Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[F:15][C:16]([F:27])([F:26])[C:17]([O:19]C(=O)C(F)(F)F)=[O:18]>CC(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]([C:17]([OH:19])([OH:18])[C:16]([F:27])([F:26])[F:15])[C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)CNC(=O)c1ccccc1Cl
Solvent: CC(C)=O
Product: O=C(NC(C(=O)O)C(O)(O)C(F)(F)F)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of above (2-chloro-benzoylamino)-acetic acid methyl ester (6 g, 26 mmol) in 30 mL of methanol, was added three equivalents of lithium hydroxide hydrate in 10 mL of water. The solution was stirred at room temperature for 1 hour, concentrated and mixed with water. Citric acid was added until pH of the solution was adjusted to pH 2 to 3. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to give (2-chloro-benzoylamino)-acetic acid as a solid. To a solution of (2-chloro-benzoylamino)-acetic acid in 40 mL of acetone at −20° C. was added excess of trifluoroacetic anhydride. The mixture was warmed up to room temperature and stirred overnight. The solvent was removed under vacuum. The residue was poured into 400 mL of water and stirred for 20 min. The solid was filtered out and washed with 2×100 mL of water, and dried under vacuum to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid as a red solid. This red solid was suspended in 80 mL of methanol, and heated to reflux for 30 min. The solvent was removed and the mixture was purified by flash chromatography using ethyl acetate/hexane to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid methyl ester as a light yellow solid. The methyl ester was suspended in 100 g of phosphorus oxychloride, and stirred at 80° C. overnight. The reaction mixture was concentrated to remove excess POCl3. The remaining oil was diluted with toluene, and poured into a mixture of ice-water. The layers were separated and the organic layer was washed with water and diluted sodium bicarbonate and then concentrated to dryness. The solid was dissolved in 30 mL of methanol and treated with 2.5 equivalent of lithium hydroxide in 30 mL of water, and stirred for 30 min. Methanol was removed under vacuum, and the mixture was diluted with water. pH of the solution was adjusted to about 3 with 12 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by flash chromatography to give 1.67 g of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid as a light yellow solid. LCMS calcd for C11H5ClF3NO3 (m/e) 291, obsd 292 (M+H).
Reaction SMILES: [O:1]=[C:2]([O:14]C1CCCCO1)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[H-].[Na+].Cl>CN(C)P(=O)(N(C)C)N(C)C.O1CCOCC1.O.C(OCC)(=O)C>[CH3:11][O:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]2([C:2]([OH:14])=[O:1])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)=[O:9]
Reactant: BrCCCCCBr
Reactant: COC(=O)c1ccc(CC(=O)OC2CCCCO2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1ccc(C2(C(=O)O)CCCCC2)cc1
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
The crude methyl 4-[2-oxo-2-(tetrahydro-2H-pyran-2-yl-oxy)ethyl]benzoate (E12) (1.64 g) (0.671 g, 3.45 mmol)) and 1,5-dibromopentane (1.200 g, 5.21 mmol) were dissolved in dry hexamethylphosphoric triamide (6 ml) and the mixture was cooled in an ice bath. To the cooled solution, a 60% suspension of NaH in mineral oil (0.425 g, 10.62 mmol) was added and the reaction mixture was stirred at ice bath temperature for 15 minutes and 1.5 hours at room temperature. The reaction mixture was diluted with dioxane (20 ml) and water (15 ml), and the pH of the medium was brought to pH 1 with conc. HCl (3 ml). The reaction mixture was stirred for 20 minutes and poured into ethyl acetate (100 ml). The organic layer was washed with 2N HCl (2×50 ml), brine (50 ml), and dried (Na2SO4). The solvents were evaporated and the residue was chromatographed on silicagel (50 g) with toluene-ethyl acetate-acetic acid (8:2:0.1) as eluent to give the title compound (0.621 g, 68.5% based on E11) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 0.94-2.09 (8H, m); 2.25-2.65 (2H, m); 3.88 (3H, s); 7.49 (2H, d, J=8.6 Hz); 7.96 (2H, d, J=8.6 Hz); 10.07 (1H, br s).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][CH2:47][CH2:48][S:49]([NH2:52])(=[O:51])=[O:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][CH2:47][CH2:48][S:49]([NH2:52])(=[O:50])=[O:51])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(N)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 3-piperazin-1-yl-propane-1-sulfonic acid amide dihydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C36H47N6O4SCl2 [(M+H)+] 729.2751, observed 729.2754.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]([CH3:15])[C:8](=[O:14])[CH:9]3[CH2:13][CH:10]32)=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:28](O)=[O:29]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]([CH3:15])[C:8](=[O:14])[CH:9]3[CH2:13][CH:10]32)=[CH:5][C:4]=1[CH:28]=[O:29]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(c1)C1CC1C(=O)N2C
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc2c(cc1C=O)N(C)C(=O)C1CC21
Temperature: 25 °C
Yield: 42 %

