Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[C:34]1([NH:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH:40]([CH2:41][CH2:42][NH:43][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:31]1[CH:30]=[CH:29][C:28]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:7])=[O:18])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCCNc1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)NCCNc2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and N1-phenyl-1,2-ethanediamine, the title compound was obtained in 93% purity by HPLC. MS(ESI+): m/z=457.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.[CH3:8][C:9]1[N:14]=[C:13]([SH:15])[N:12]=[C:11]([OH:16])[CH:10]=1.C(N(CC)CC)C>C(O)C>[CH3:8][C:9]1[N:14]=[C:13]([S:15][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)[N:12]=[C:11]([OH:16])[CH:10]=1
Reactant: BrCc1cncs1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cncs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.9 %

Procedure:
A mixture of 5-(bromomethyl)-1,3-thiazole (4.3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (427 mg, 3.0 mmol), and triethylamine (1.7 mL, 12.0 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The mixture was evaporated and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL), and then dried in vacuo. The crude product was purified by flash chromatography (0-5% MeOH/CH2Cl2), affording the title compound (28 mg, 4% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.09 (s, 3H), 4.64 (s, 2H), 4.16 (s, 2H), 6.02 (s (br), 1H), 7.87 (d, 1H, J=0.8 Hz), 8.94 (s, 1H); M+240.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:14]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (2.5 g, 5.89 mmol) and 10% palladium on activated carbon (900 mg) in methanol (600 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb for 5 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (1.7 g, 68%) as a white solid which was used without further purification: LC/MS m/e calcd for C23H26N2O4S [M+H]+ 427.54, observed 426.8; 1H NMR (400 MHz, CDCl3) δ ppm 10.81 (br. s., 1H), 8.79 (br. s., 1H), 8.56 (s, 1H), 7.88-7.93 (m, J=8.3 Hz, 2H), 7.48-7.53 (m, J=8.1 Hz, 2H), 6.48 (s, 1H), 5.31 (s, 1H), 4.30 (t, J=7.7 Hz, 1H), 3.99 (s, 3H), 3.03 (s, 3H), 2.12-2.33 (m, 2H), 1.59-1.86 (m, 4H), 1.45-1.56 (m, 2H), 1.15-1.29 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)CCC1=O>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[C:5]([Cl:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2cc(=O)c3c(N)cccc3o2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(=O)c3c(N)ccc(Cl)c3o2)cc1
Yield: 11.7 %

Procedure:
2.0 g (7.93 mmol) of 5-amino-2-(4-aminophenyl)-4H-1-benzopyran-4-one (EP-A-374789) was dissolved in 50 ml of dioxane, 1.59 g (11.9 mmol) of N-chlorosuccinimide was added and the mixture was stirred under heating at reflux for 5 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform: acetone=4:1) to give 0.61 g (27%) of crude product. Further recrystallization from chloroform/methanol afforded 266 mg (12%) of Compound 2.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1.[ClH:20].O1CCOCC1.CO>C(OCC)C>[ClH:20].[ClH:20].[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: Cc1ncsc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: Cc1ncsc1N1CCNCC1
Yield: 86.8 %

