Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13])([O-:5])=[O:4].[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH2:38][CH2:39]Br)[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3>CN(C=O)C.CCOC(C)=O>[Br:36][C:31]1[CH:30]=[CH:29][C:28]2[N:27]([CH2:37][CH2:38][CH2:39][N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N+:3]([O-:5])=[O:4])(=[O:14])=[O:13])[C:26]3[C:34]([C:33]=2[CH:32]=1)=[CH:35][C:23]([Br:22])=[CH:24][CH:25]=3
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccccc1
Reactant: BrCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCCn1c2ccc(Br)cc2c2cc(Br)ccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
Crushed KOH (0.0024 g, 0.0431 mmol) was added to 2-nitro-N-phenylbenzenesulfonamide (0.0100 g, 0.0359 mmol) in 0.2 mL DMF solution and the mixture was stirred for 30 min. 3,6-dibromo-9-(3-bromopropyl)-9H-carbazole (Example 35, 0.0240 g, 0.0538 mmol) in 0.3 mL DMF solution was added dropwise into the mixture and it was stirred at room temperature overnight. The crude reaction mixture was diluted with 20 mL EtOAc and washed with water 5×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.0082 g white solid as impure product, purity 66.9% (impurity is starting Ns-aniline; used without additional purification), yield 35.5%.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]=2[C:4](O)=[N:3][CH:2]=1.O=P(Cl)(Cl)[Cl:16].[OH-].[NH4+]>>[Cl:16][C:4]1[C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1CCCCCC2
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ncnc2c1CCCCCC2
Temperature: 100 °C
Yield: 98 %

Procedure:
A mixture of 5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol (0.66 g; 3.7 mmol; 1.0 equiv) in 3.3 mL of POCl3 (37 mmol; 10 equiv) was heated at 100° C. for 2 hours. The reaction was cooled and poured onto ice. The solution was adjusted to ca. pH 5 with ammonium hydroxide. The oil was extracted with ether and the extract was dried over MgSO4. The solvent was evaporated to give 4-chloro-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine t as a clear yellow oil (0.71 g; 98% yield).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([O:13]/[N:14]=[C:15](/[C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)\[C:16]([OH:18])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]CO>CS(C)=O>[C:1]([O:5][C:6]([C:8]1([O:13]/[N:14]=[C:15](/[C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)\[C:16]([O:18][CH3:24])=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)O)c2ccco2)CCCC1
Reactant: CCO
Solvent: CS(C)=O
Product: COC(=O)/C(=N\OC1(C(=O)OC(C)(C)C)CCCC1)c1ccco1
Yield: 96 %

Procedure:
This compound was prepared from Z-2-(1-tert-butoxycarbonylcyclopent-1-yloxyimino)-2-(fur-2-yl)acetic acid by the method described in Preparation 7(a) above, λmax (EtOH), 280.5 nm (ε17,300), νmax (Nujol) 1740, 1725 (sh) cm-1 (CO2R), τ(DMSO d6) 2.10, 3.18, 3.34 (α-furyl); 6.11 (CO2Me), 7.6-8.8 (cyclopentyl), 8.60 (CMe3). Yield 96%.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=[O:16])[CH3:15])[CH3:2].[BrH:17].BrBr>CC(O)=O>[Br:17][CH2:15][C:14]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[CH2:1][CH3:2])=[O:16]
Reactant: Br
Reactant: CCc1c(C(C)=O)cnn1-c1ccccc1
Agent: BrBr
Solvent: CC(=O)O
Product: CCc1c(C(=O)CBr)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5.40 g (25.3 mmol) of 1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone in HOAc (30 mL) was added HBr in HOAc (30 mL). Bromine (1.42 ml, 27.7 mmol) was added dropwise and the mixture was stirred at rt for 45 minutes and was poured into ice water (500 mL). The liquid was decanted and remaining residue was washed with water, then dissolved in CH2Cl2 (500 mL) and washed with sat NaHCO3, dried over MgSO4, and concentrated to give 7.20 g of 2-bromo-1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanone.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.Br[CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].C(O)(=O)C>CN(C)C=O.O>[Cl:3][C:4]1[C:5]([C:14]([CH2:26][N:27]2[C:31](=[O:32])[C:30]3[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]2=[O:37])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CN1C(=O)c2ccccc2C1=O)(C(=O)OCC)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.25 h