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 972 mg (4.8 mmol) 6-Methoxy-3-methyl-1,1a,3,7b-tetrahydro-3-aza-cyclopropa[a]naphthalen-2-one, 40 ml of trifluoroacetic acid and 806 mg (5.7 mmol) of hexamethylene tetraamine. The mixture was stirred under reflux for 1.5 hours and then cooled to ambient temperature. The reaction mixture was quenched in 200 ml ice and then treated with solid sodium carbonate until pH 9 was reached. The aqueous phase was extracted with chloroform (3×30 ml). The combined organics were then washed with brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue was taken up in ethyl acetate whereupon crystals formed. Four crops totaling 373 mg were obtained. The mother liquors were purified by silica gel column chromatography eluting with 1/1 ethyl acetate/hexane to afford another 98 mg (total yield 42%) of a white solid which was used directly in the following step. Mass spectrum APCI m/e 232 (p+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.Br[C:39]1[S:40][C:41]2[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:39]3[S:40][C:41]4[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=4[N:43]=3)[CH2:14][C@H:13]2[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(CC)CC)nc1Cl
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC(CC)CC)C3)sc12
Yield: 18.1 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-[(1-ethylpropyl)amino]piperidine-1-carboxylate obtained in Example (215a) (49.0 mg, 0.111 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (35 mg, 0.122 mmol) and sodium carbonate (118 mg, 1.11 mmol), to obtain 11 mg of the title compound (18%) as a pale yellow oily substance.
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6]2[S:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3]1.CI.[C:14](O)(=O)C>[OH-].[Na+]>[CH3:14][S:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]c(=S)[nH]c2sccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSc1nc2sccc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-thioxo-2,3-dihydro-1H-thieno[2,3-d]pyrimidin-4-one (25.4 g, 0.138 mol) in 1N aqueous NaOH (600 mL) at room temperature was added methyl iodide (10.3 mL, 1.2 eq). The resulting mixture was stirred vigorously for about 2.5 hours. The reaction mixture was cooled to 0° C. and acetic acid was added (about 80 mL) until about pH=4.5 was reached. A fine precipitate was filtered and dried overnight to afford the title compound as a fine tan powder (24.8 g) (M+=198, M.P.=231.6–235.0° C.).
Reaction SMILES: CS(O[C@@H:6]1[CH2:15][O:14][C@H:13]2[C@@H:8]([O:9][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:11][CH2:12]2)[CH2:7]1)(=O)=O.C([O-])(=[S:24])C.[K+].[Na].[Cl-].[NH4+]>CN(C=O)C.CO>[C:16]1([CH:10]2[O:9][C@H:8]3[CH2:7][C@@H:6]([SH:24])[CH2:15][O:14][C@@H:13]3[CH2:12][O:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Product: S[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (4aR,7S,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl methanesulfonate (110 mg, 0.350 mmol) under nitrogen in anhydrous DMF (2.0 mL) was added potassium thioacetate (180 mg, 1.575 mmol). The mixture was degassed by pulling a vacuum and introducing nitrogen (3×). The mixture was heated at 80° C. for 5.5 hours. Upon cooling to room temperature, the mixture was diluted with diethyl ether (30 mL), and then washed with brine (20 mL). The aqueous layer was extracted again with diethyl ether (30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was chromatographed using a Biotage™ 20 g (2×10 g in series) silica gel cartridge by eluting with 0-30% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The product fractions were combined and concentrated under reduced pressure. The resultant white solid (58 mg, 0.197 mmol) was dissolved in anhydrous methanol (2.0 mL) under nitrogen. In a separate vessel, metallic sodium (9 mg, 0.39 mmol) was dissolved in anhydrous methanol (1.0 mL), then added to the reaction mixture containing the thioester. After stirring for 30 minutes at room temperature, the mixture was poured into saturated aqueous ammonium chloride (30 mL). The mixture was extracted with DCM (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to provide the title compound as an off-white solid. LC-MS: calculated for C13H16O3S 252.08, observed m/e: 253.11 (M+H)+ (Rt 1.82/4 min).
Reaction SMILES: C[NH:2]C.BrC[C:6]1[N:11]=[C:10]([N:12]2[C:16](=O)C3=CC=CC=C3[C:13]2=O)[CH:9]=[CH:8][CH:7]=1>C(O)C>[CH3:13][N:12]([CH3:16])[C:10]1[N:11]=[C:6]([NH2:2])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cccc(N)n1
Reaction time: 2 h