Procedure:
To a solution of tert-butyl 4-(4-methylthiazol-5-yl)piperazine-1-carboxylate (265 mg, 0.935 mmol) in diethyl ether (10 mL) was added HCl (4N in dioxane, 4.5 mL, 18 mmol) after which a precipitate formed immediately. 1,4-Dioxane (5 mL) was added to dissolve the precipitate. The mixture was stirred at room temperature for three days after which additional HCl (4N in dioxane, 5 mL, 20 mmol) and methanol (5 ml) was added. Stirring was continued for another day, the precipitate formed was collected by filtration, washed with diethylether and dried under reduced pressure to yield 208 mg of a yellow solid (0.812 mmol, 87%). MS (ESI) m/z=184.1 [M+1]+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9](=[O:18])[CH2:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH3:7]>C(Cl)(Cl)Cl>[CH2:6]([O:8][C:9](=[O:18])[CH:10]([Cl:4])[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH3:7]
Reactant: C=CC(C)(C)C(=O)CC(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=CC(C)(C)C(=O)C(Cl)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Sulfuryl chloride (0.84 ml, 10.4 mmol) was added to a cooled (0° solution of 4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (1.83 g, 9.93 mmol) in chloroform (7 ml). The resulting mixture was allowed to warm to room temperature and stir for 30 min, after which it was heated under reflux for 2 h. After cooling to room temperature the reaction mixture was diluted with chloroform, then was washed with sodium bicarbonate, water then brine. The organic phase was dried and evaporated to afford, as a brown oil, 2-chloro-4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (2.01 g, 93%). (Hayashi et al., J. Org. Chem., 65:8402-8405 (2000).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[N:7]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[SH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]=[C:8]1[C:9]2[C:14]3[C:13](=[C:2]([S:21][C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])[CH:3]=[CH:4][C:5]=3[C:6](=[O:20])[N:7]1[CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=2
Reactant: O=C(O)CN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Reactant: O=C(O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CN1C(=O)c2cccc3c(Sc4ccccc4C(=O)O)ccc(c23)C1=O
Yield: 64 %

