was stirred under H2 (1 atm) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatograph (petroleum ether—EtOAc, 5:1) to give (3-amino-4-tert-butyl-phenyl)-carbamic acid tert-butyl ester (D-10) as a brown oil (2.5 g, 93%). 1H NMR (CDCl3) δ 7.10 (d, J=8.4 Hz, 1 H), 6.92 (s, 1 H), 6.50-6.53 (m, 1 H), 6.36 (s, 1 H), 3.62 (br s, 2 H), 1.50 (s, 9 H), 1.38 (s, 9 H); ESI-MS 528.9 m/z (2M+H+).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[Br:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:9]([O:26][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:19][Br:18])=[CH:21][CH:22]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(COC(=O)c1ccc(CBr)cc1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
Triethylamine (16 ml, 115 mmol) and bromoacetophenone (22.9 g, 115 mmol) were dissolved in 450 ml of ethyl acetate. The solution was stirred at 50° C. and 4-(bromomethyl)benzoic acid (17.5 g, 155 mmol) was added in seven equal portions over a three hour period. Stirring was continued for an additional 8 hours at 50° C. Precipitated triethylaminehydrobromide was removed by filtration and the ethyl acetate solution was washed with (3×150 ml each) of 10% citric acid, brine saturated sodium bicarbonate and brine. The organic phase was dried with sodium sulfate and concentrated in vacuo. The residue was recrystallized from dichloromethane-petroleum ether to give fine white crystals (10.2 g, 27% yield). 1H NMR (DMSO-d6) δ 7.99 (m, 4H), 7.69-7.54 (m, 5H), 5.74 (s, 2H), 4.77 (s, 2H); 13C NMR (DMSO-d6) δ 193.7, 165.9, 144.6, 134.9, 131.2, 131.0, 130.7, 130.6, 130.2, 129.9, 128.8, 128.6, 68.2, 34.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[C:6]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:7]=1.[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:4]1[CH:5]=[C:6]([S:8][CH:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH:7]=[C:2]([F:1])[CH:3]=1)=[O:21]
Reactant: CN1CCC(Sc2cc(N)cc(F)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1COCCO1
Product: CN1CCC(Sc2cc(F)cc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
Combine 3-fluoro-5-(1-methyl-piperidin-4-ylsulfanyl)-phenylamine (preparation 114, 0.11 g, 0.46 mmol), 1,4-dioxane (5 mL) and 2-chloro-4-fluoro-benzoyl chloride (0.09 g, 0.46 mmole), stir and heat at reflux. After 3 hr., cool to ambient temperature. Load on an SCX column (10 g), wash with methanol, elute with 2M ammonia/methanol. Concentrate eluent. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain the title compound (0.03 g, 17%). Mass spectrum: Obs. m/z 397.0974; calc. m/z 397.0953; 1H NMR (CDCl3) free base: 7.9 (bs, 1H), 7.8 (m, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 3.2 (m, 1H), 2.8 (m, 2H), 2.3 (s, 3H), 2.0 (m, 4H), 1.7 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([NH:20][CH2:21][CH2:22][O:23][CH3:24])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:25]>CO>[NH2:25][C:2]1[C:11]2[N:12]=[C:13]([NH:20][CH2:21][CH2:22][O:23][CH3:24])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Reactant: N
Solvent: CO
Product: COCCNc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 150 °C

Procedure:
1-{4-Chloro-2-[(2-methoxyethyl)amino]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (2.1 g, 6.2 mmol) and ammonia (25 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated overnight in an oven at 150° C. and then allowed to cool to ambient temperature. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluting with 2% methanol in dichloromethane with 1% ammonium hydroxide added.) The isolated product was dried under high vacuum overnight to provide 1.08 g of 1-{4-amino-2-[(2-methoxyethyl)amino]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a white solid, mp 176-178° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[N:9]=[CH:8][N:7]2[N:10]=[CH:11][N:12]=[C:6]2[C:5]=1[CH2:13][CH2:14][CH3:15]>CC(O)=O>[Br:1][CH2:3][C:4]1[N:9]=[CH:8][N:7]2[N:10]=[CH:11][N:12]=[C:6]2[C:5]=1[CH2:13][CH2:14][CH3:15]
Reactant: BrBr