Procedure:
To ethanol (140 ml) saturated with dimethylamine gas at ice bath temperature is added 6-bromomethyl-2-phthalimido-pyridine (13.6 gm, 43 mmol). After stirring for 2 hours, the solution is concentrated to half volume to remove any excess dimethylamine. Hydrazine hydrate (2.4 ml) is added and refluxed for 2 hours. The reaction is cooled, filtered to remove precipitated byproduct and evaporated to dryness. The residue is dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to give 3.8 gm of 6-dimethylamino-2-amino pyridine as an oil.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][S:29][CH2:30][CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[CH2:12][C@@H:11]([O:36][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][S:29][CH2:30][CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[CH2:12][C@@H:11]([OH:36])[CH2:10]1
Reactant: CC(C)(O)CCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)CCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 95.5 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(3-hydroxy-3-methylbutylthiomethyl)androsta-5,7,16-triene (63.5 mg, 0.0981 mmol), a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (1 ml) and tetrahydrofuran (1 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (reflux under heating for 5.5 hours), worked up and purified by preparative thin layer chromatography (2 sheets (each 0.5 mm thickness), dichloromethane:ethanol=9:1, developed once) to give the titled compound (39.2 mg, 95%) as a colorless oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:35]=[CH:34][C:15]2[CH2:16][CH2:17][C:18]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[O:19][C:14]=2[C:13]=1[CH2:36][CH2:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1>>[O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:35]=[CH:34][C:15]2[CH2:16][CH2:17][C:18]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[O:19][C:14]=2[C:13]=1[CH2:36][CH2:37][CH3:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(OCCCOc2ccccc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Product: CCCc1c(OCCCOc2ccccc2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2
Yield: 94.3 %

Procedure:
The title compound (118 mg), m.p. 130.5°-132.5° C., was prepared by the method of Example 22 substituting the title product of Example 55 (140 mg) for the title product of Example 21.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=O)=O.C(OC([NH:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]2)=[CH:38][C:37]=1[O:55][CH3:56])=O)(C)(C)C.FC(F)(F)C(O)=O>C(O)C(F)(F)F>[CH3:56][O:55][C:37]1[CH:38]=[C:39]([CH:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]2)[CH:40]=[CH:41][C:36]=1[NH:35][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C

Procedure:
Methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I15) (200 mg, 0.497 mmol) and tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I19) (303 mg, 0.745 mmol) were dissolved in trifluoroethanol (4 mL). Trifluoroacetic acid (200 μL) was added and the resulting mixture was heated at 100° C. under microwave irradiation for 1 hour. The crude reaction mixture was adsorbed onto silica gel and separated by silica gel chromatography (0-20% MeOH/DCM) to give the title compound (I20) (215 mg, 82%) as a light brown liquid; 1H NMR (400 MHz, d5-Acetone) δ 8.64 (s, 1H), 8.37 (dd, J=8.3, 3.7 Hz, 1H), 7.29 (ddd, J=13.2, 6.9, 1.7 Hz, 3H), 7.22 (ddd, J=8.9, 6.1, 1.7 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 6.97 (dd, J=8.3, 1.5 Hz, 1H), 3.98 (d, J=7.4 Hz, 3H), 3.82 (s, 2H), 3.74-3.60 (m, 5H), 3.27 (t, J=11.7 Hz, 2H), 3.22-3.06 (m, 4H), 3.00 (s, 1H), 2.34-2.17 (m, 2H), 2.12 (dd, J=4.0, 3.5 Hz, 2H), 2.08 (dt, J=6.6, 2.2 Hz, 3H). LCMS Method C: rt 5.23 min; m/z 529.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH:12](OCC)=[O:13]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH:11][CH:12]=[O:13])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)Cc1cccc(N)c1
Reactant: CCOC=O
Product: CC(Cc1cccc(N)c1)NC=O
Reaction time: 10 h