Procedure:
A mixture of 6-chloro-1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid (10.0 g, 34.5 mmoles, described in Example 2); 2-mercaptobenzoic acid (5.85 g, 37.9 mmoles) and anhydrous potassium carbonate (9.54 g, 37.9 mmoles) in dimethylformamide (300 ml) was heated at reflux for 3 hr. The product in the form of its sodium salt was precipitated from the reaction mixture. The precipitate was collected by filtration and dissolved in water. The solution of the sodium salt was rendered acidic with 2 N hydrochloric acid. The resulting precipitate was collected, dried and crystallized from dimethylformamide and water to give 9.0 g of the title compound; mp 339°-341° C.; UV (MeOH) 231, 254, 336 and 346, ε=31,450, 15,810, 8,760 and 9,210, respectively; IR (CHCl3) 2900, 1725, 1710, 1675 cm-1 ; NMR (CDCl3) δ 4.7 (s, 2H), 6.5-8.6 (m, 9H), 13.0 (broad, 1H); Anal. Calc'd: C, 61.91%; H, 3.22%; N, 3.44%; Found: C, 61.51%; H, 3.21%; N, 3.73%.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=1[F:18])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:19]C(OC(C)=O)=O.C(OCC)(OCC)OCC.[NH2:36][C:37]1([CH2:41][CH:42]([OH:44])[CH3:43])[CH2:40][CH2:39][CH2:38]1>C1(C)C=CC=CC=1>[OH:44][CH:42]([CH3:43])[CH2:41][C:37]1([NH:36][CH:19]=[C:3]([C:2](=[O:1])[C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=2[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:40][CH2:39][CH2:38]1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CC(O)CC1(N)CCC1
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1(CC(C)O)CCC1)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A stirred solution of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (2.45 g, 9.27 mmol), Ac2O (5.30 mL, 56.1 mmol) and triethyl orthoformate (3.10 mL, 18.6 mmol) was heated at 120° C. for 3 hours. The mixture was concentrated in vacuo and dried under high vacuum. To 1-[1-aminocyclobutyl]-2-propanol (1.20 g, 9.29 mmol) in anhydrous toluene (10 mL) was slowly added to a mixture of the residue in anhydrous toluene (30 mL) at 0° C. and stirred at room temperature for 2 hours. The solvent was removed by evaporation. Flash chromatography (AcOEt:Hexane=1:1) of the residue gave the title compound as a pale yellow solid (3.10 g, 83%). 1H-NMR (400 MHz, CDCl3) δ 0.95 (0.6H, t, J=7.3 Hz), 1.09 (2.4H, t, J=7.3 Hz), 1.29 (3H, d, J=6.1 Hz), 1.51 (1H, brs), 1.83-2.05 (4H, m), 2.18-2.35 (3H, m), 2.41-2.53 (1H, m), 3.95-4.15 (3H, m), 6.96-7.13 (1H, m), 8.27 (0.8H, d, J=14.7 Hz), 8.31 (0.2H, d, J=14.7 Hz), 10.30 (0.2H, d, J=13.4 Hz), 11.56 (0.8H, d, J=13.4 Hz).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:34]1[C@H:39]([CH3:40])[CH2:38][N:37]([C@H:41]([C:48]2[CH:60]=[CH:59][C:51]([C:52]([N:54]([CH2:57][CH3:58])[CH2:55][CH3:56])=[O:53])=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:36]([CH3:61])[CH2:35]1)C=C.C(O)(=O)C1C(=CC=CC=1)S>O1CCCC1>[CH3:61][C@H:36]1[CH2:35][NH:34][C@H:39]([CH3:40])[CH2:38][N:37]1[C@H:41]([C:48]1[CH:49]=[CH:50][C:51]([C:52]([N:54]([CH2:57][CH3:58])[CH2:55][CH3:56])=[O:53])=[CH:59][CH:60]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2ccccc2)c2ccc(C(=O)N(CC)CC)cc2)C[C@H]1C
Agent: O=C(O)c1ccccc1S
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)NC[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of bis(dibenzylidineacetone)palladium (1.438 g, 2.5 mmol) and 1,4-bis(diphenylphosphino)butane (1.066 g, 2.5 mmol) in tetrahydrofuran (20 mL) was stirred under nitrogen at room temperature for 15 min, then added via syringe to a stirred solution under nitrogen of 4-((alpha-S)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (20.98 g, 50 mmol) and thiosalicylic acid (9.25 g, 60 mmol) in anhydrous tetrahydrofuran (100 mL). The reaction mixture was stirred under nitrogen for 2 h at room temperature, then evaporated to dryness, the residue dissolved ethyl acetate (120 mL) and diluted with ether (300 mL). The solution was washed with dilute sodium carbonate solution (saturated:H2O, 1:3, 3×200 mL). The organic solution was diluted with pentane (800 mL) and extracted with 3M-hydrochloric acid (5×40 mL), followed by M-hydrochloric acid (3×50 mL, alternating with water (3×50 mL)). The combined aqueous extracts were filtered to remove a small amount of suspended solid and the pH adjusted to 12 with 5-M NaOH. The resulting oily suspension was extracted with methylene chloride (3×150 mL), the combined organic extracts dried over anhydrous sodium sulfate and evaporated to dryness to yield 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide as a very pale yellow solid (18.07 g, 97.8%). The product showed a single spot on thin layer chromatography (silica gel, EM60F264, 4% NH4OH/10% EtOH in ethyl acetate, Rf=0.25). and was used without further purification. Calc. for C24H33N3O 0.2 H2O: C, 75.24; H, 8.79; N, 10.97. Found C, 75.24; H, 8.87; N, 10.86%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:38]=[CH:37][C:18]3[N:19]=[CH:20][N:21]([C:22]4[S:23][C:24]([C:34](=[O:36])[NH2:35])=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=5)[N:26]=4)[C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>ClCCl>[Cl:33][C:29]1[CH:28]=[C:27]([C:25]2[N:26]=[C:22]([N:21]3[C:17]4[CH:16]=[C:15]([O:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:38]=[CH:37][C:18]=4[N:19]=[CH:20]3)[S:23][C:24]=2[C:34]([NH2:35])=[O:36])[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1sc(-n2cnc3ccc(OC4CCNCC4)cc32)nc1-c1cccc(Cl)c1
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To 0.10 g (0.18 mmole) of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-yl]-3H-benzoimidazol-5-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (I.21a) in 5 mL of dichloromethane at 0 degrees, was added 5 mL of dichloromethane-trifluoroacetic acid (1:1). The mixture was stirred at 0 degrees for 1 hour and then concentrated under reduced pressure. The residue was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from methanol to give 0.050 g 4-(3-chloro-phenyl)-2-[6-(piperidin-4-yloxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.21). MH+/Z=454
Reaction SMILES: [NH2:1][C:2]([C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)=[O:3].CN(C(ON1N=NC2[CH:21]=[CH:22][CH:23]=[N:24][C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:24]1([C:7]([C:4]2([C:2]([NH2:1])=[O:3])[CH2:6][CH2:5]2)=[O:9])[CH2:23][CH2:22][CH2:21][CH2:19]1
Reactant: NC(=O)C1(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1(C(=O)N2CCCC2)CC1
Reaction time: 0.5 h