Procedure:
To a suspension of 60% sodium hydride (0.65 g) in dry dimethylformamide (20 ml) at 0° C. was added a solution of diethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)malonate (5 g) in dry dimethylformamide (10 ml) and the mixture was stirred for 15 minutes. A solution of N-bromomethylphthalimide (3.55 g) in dry dimethylformamide (10 ml) was added dropwise and the mixture was warmed with stirring to 22° C. over 18 hours. Glacial acetic acid (1 ml) was added and the mixture was poured into cold water (500 ml). The aqueous solution was extracted with diethyl ether (3×150 ml) and the combined extract was water washed (3×100 ml). The organic extract was dried (MgSO4) and evaporated to give a crude product. Trituration with diethyl ether/light petroleum (b.p. 40-60° C.) (1:1) gave the title compound, m.p. 159-61° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[NH:5][C:6]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10]C(C)(C)C)=[O:9]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[NH:5][C:6]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1cccc(Nc2cc(CCc3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2cc(CCc3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(3-methylanilino)-4-phenethylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 77-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(3-methylanilino)-4-phenethylbenzoic acid 15 mg of white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]2[N:12]=[C:11]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[S:10][C:6]=2[N:7]=[CH:8][N:9]=1.C(N(CC)C(C)C)(C)C.C(O)(=O)C.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O.C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4]1[C:5]2[N:12]=[C:11]([NH:13][C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH2:40][C:39]4[CH:42]=[CH:43][CH:44]=[C:37]([C:36]([F:35])([F:45])[F:46])[CH:38]=4)[CH2:20][CH2:21]3)=[O:15])[S:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: COc1ncnc2sc(NC(=O)N3CCNCC3)nc12
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)O
Product: COc1ncnc2sc(NC(=O)N3CCN(Cc4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
A solution of piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide hydrochloride (2 g, 6.0 mmol) in methanol (200 mL) was treated with N,N-diisopropylethylamine (2.2 mL, 12.6 mmol). The mixture was stirred at 25° C. for 10 min until a clear solution formed. At this time, the reaction was treated with acetic acid (1.75 mL, 30.6 mmol), 3-trifluoromethy-benzaldehyde (2.4 mL, 17.9 mmol) and sodium cyanoborohydride (1.1 g, 17.7 mmol). This mixture was stirred at 25° C. overnight. The reaction was then concentrated in vacuo and partitioned between methylene chloride and an aqueous phosphate buffer (pH=7). The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give a solid. This solid was dissolved in methanol and absorbed onto silica gel (4 g). ISCO chromatography (330 g, Silica, gradient elution 5/95 methanol/methylene chloride) afforded 4-(3-trifluoromethyl-benzyl)-piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (1.56 g, 58%) as a white solid; LRMS for C19H19F3N6O2S (M+H)+ at m/z=453. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[N:27]1[CH:32]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:30]=[N:29][CH:28]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 66 using 5-bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 67.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (Condition 3) tR=1.07 min, m/z=430.4 [M+H]+, m/z=428.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.94 (m, 4H) 3.15 (t, J=6.15 Hz, 4H) 7.37 (d, J=8.78 Hz, 2H) 7.86 (d, J=8.91 Hz, 2H) 8.11 (d, J=2.01 Hz, 1H) 8.80 (d, J=1.88 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[N:11][N:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[NH2:21].N1C=CC=CC=1.[Cl:28][CH:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:30](Cl)=[O:31]>CN(C)C=O>[Cl:28][CH:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:30]([NH:21][C:9]1[N:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[N:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:31]
Reactant: Nc1c(-c2ccccc2F)nnn1CSc1ccccc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1c(-c2ccccc2F)nnn1CSc1ccccc1)C(Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a cold (0° C.), stirred solution of 5-(2-fluorophenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-ylamine (1.30 g, 4.32 mmol) in dimethylformamide (30 ml) under nitrogen was added pyridine (0.46 ml, 5.62 mmol) followed by rac-α-chlorophenylacetyl chloride (0.79 ml, 4.97 mmol). The reaction mixture was stirred at 0° C. for 1 hour and subsequently poured into distilled water (200 ml). The aqueous solution was extracted with ethyl acetate (2×100 ml) and the combined organic extracts were washed with citric acid (100 ml, 10% aqueous), sodium hydrogencarbonate (100 ml, sat. aqueous), water (100 ml), brine (100 ml) and dried (Na2SO4). The solvent was removed in vacuo and the resulting oil was crystallised from hot diethyl ether to afford 2-chloro-N-[5-(2-fluoro-phenyl)-3-phenylsulfenylmethyl-3H-1,2,3-triazol-4-yl]-2-phenylacetamide (1.514 g, 78%) as a pale solid. δH (400 MHz, CDCl3) 5.37 (1H, s, CHCl), 5.49 (1 H, d, J=14.4, PhSCH2A), 5.61 (1H, d, J=14.4, PhSCH2B), 7.11 (1H, dd, J=11 and 8.6, ArH), 7.24-7.44 (12H, m, ArH), 7.82 (1H, td, J=7.6 and 1.4, ArH), 8.21-8.19 (1H, m, NH); m/z (ES+) 453 (35 ClM+H+) and 455 (37 ClM+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])=[N:18][N:19]=2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]([CH:40]=O)[CH:31]=1.ClCCCl>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:28])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:40][C:32]4[CH:31]=[N:30][C:39]5[C:34]([CH:33]=4)=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:26][CH2:27]3)=[O:21])=[N:18][N:19]=2)(=[O:11])=[O:12])=[C:5]([CH3:29])[CH:4]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCNCC3)o2)c(C)c1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(Cc4cnc5ccccc5c4)CC3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure CD using 4-methoxy-N,2,6-trimethyl-N-{[5-(piperazin-1-ylcarbonyl)-1,3,4-oxadiazol-2-yl]methyl}benzenesulfonamide (42 mg, 0.10 mmol), quinoline-3-carbaldehyde (18 mg, 0.12 mmol), STAB (42 mg, 0.2 mmol) DCE (0.8 mL) and a few 4 Å molecular sieves. The crude product was purified using prep method D.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:4][C@H:3]1[OH:13].C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:7]1([N:5]2[CH2:4][C@@H:3]([OH:13])[C@H:2]([NH:1][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:6]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N[C@@H]1CN(C2CCCCC2)C[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(N[C@@H]1CN(C2CCCCC2)C[C@H]1O)c1ccccc1

