Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[Si](C=[N+]=[N-])(C)(C)C.[F:20][C:21]1[C:22]([CH2:31][CH2:32][CH3:33])=C(C=[CH:27][C:28]=1[O:29][CH3:30])C=O>O1CCCC1>[C:10]([C:9]1[CH:8]=[CH:27][C:28]([O:29][CH3:30])=[C:21]([F:20])[C:22]=1[CH2:31][CH2:32][CH3:33])#[CH:11]
Reactant: [Li]CCCC
Reactant: CCCc1c(C=O)ccc(OC)c1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C#Cc1ccc(OC)c(F)c1CCC
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
To a solution of diisopropylamine (0.841 mL, 6.0 mmol) in tetrahydrofuran (15 mL) at −78° C. under nitrogen was added slowly the solution of n-butyllithium (3.75 mL, 6.0 mmol, 1.6M in hexanes). After stifling for 30 minutes, the solution of TMS-diazomethane (3.0 mL, 6.0 mmol, 2M in hexanes) was added slowly into the reaction mixture. The mixture was stirred for 30 minutes then was added the solution of 3-fluoro-4-methoxy-2-propylbenzaldehyde (597) (0.589 g, 3.0 mmol) in tetrahydrofuran (3 mL). The resulting mixture was stirred at room temperature for 12 hours, quenched with saturated ammonium chloride and extracted with ethyl ether. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes) to provide 1-ethynyl-3-fluoro-4-methoxy-2-propylbenzene (626) (0.180 g, 31.2%) as a colorless oil.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([C:24]([OH:26])=O)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([C:24]([Cl:3])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(-c2cccnc2C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(-c2cccnc2C(=O)Cl)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (8 mL) and N,N-dimethylformamide (few drops) are added to a solution of 3-(3-methoxy-phenyl)-pyridine-2-carboxylic acid (11.86 g) in dichloromethane (80 mL). The mixture is heated to 40° C. and stirred at this temperature overnight. The solution is then concentrated and the residue is taken up in toluene and concentrated again to give the crude title compound that is used without further purification in the next step. Yield: 12.80 g (crude).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2([CH3:20])[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)[C:6]1=[O:21].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2([CH3:20])[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]2)[C:6]1=[O:21]
Reactant: CC1(N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CCC(=O)CC1
Yield: 91 %

Procedure:
Dissolve 3-(2,4-dichloro-benzyl)-1-(8-methyl-1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (1.33 g, 3.35 mmol) in acetone (100 mL) and add TsOH (0.58 g, 3.35 mmol). Stir the reaction at room temperature for 24 hours until the starting material has been gone. Add saturated NaHCO3 (100 mL) and extract the aqueous layer with ethyl acetate (3×200 mL). Combine the organic layers and dry with Na2SO4, filter and concentrate to give 1.08 g (91%) of 3-(2,4-Dichlorobenzyl)-1-(1-methyl-4-oxocyclohexyl)pyrrolidin-2-one as a white solid.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42]>CN(C=O)C>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([NH:27][C:26]1[C:25]([CH:22]([CH3:24])[CH3:23])=[CH:31][CH:30]=[CH:29][C:28]=1[CH:32]([CH3:34])[CH3:33])=[O:42]
Reactant: O=C(O)CCCCCBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.7 %

Procedure:
WSC (1.2 g, 11 mmols) and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,6-diisopropylaniline (1.97 g, 10 mmols) and 6-bromohexanoic acid (2.93 g, 15 mmols), and stirred at room temperature for 15 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer:hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 2.15 g (61%) of 6-bromo-N-(2,6-diisopropylphenyl)hexanamide as colorless needle-like crystals.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:7]=3[N:6]=2)[CH2:2]1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:16][C:17]1[C:22]([N:1]2[CH2:4][CH:3]([C:5]3[NH:9][C:8]4[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:7]=4[N:6]=3)[CH2:2]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: N#Cc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc2[nH]c(C3CN(c4nccnc4Cl)C3)nc2c1
Temperature: 80 °C
Yield: 51.2 %