Procedure:
To 1-(aminocarbonyl)-1-cyclopropane carboxylic acid (Aldrich; 25 g, 193.6 mmol) in DCM (625 mL) was added HATU (73.61 g, 193.6 mmol) and the suspension stirred for 30 minutes. Pyrrolidine (Aldrich; 24.25 mL) and Hunig's base (67 mL) was added and the reaction stirred at room temperature over the weekend.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[C:14]([O:24][CH3:25])=[C:15]([CH:21]=[CH:22][CH:23]=3)[O:16][CH2:17][C:18](O)=[O:19])[N:10]([C:26](=[O:36])[C:27]3[C:32]([F:33])=[CH:31][C:30]([F:34])=[CH:29][C:28]=3[F:35])[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=[N:61][C:56]2[CH:57]=[CH:58][CH:59]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(NC)CC1>CN(C=O)C>[CH:57]1([CH2:56][NH:61][C:18](=[O:19])[CH2:17][O:16][C:15]2[CH:21]=[CH:22][CH:23]=[C:13]([CH:11]3[N:10]([C:26](=[O:36])[C:27]4[C:32]([F:33])=[CH:31][C:30]([F:34])=[CH:29][C:28]=4[F:35])[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[S:12]3)[C:14]=2[O:24][CH3:25])[CH2:59][CH2:58]1
Reactant: COc1c(OCC(=O)O)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC1CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCC(=O)NCC2CC2)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 12 h

Procedure:
To a solution of {3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetic acid (0.029 mmol) in 1 mL of DMF is added DIEA (0.058 mmol), HATU (0.058 mmol) and cyclopropyl methylamine (0.058 mmol). The reaction mixture is stirred for 12 hours. The mixture is purified by preparative LC/MS (20-100% MeCN/H2O) to give N-cyclopropylmethyl-2-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetamide: 1H NMR (400 MHz, CDCl3) δ 7.55-7.51 (m, 3H), 7.12-6.99 (m, 4H), 6.9 (d, J=7.6 Hz, 2H), 6.77 (t, J=8.4 Hz, 2H), 4.56 (s, 2H), 4.08 (s, 3H), 3.26-3.2 (m, 2H), 1.02-0.99 (m, 1H), 0.57-0.52 (m, 2H), 0.25 (m, 2H); LC/MS (ES+): 574.1 (M+1)+.
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:22])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2].[BH4-].[Na+].[C:25](O)(=O)[CH3:26]>>[CH2:1]([N:3]([CH2:25][CH3:26])[CH:4]([CH3:22])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2]
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1

Procedure:
Prepared by the method described for Example 59 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.010 moles), glacial acetic acid (20 ml), and sodium borohydride (2.3 g, 0.061 moles). Recrystallization from ethanol gave the product (2.0 g) as the dihydrochloride, mp 254° C. (dec.).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1OC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].[C:23]1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].CC1C=CC(C(Cl)=O)=CC=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:4]=[CH:3][C:20]([CH3:23])=[CH:19][CH:18]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: COc1ccccc1OC
Agent: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1OC