Reactant: CCCc1c(C)ncn2ncnc12
Solvent: CC(=O)O
Product: CCCc1c(CBr)ncn2ncnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Br2 (0.153 ml, 3 mmol) is added dropwise to a solution of 7-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine (3 mmol) heated at 100° C. in HOAc (10 ml). After the addition, the mixture is stirred at 100° C. overnight. The solvent is removed in vacuo and the residue dissolved in EtOAc (15 ml), washed with Na2S2O3 solution (sat. 5 ml), followed by NaHCO3 (10 ml), and brine (10 ml). The organic phase is dried (Na2SO4) and evaporated. The resulting yellow oil is purified by PTLC, which provides the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:12])[S:5][C:6]=1[CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9].[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.Cl>O>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:12][C:4]2[S:5][C:6]([CH2:7][C:8]([Cl:11])([Cl:9])[Cl:10])=[C:2]([CH3:1])[N:3]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1nc(N)sc1CC(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: Cc1nc(NS(=O)(=O)c2cccc(Cl)c2C)sc1CC(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 76 %

Procedure:
The title compound was prepared similar to EXAMPLE 6 according to METHOD A from 4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-ylamine (123 mg, 0.5 mmol) and 3-chloro-2-methylbenzenesulfonyl chloride (112.5 mg, 0.5 mmol). The solution was allowed to stand at r.t. overnight. Water (5 mL) was added and the resulted solution was made acidic with conc. HCl. The precipitate was filtered, washed with water and dried. Flash column chromatography of the precipitate on silica gel, eluted with a mixed solvents of ethyl ether and hexane (2:1) gave the title compound as a solid (165 mg, 76% yield). The product can be recrystallized from ethyl acetate and hexane: MS m/e: 439, 437, 435, 433.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.F[C:13]1[CH:27]=[CH:26][C:16]([CH2:17][N:18]2[CH2:23][CH2:22]O[CH:20]([CH2:24][NH2:25])[CH2:19]2)=[CH:15][CH:14]=1>>[CH2:17]([N:18]1[CH2:23][CH2:22][CH:24]([NH:25][C:4]2[C:5]([C:6]([NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=3)=[O:7])=[CH:10][CH:11]=[CH:2][N:3]=2)[CH2:20][CH2:19]1)[C:16]1[CH:26]=[CH:27][CH:13]=[CH:14][CH:15]=1
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(NC(=O)c2cccnc2NC2CCN(Cc3ccccc3)CC2)nc1
Yield: 28.6 %

Procedure:
The title compound was prepared in the same manner as in Example 32, with the exception that methyl 6-aminonicotinate, instead of 4-(4-fluorobenzyl)morpholin-2-ylmethylamine, was used in the same molar amount (Total yield: 28.6%). 1H NMR (CDCl3) δ 8.92 (s, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 8.29 (d, 1H), 8.18 (d, 1H), 7.78 (d, 1H), 7.35 (m, 5H), 6.53 (m, 1H), 4.13 (m, 1H), 3.97 (s, 3H), 3.56 (s, 2H), 2.86 (d, 2H), 2.28 (t, 2H), 2.09 (d, 2H), 1.65 (m, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[OH:27])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(O)c(O)c2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OCc3ccc(C)cc3)c(O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
Ethyl 4-[3-(3,4-dihydroxybenzoyl)indol-1-yl]butanoate (5.70 g) was dissolved in N,N-dimethylformamide (40 ml). α-bromo-p-xylene (3.72 g) and potassium carbonate (2.57 g) were added to the resultant solution and stirred for 3 hours at room temperature. The reaction mixture was poured into 2N HCl and extracted with ethyl acetate. The resultant extract was sequentially washed with saturated sodium bicarbonate solution and brine, and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), obtaining 2.77 g of ethyl 4-{3-[3-hydroxy-4-(4-methylphenylmethoxy)benzoyl]indol-1-yl}butanoate (2.77 g) as light brown crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:36]#[C:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC(C)C)c2)cc1C