Procedure:
The mixture of 2-azetidin-3-yl-1H-benzoimidazole-5-carbonitrile (1.7 g, 8.8 mmol), 2,3-dichloro-pyrazine (1.43 g, 9.7 mmol) and K2CO3 (2.4 g, 17.6 mmol) in CH3CN (20 mL) was heated to 80° C. for 10 h, then it was concentrated and partitioned between DCM and H2O. The organic layer was dried over Na2SO4, and concentrated to give the desired compound (1.4 g, 65%). The crude product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]([CH:14]3[CH2:16][CH2:15]3)[C:11]([C@@H:17]([NH:19][C:20]3[N:28]=[CH:27][N:26]=[C:25]4[C:21]=3[N:22]=[CH:23][N:24]4[CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH3:18])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:35])=[O:4].O[Li].O.Cl>CO.O>[CH:14]1([N:12]2[C:13]3[C:5]([C:3]([OH:4])=[O:2])=[C:6]([F:35])[CH:7]=[CH:8][C:9]=3[N:10]=[C:11]2[C@@H:17]([NH:19][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][N:24]3[CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH3:18])[CH2:15][CH2:16]1
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(C3CC3)c12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C(=O)O)c2n1C1CC1
Temperature: 80 °C
Yield: 21.5 %

Procedure:
A solution of 3-cyclopropyl-5-fluoro-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid methyl ester (607 mg, 1.27 mmol) and LiOH.H2O (266 mg, 6.33 mmol) in MeOH (20 mL) and water (2 mL) was heated at 80° C. for 22 h. Additional LiOH.H2O (266 mg) was added and the mixture heated at 80° C. for 5 h. After cooling to RT, the pH of the mixture was adjusted to 4 by addition of 1M aqueous HCl. The organic solvent was removed under reduced pressure and the aqueous phase extracted with EtOAc. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in DCM) to afford the title compound (127 mg, 21% over 2 steps) as a white solid. LCMS (Method C): RT 2.17 min [M+H]+ 466.22.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([NH:10][NH2:11])[C:5]([C:6]#[N:7])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:3]=1.B([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[C:30]([F:37])[CH:29]=1)(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:7][C:6]1[C:5]2[C:4]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[N:3][C:2]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[C:30]([F:37])[CH:29]=3)=[CH:9][C:8]=2[NH:10][N:11]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: N#Cc1c(NN)cc(Cl)nc1-c1ccc(Oc2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1n[nH]c2cc(-c3ccc(C(=O)O)c(F)c3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-chloro-4-hydrazinyl-2-(4-phenoxyphenyl)nicotinonitrile (9.5 mg, 0.028 mmol), 4-borono-2-fluorobenzoic acid (14.5 mg, 0.079 mmol), 2 M aqueous potassium phosphate (0.071 mL, 0.141 mmol) and PdCl2(dppf)-CH2Cl2 adduct (4.6 mg, 5.63 μmol) in DMF (0.45 mL) was degassed by vacuum-N2 refill cycle twice. The sealed tube was then heated at 85° C. under N2. After 1.5 h, no desired product was detected. Additional 4-borono-2-fluorobenzoic acid (21.4 mg), PdCl2(dppf)-CH2Cl2 adduct (11 mg), potassium phosphate (0.14 mL) and DMF (0.3 mL) were added. The mixture was again degassed by vacuum-N2 refill cycle twice and stirred at 85° C. for 20 h. The mixture was diluted with 1 N aqueous HCl (0.7 mL) and MeOH (0.8 mL), and purified by reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 60-90% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), to give Example 245 as yellow powder (2.7 mg, 14% yield), assumed as bis-TFA salt. 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (1H, t, J=7.65 Hz), 7.89-7.93 (2H, m), 7.86 (1H, s), 7.77-7.84 (2H, m), 7.44-7.50 (2H, m), 7.24-7.30 (3H, m), 7.15-7.19 (2H, m); MS (ES+) m/z: 441.2 (M+H); LC retention time: 3.438 min (analytical HPLC Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1.Cl.[CH3:18][O:19][NH2:20]>N1C=CC=CC=1>[CH3:18][O:19][N:20]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(Cc1cnccn1)c1ccccc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(Cc1cnccn1)c1ccccc1Cl

Procedure:
3 g of 2'-chloro-2-(2-pyrazinyl)-acetophenone and 0.8 g of O-methylhydroxylamine hydrochloride are dissolved in 10 ml of pyridine and the mixture is heated at 80° for 30 minutes. The pyridine is then removed under reduced pressure and water is added to the crude product. Thereupon, the mixture is extracted with ethyl acetate and the organic phase is dried over sodium sulfate and concentrated to yield 2'-chloro-2-(2-pyrazinyl)-acetophenone O-methyl oxime as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:12]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8](=[O:9])(=[O:10])[NH:11]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1S(N)(=O)=O
Product: O=S1(=O)NC(c2ccccc2)Nc2ccccc21