Procedure:
This compound was prepared in a manner analagous to Example 2, using 8.1 g of trans-4-amino-1-cyclohexyl-3-pyrrolidinol, 10 g of potassium carbonate and 6.2 g of benzoyl chloride. After filtration and solvent evaporation, the residue crystallized and was recrystallized from acetone. Yield was 5.8 g (45%), m.p. 154.0°-155.5° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:12])[C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:12])[C:9]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:11]
Reactant: C[C@@H](OC1CCCCO1)C(=O)O
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
Anhydrous tetrahydrofuran (250 ml) was added to (2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionic acid (32 g). To the mixture was added by portions 1,1'-carbonyl-diimidazole (35.8 g), with stirring at room temperature during 10 minutes. The resultant mixture was stirred for 30 minutes at room temperature and, then, cooled with ice, to which was added dropwise morpholine (38.3 g) during 15 mintues, followed by stirring for 15 minutes in an ice-bath. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in dichloromethane (300 ml). The solution was washed with a saturated aqueous solution of sodium chloride (50 ml) and dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel chromatography (eluent: hexane-ethyl acetate=1:4) to afford N-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (25.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[C:13]1([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[S:27](Cl)(=[O:29])=[O:28])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:27](/[CH:26]=[CH:25]/[C:22]2[CH:23]=[CH:24][C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=2)(=[O:29])=[O:28])[C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: Nc1cccc(F)c1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1c(F)cccc1NS(=O)(=O)/C=C/c1ccc(-c2ccccc2)cc1
Reaction time: 12 h
Yield: 19.2 %

Procedure:
2-Amino-6-fluoro-benzenesulfonamide (38 mg, 200 μmol) and (E)-2-(4-phenylphenyl)ethenesulfonyl chloride (56 mg, 200 μmol) were dissolved in pyridine (1.5 mL) and the reaction mixture was shaken for 12 h. The solvent was removed in vacuum and the residues were purified by HPLC to give the product (16.6 mg, 19%).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][N:21](C(OCC5C=CC=CC=5)=O)[C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+]>C(O)C.Cl>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][NH:21][C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CN2CCc3c(c4cccc(F)c4n3C)C2=O)ncn1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Yield: 71.5 %

Procedure:
A solution of phenylmethyl 4-[(6-fluoro-2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3-b]indol-2-yl)methyl]-5-methyl-1H-imidazole-1-carboxylate (100 mg) in ethanol (20 ml) and 2N hydrochloric acid (10 ml) was heated on a steam bath for 10 min. The cooled reaction mixture was then added to water (5 ml) and 2N sodium hydroxide (20 ml), and extracted with ethyl acetate (2×75 ml). The combined, dried organic extracts were adsorbed onto silica and purified by FCC eluting with System A (100:8:1) to give a solid which was triturated with ether to give the title compound (50 mg), m.p. 232°-233°.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O>C(O)(=O)C.O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH:11]=[CH:10]1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O
Reaction time: 48 h