Reactant: C#Cc1ccccc1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(SCc2cc(C#Cc3ccccc3)cc(OCC(C)C)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and phenylacetylen (262 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 130 mg (45%). HPLC-MS: m/z: 489.1 (M+H)+; Rt: 3.01 min
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C[CH2:31][N:32](CC)[CH2:33]C.CNC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:32]([CH3:33])[CH3:31])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CCN(CC)CC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and dimethyl amine (0.33 mL, 2.0 M solution in THF, 0.65 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 80 mg (75%) of the title compound as an off white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=O)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].Cl.[NH2:30][OH:31].O>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[N:30][OH:31])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=NO)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
7-Oxo-5-androstene-3β,17β-diol diacetate (1 g, 2.57 mmol) and hydroxylamine hydrochloride (0.5 g) were taken in dry pyridine (8 Ml) and heated in a steam bath for 2 h. The reaction mixture was poured into water and precipitate obtained was filtered, washed with water and dried. The crude product on crystallization from methanol afforded pure oxime 7-oximino-5-androstene-3β,17β-diol diacetate (0.85 g, 86.54%), mp 236-238° C. (lit 226° C.) [Singh H., et al Indian J. Chem. 1969, 7, 1084-1087].
Reaction SMILES: C(=[C:8]1/[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([Br:18])[CH:15]=[N:16][C:17]/1=2)/C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[OH:39]>C(Cl)Cl>[Br:18][C:14]1[CH:15]=[N:16][C:17]2[C:8](=[O:39])[CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: Brc1cnc2c(c1)CCC/C2=C\c1ccccc1
Reactant: CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CCCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A solution of (E)-8-benzylidene-3-bromo-5,6,7,8-tetrahydroquinoline (0.82 g, 2.5:1 mixture with benzaldehyde) in MeOH (40 mL) and DCM (40 mL) was cooled to −78° C. and ozone was bubbled through the solution for 5 min until the solution turned light blue. Oxygen was passed through the solution for 10 min until the solution turned colorless and triphenylphosphine (1.03 g, 3.93 mmol) was added. The solution was removed from the dry ice/acetone bath and allowed to warm to RT. The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated. Purification by flash column chromatography on silica gel eluting with 30% to 70% EtOAc in heptane) gave 3-bromo-6,7-dihydroquinolin-8(5H)-one (0.460 g, 2.04 mmol, 75% yield) as a white solid. LC/MS (ESI+) m/z=225.9 (M+H). Calculated for C9H8BrNO 225.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[NH2:26][C:27]1[S:28][CH2:29][CH2:30][N:31]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:26][C:27]3[S:28][CH2:29][CH2:30][N:31]=3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1=NCCS1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1=NCCS1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 9.3 %

Procedure:
A suspension of 2-(4-chlorophenyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3.5 hours with a stream of nitrogen bubbling through it. Solid 2-amino-2-thiazoline (2.67 g, 0.0261 mole) was added to the reaction mixture. The resulting suspension was allowed to stir at room temperature overnight. The solvent was evaporated under reduced pressure to give a white solid. The solid was triturated in water (200 ml), filtered, and the filter cake was rinsed twice more with water. The resulting solid was heated in boiling isopropyl alcohol to dissolve most of it, filtered while hot, and cooled to room temperature. A white precipitate formed. Water was added, and the white solid was filtered and rinsed once with isopropyl alcohol and twice with isopropyl ether. A 1.0-g sample of the resulting 3.3 g of white solid was dried at high vacuum to give 0.6 g (29%) of title compound, mp. 227°-229° C.