Procedure:
2-Aminobenzenesulfonamide was transformed by Method G (using benzaldehyde). M.p. 125.5-128.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([CH2:14][C:15]2[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([F:26])=[N:9][C:10]=2[NH2:25].[C:27]([S:31](Cl)=[O:32])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[NH2:25][C:10]1[N:9]=[C:8]([F:26])[N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([CH2:14][C:15]1[C:23]([I:24])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:32]
Reactant: CC(C)(C)S(=O)Cl
Reactant: NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)S(=O)NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a solution of 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (80 mg, 0.17 mmol) in DCM (3 mL) was added t-butylsulfinyl chloride (28 uL, 0.25 mmol) and triethylamine (30 uL, 0.25 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield WS60 as a white solid (45 mg, 46%). 1H NMR (500 MHz, CDCl3): δ 7.28 (s, 1H), 6.62 (s, 1H), 6.04 (brs, 2H), 5.97 (s, 2H), 4.60 (t, J=6.5 Hz, 1H), 4.24 (s, 2H), 4.20 (m, 1H), 4.09 (m, 1H), 3.13 (m, 1H), 2.97 (m, 1H), 2.00 (m, 1H), 1.85 (m, 1H), 1.27 (s, 9H). HRMS (ESI) m/z [M+H]+ calcd. for C20H25IFN6O3S, 575.0725. found 575.0738.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[CH:19]1([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.[C:27]1([CH2:33][CH2:34][C:35](=[CH2:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:39]([O:38][C:36]([CH:35]([CH2:34][CH2:33][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:43][C:19]1([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:37])([CH3:40])([CH3:41])[CH3:42]
Reactant: C=C(CCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C(CCc1ccccc1)CC1(C(=O)O)CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To diisopropylamine (5.13 g, 50.9 mmol) in tetrahydrofuran (THF) (20 ml) at -60° C., add n-BuLi hexane solution (20.3 ml of 2.5M, 50.9 mmol). Warm to 0° C., cool again to -60° C. and add cyclopentanecarboxylic acid (2.89 g, 25.4 mmol). Warm to 0° C. for 2.5 hr., cool again and add t-butyl 2-(2-phenylethyl)acrylate (5.90 g, 25.4 mmol) in THF (10 ml). After 2 h., warm to 0° C., quench with 5N HCl, extract with hexane, wash with 1N NaHCO3, and concentrate to a solid. Chromatograph on silica, eluting with hexane-ether-HOAc 60:40:1 to obtain an oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1.[C:17]([C:19]1[CH:20]=[C:21]([S:26]([N:29]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=2[O:44][CH3:45])[C:30]2[S:31][CH:32]=[CH:33][N:34]=2)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1F)#[N:18]>CN(C=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:24]2[CH:23]=[CH:22][C:21]([S:26]([N:29]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=3[O:44][CH3:45])[C:30]3[S:31][CH:32]=[CH:33][N:34]=3)(=[O:28])=[O:27])=[CH:20][C:19]=2[C:17]#[N:18])=[C:6]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1
Reactant: Cn1nccc1-c1cc(Br)ccc1O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Oc3ccc(Br)cc3-c3ccnn3C)c(C#N)c2)c(OC)c1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a slurry of sodium hydride (54 mg, 1.4 mmol, 60% in mineral oil) in DMF (1 mL) was added 4-bromo-2-(1-methyl-1H-pyrazol-5-yl)phenol (Preparation 89, 210 mg, 0.83 mmol) as a solution in DMF (3 mL). After stirring for 30 minutes, 3-cyano-N-(2,4-dimethoxy-benzyl)-4-fluoro-N-thiazol-2-yl-benzenesulfonamide (Preparation 90, 415 mg, 0.957 mmol) was added. After 3 hours the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by automated flash column chromatography using a 0-100% ethyl acetate/dichloromethane gradient provided the title compound (482 mg, 87%) as a yellow foam.
Reaction SMILES: [S:1]1[C@H:12]2[CH2:13][C@@H:14]([OH:25])[C@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[O:26]1CC[CH2:28][CH2:27]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>OCCO>[OH:26][CH2:27][CH2:28][O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[S:1][C@H:12]2[CH2:13][C@@H:14]([OH:25])[C@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10]1
Reactant: C1CCOC1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)O)S[C@H]2C[C@H]1O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)OCCO)S[C@H]2C[C@H]1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 70 mg of (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15-dihydroxyprost-13-enoic acid (prepared as described in Example 2), 3 ml of tetrahydrofuran and 34.5 μl of triethylamine was stirred at room temperature for 5 minutes, and then stirred with 27.7 μl of pivaloyl chloride. To the mixture were added 70 μl of triethylamine and 0.5 ml of 2-hydroxyethanol, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (2:1) as eluent to give 92 mg of the title compound having the following physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([Cl:65])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([Cl:65])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(Cl)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52 %