Procedure:
A 125 mg (0.3 mmol) portion of the prostaglandin E1 analogue of Example 3 (14-Phenyl-11α,15R-dihydroxy-9-oxoprost-10,13E-dien-1-oic acid) was stirred into 10 ml of acetic acid-water (2:1) at 50° C. under an inert atmosphere. Progress of the reaction was followed by thin layer chromatography. After 48 hours, the reaction mixture was extracted with ether. Ether layers obtained were combined and washed to neutrality with brine. Removal of the solvent yielded a yellow oil. The oil was azeotroped with toluene and chromatographed on 70 g SG-60, and eluted with benzene-ethanol (19:1) to yield 102 mg of the PGA1 analogue.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[NH:11]1[CH2:21][CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12]1.N1CCC[C@@H](C(OCC)=O)C1.C([C@@H]([C@H](C([O-])=O)O)O)([O-])=O>C(O)(C)C.O>[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[NH:11]1[CH2:21][CH2:20][CH2:19][C@@H:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: CCOC(=O)C1CCCNC1
Agent: CCOC(=O)[C@@H]1CCCNC1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 62.5 °C
Reaction time: 0.42 h

Procedure:
L-(+)-Tartaric acid (47.74 g, 318 mmol) was suspended in 265 g of isopropyl alcohol and 16.91 g of water. The mixture was heated to 60-65° C. to afford a homogeneous solution. One equivalent of (±)-ethyl nipecotate (50 g, 318 mmol) was added while the temperature was maintained at or below 75° C. The mixture was stirred at 70-75° C. for 20-30 minutes, then cooled to 60° C. over 60 minutes. Seed crystals of (R)-(−)-ethyl nipecotate-L-(+)-tartrate (25 mg, 0.08 mmol) were added and the reaction was cooled to 26-30° C. over three hours. The temperature was maintained at 26-30° C. for 30 minutes until precipitation was complete. The product was isolated (62.0 g, 94.8% de) and washed twice with a mixture of isopropyl alcohol (21.05 g) and water (1.34 g). The crude product was slurried in a mixture of isopropyl alcohol (188 g) and water (12 g) at 73-77° C. After stirring for 10-20 minutes, the suspension was cooled to 26-30° C. Temperatures exceeding 30° C. will result in less yield, while a temperature of less than 25° C. resulted in de<98%. The product was isolated by filtration and washed twice with a mixture of isopropyl alcohol (21.05 g) and water (1.34 g). This afforded the title compound as a white powder in 72% yield, 98.8% de.
Reaction SMILES: Cl[Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[OH:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].N1C=CN=C1>CN(C)C=O.O>[CH:3]([Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[O:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])([CH3:5])[CH3:4]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=Cc1cccc(CCO)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCCc1cccc(C=O)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
Chlorotriisopropylsilane (0.640 g, 0.71 mL, 3.3 mmol) was added dropwise to a 0° C. cooled solution of 13 (0.450 g, 3.0 mmol) and 1H-imidazole (0.410 g, 6.0 mmol) in anhydrous N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 0° C. for 3 h and then diluted with water. The resulting mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using ethyl acetate-hexanes 1:9 as eluent to furnish the desired compound as colorless oil. Yield: 96%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[F:9][C:10]([F:21])([F:20])[C:11]1[C:12](F)=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].C1CCCCC1>CN(C=O)C>[F:9][C:10]([F:20])([F:21])[C:11]1[C:12]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cccc(C(F)(F)F)c1F
Reactant: Nc1ccccc1S
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: N#Cc1cccc(C(F)(F)F)c1Sc1ccccc1N

Procedure:
Using a procedure analagous to that of Example 3(a), 2-aminothiophenol (6.26 g, 50 mmol) was combined with 3-trifluoromethyl-2-fluorobenzonitrile (1 eq) in DMF solvent (50 ml) to give the title compound as a white solid from cyclohexane (10.41 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1)[CH3:2].[C:32](Cl)(=[O:34])[CH3:33]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][N:23]([C:32](=[O:34])[CH3:33])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CNCc2ccccc2)c1
Reactant: CC(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN(Cc2ccccc2)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-(benzylamino-methyl)-4-bromo-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and acetyl chloride.