Procedure:
A mixture of 1-(3'-amino-phenyl)-2-amino-propane and 12.5 ml of ethyl formate was boiled for 10 hours, and then the reaction mixture was evaporated, leaving 1-(3'-aminophenyl)-2-(formyl-amino)-propane. 4.45 gm of this amide were dissolved in 25 ml of pyridine, 2.6 ml of chlorothioformic acid-S-ethyl ester were added to the solution at 10°-20° C., and the mixture was allowed to stand for a few hours. Thereafter, the reaction solution was poured into ice water, and the aqueous mixture was extracted with ether. The ethereal extract was washed five times with water and once briefly with 1/10 N hydrochloric acid, and was then evaporated, leaving as a residue 1-[3'-(ethylthiocarbonyl-amino)-phenyl]-2-(formyl-amino)-propane. The residue was added to a mixture of 75 ml of methanol and 5 ml of concentrated hydrochloric acid, and the mixture was allowed to stand for three days at room temperature. Thereafter, the resulting solution was evaporated, the residue was triturated with acetonitrile, and the crystalline product formed thereby was recrystallized from acetonitrile and a little water, yielding the hydrochloride of the formula ##STR21## which had a melting point of 185°-186° C.
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][S:9][C:8]=2[CH:15]=1)([O-])=O.[NH2:16]C1C=C2C(C(C(N(C(OC(C)(C)C)=O)C)=O)=CN2C(OC(C)(C)C)=O)=CC=1>>[NH2:16][C:5]1[CH:4]=[CH:15][C:8]2[S:9][CH:10]=[C:11]([C:12]([NH2:14])=[O:13])[C:7]=2[CH:6]=1
Reactant: NC(=O)c1csc2cc([N+](=O)[O-])ccc12
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1cn(C(=O)OC(C)(C)C)c2cc(N)ccc12
Product: NC(=O)c1csc2ccc(N)cc12

Procedure:
Obtained as a mixture from the reaction of a mixture of 6-nitro-benzo[b]thiophene-3-carboxylic acid-amide and 5-nitro-benzo[b]thiophene-3-carboxylic acid-amide (Example IXXX (9)). The crude product is further reacted directly in Example XI (42).
Reaction SMILES: [C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CS(C)=O>[C:1]([C@@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@H]2C(=O)c1ccccc1

Procedure:
Into a 250 ml 3-neck round bottom flask is placed 17β-Benzoyl-estra-1,3,5(10)-triene-3-carboxylic acid and an excess of sodium hydroxide. To the flask is added dimethyl sulfoxide as a solvent. The mixture is heated to reflux for 3 hours. Standard workup followed by isolation by preparative HPLC yields title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1ccc(Sc2ccc(Cl)c(Cl)c2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(Sc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
To a stirred solution of 4-[(3,4-dichlorophenyl)sulfanyl]benzoic acid (Preparation 151, 200 mg, 0.67 mmol) in dichloromethane (5 mL) was added methanesulphonamide (192 mg, 2.01 mmol), 4-dimethylaminopyridine (245 mg, 2.01 mmol) and N-(3-dimethylaminopropyl)-M-ethylcarbodiimide hydrochloride (384 mg, 2.01 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, washed with 1M hydrochloric acid solution and water, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by preparative HPLC to afford the title compound as a white solid (34 mg, 12%).
Reaction SMILES: Cl[C:2]1([F:12])[CH2:7][C:6]([CH3:8])=[C:5]([CH3:9])[CH2:4][C:3]1(F)[F:10].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:10][C:3]1[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=1[F:12]
Reactant: CC1=C(C)CC(F)(Cl)C(F)(F)C1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: Cc1cc(F)c(F)cc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-chloro-1,2-dimethyl-4,4,5-trifluorocyclohexene of 12.6 g prepared in Example 14 was added 1.0 g of benzyltriethylammonium chloride, and then the reaction mixture was heated to 80° C. followed by slowly adding 40 g of 50% aqueous sodium hydroxide solution for 30 min. The reaction mixture was stirred for additional 2 hours at 80° C., and then the resultant was purified by steam distillation followed by separating the aqueous layer. The organic layer was dried with calcium chloride, and then 7.3 g of the desired product was collected by fractional distillation at temperature 150° C. as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[CH2:19][C:20]1[C:25]([F:26])=[CH:24][N:23]=[CH:22][C:21]=1[F:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:27][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:26])[C:20]=1[CH2:19][O:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Fc1cncc(F)c1CCl
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cncc3F)cc(C)cn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5.0 g (21.34 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 87A and 3.83 g (23.48 mmol) of 4-(chloromethyl)-3,5-difluoropyridine from Example 115A were initially charged in 306 ml of abs. DMF, and 20.8 g (64.03 mmol) of caesium carbonate were added. The reaction mixture was stirred at 60° C. overnight. The reaction mixture, cooled to RT, was filtered, washed with ethyl acetate and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate gradient=4:1 to 2:1). This gave 5.40 g (70% of theory) of the target compound.