Procedure:
To a solution of 100 mg (0.47 mmol) 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 150 mg of TBTU (0.47 mmol) in 7 ml DMF, were added 0.4 ml (2.34 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 150 mg (0.47 mmol) (4-tert-butyl-benzyl)-[2-(3-chloro-4-fluoro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; diethylether/heptane 1:1; then 8 g silicagel DCM/heptane 70:30 to 90:10) to give 130 mg light yellow foam (52%). MS (EI) 514.1 (M)+.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([N:72]4[CH2:77][CH2:76][O:75][CH2:74][CH2:73]4)=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(N2CCOCC2)ccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCOCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 90 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Methoxy-4-morpholin-4-yl-benzaldehyde were reacted to produce the title compound (90%). 1H NMR (d-chloroform): 13.72 (br s, 1H), 8.19 (d, J=8 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J=9 Hz, 1H), 6.62 (dd, J=2.9 Hz, 1H), 6.47 (m, 2H), 6.40 (dd, J=2.6 Hz, 1H), 5.95 (br s, 1H), 5.48 (br s, 1H), 5.42 (d, J=8 Hz, 1H), 4.15 (s, 3H), 3.91 (t, J=5 Hz, 4H), 3.33 (t, J=5 Hz, 4H), 3.16 (s, 1H), 3.02 (s, 1H), 2.71 (d, J=8 Hz, 1H), 2.34 (d, J=9 Hz, 1H), 1.69 (d, J=9 Hz, 1H). MS: 496.06 (M+H). HPLC retention time: 2.48 minutes (G Method).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:13][O:14]C1C=C(C=CC=1OC)C(OC)=O>>[CH3:13][O:14][C:4]1[CH:5]=[C:6]([C:9]([NH2:12])([CH3:10])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Reactant: COc1ccc(C(C)(C)N)cc1
Product: COc1ccc(C(C)(C)N)cc1OC
Yield: 61 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 3,4-dimethoxybenzoate, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 61%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]=[C:12]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:13][C:14]=2[C:15]([O:17]CC)=[O:16])[CH3:9])=[CH:4][CH:3]=1.O1CCCC1.CO.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]=[C:12]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:13][C:14]=2[C:15]([OH:17])=[O:16])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1C(C)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(c1ccc(Cl)cc1)c1nc(N2CCOCC2)sc1C(=O)O
Temperature: 65 °C
Yield: 91.9 %

Procedure:
To a solution of ethyl 4-[1-(4-chlorophenyl)ethyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (1.42 g, 0.00373 mol) in tetrahydrofuran (30.2 mL, 0.373 mol) and methanol (6.04 mL, 0.149 mol) was added sodium hydroxide (1.0N in water, 29.8 mL, 0.0298 mol), and the resulting cloudy mixture was heated at 65° C. for 5 hours. The reaction was cooled to room temperature, diluted with water, and adjusted to pH 3.0 via addition of 1N aqueous HCl. The mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford 4-[1-(4-chlorophenyl)ethyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid (121) (1.21 g, yield 92%) as a white solid. LCMS: (FA) ES+ 353; NMR (400 MHz, DMSO) δ 12.70 (bs, 1H), 7.37-7.34 (m, 2H), 7.33-7.30 (m, 2H), 5.09 (q, J=7.2, 1H), 3.69-3.76 (m, 4H), 3.48-3.39 (m, 4H), 1.49 (d, J=6.8, 3H).