Procedure:
The title compound was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (3.9 mL, 28 mmol), aluminum chloride (4.1 g, 31 mmol) and 4-methylbenzoyl chloride (4.6 mL, 29 mmol) with a reaction time of 6 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 4.22 g (59%) of the product as a white solid: mp 121.5-122° C.; 1H NMR (CDCl3) δ7.70-7.67 (d, J=8 Hz, 2 H), 7.48-7.26 (m, 4 H), 6.91-6.88 (d, J=8.3 Hz, 1 H), 6.96 (s, 3 H), 3.94 (s, 3 H), 2.44 (s, 3 H); (CDCl3) δ195.1, 152.6, 148.8, 142.4, 135.3, 130.3, 129.8, 128.7, 125.0, 112.0, 109.6, 55.9, 55.8, 21.4; Anal. Calcd for C16H16O3. Theoretical: C, 74.98; H, 6.29. Found: C, 74.84; H, 6.43.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]([O:12][NH:13][CH:14]([C:16]1[CH:20]=[CH:19][N:18]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH:17]=1)[CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CCOCC>[CH3:1][NH:2][C:3]([N:13]([CH:14]([C:16]1[CH:20]=[CH:19][N:18]([C:21]2[C:22]([CH3:28])=[CH:23][CH:24]=[CH:25][C:26]=2[CH3:27])[CH:17]=1)[CH3:15])[O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: Cc1cccc(C)c1-n1ccc(C(C)NOCc2ccccc2)c1
Reactant: CN=C=O
Solvent: CCOCC
Solvent: O
Product: CNC(=O)N(OCc1ccccc1)C(C)c1ccn(-c2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl isocyanate (5 ml) is added to a solution of 2.1 g of N-benzyloxy-1-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-ethylamine in 200 ml of ether and the solution is stirred at room temperature for 24 hours. Excess water is added and the mixture is stirred for 3 hours. The organic layer is separated, washed with brine, dried over magnesium sulfate and evaporated to dryness to yield N-(N'-methylcarbamoyl)-N-benzyloxy-1-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-ethylamine.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C@@H:9](Br)[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:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[C:26](=O)(O)[O-:27].[Na+]>CO>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH:9]([O:27][CH3:26])[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:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@@H](Br)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1C=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a clear solution of 3β-acetoxy-7α-bromoandrost-5-ene-17-one, 25, (0.5 g) in methanol (20 mL) was added silica gel (2.0 g, 70-230 mesh) and the mixture was stirred for 2 h at room temperature. The methanolic solution was cooled, neutralized with saturated sodium bicarbonate solution, and filtered on a thin bed of celite. The clear filtrate was cooled at 0° C. to obtain the white crystalline 7-methoxy derivative 26. Yield 0.32 g (72.7%), m.p. 175-78° C. The NMR spectrum of the white solid showed 55% 7β-methoxy- and 45% 7α-methoxy-compound. Spectral data described below were deduced from the spectrum of the mixture. The biological activity was assayed as the mixture (Table I).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[S:25][C:24]([CH2:26][C:27](O)=[O:28])=[CH:23][CH:22]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:27](=[O:28])[CH2:26][C:24]3[S:25][C:21]([Cl:20])=[CH:22][CH:23]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(Cl)s1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)s1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(5-chlorothiophen-2-yl)acetic acid were treated using a method similar to that described in Example 5 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.77-11.81 (bs, 1H), 8.39-8.42 (m, 1H), 7.84-8.05 (m, 2H), 7.70-7.76 (m, 1H), 7.56-7.68 (m, 4H), 6.99 (d, J=3.8 Hz, 1H), 6.92 (d, J=3.8 Hz, 1H), 3.91-3.92 (bs, 2H); MS (ESI+) M/Z 430 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9](Br)=[CH:8]2)=[O:4].[C:26]1([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2CCc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Temperature: 120 °C
Yield: 92 %

Procedure:
A mixture of 3-bromo-5-hydroxy-2-oxo-1-phenethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (166 mg, 0.41 mmol), PhSnBu3 (0.16 mL, 0.49 mmol), and PdCl2(PPh3)2 (58 mg, 0.082 mmol) in DMF (4 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (50 mL) were added. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-40% EtOAc/hexanes+2% AcOH) to give 151 mg of the title compound as a light yellow solid. MS: (+) m/z 401.30 (M+1).