Azzindani/Open_Reaction_Data huggingface dataset:
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][C:39](O)=[O:40]>CN(C=O)C>[Br:35][CH2:36][CH2:37][CH2:38][C:39]([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:40]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.9 %

Procedure:
WSC (2.3 g, 12 mmols) and HOBt (1.49 g, 15 mmols) were added to a DMF (30 ml) solution of 2,6-diisoproylaniline (1.97 g, 10 mmols) and 4-bromobutyric acid (2.71 g, 15 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. 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 1.04 g (32%) of 4-bromo-N-(2,6-diisopropylphenyl)butanamide as colorless needle-like crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Br:15])=[CH:12][CH:11]=1>CC(C)=O>[BrH:15].[CH2:7]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([I:9])=[CH:11][CH:12]=2)[N:5]=1)[CH3:8]
Reactant: CCc1nnc(N)s1
Reactant: BrCc1ccc(I)cc1
Solvent: CC(C)=O
Product: Br
Product: CCc1nn(Cc2ccc(I)cc2)c(=N)s1
Yield: 51.2 %

Procedure:
To acetone (10 ml) was added 2-amino-5-ethyl-1,3,4-thiadiazole (645 mg) and 4-iodobenzyl bromide (1.49 g), followed by heating under reflux for 3 hours. After the reaction mixture was cooled, the crystals so precipitated were collected by filtration and dried, whereby 1.09 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:26])[C:18]4[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CS(C)=[O:29].[OH-:31].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:26])[C:18]4[CH:25]=[CH:24][C:21]([C:22]([OH:29])=[O:31])=[CH:20][CH:19]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CS(C)=O
Reactant: N#Cc1ccc(C(O)c2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(C(O)c2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Reaction time: 36 h
Yield: 95 %

Procedure:
4-((1-(4-Fluorophenyl)-1H-indazol-5-yl)(hydroxy)methyl)benzonitrile (180 mg, 0.52 mmol) was dissolved in MeOH (5 mL) and DMSO (5 mL) and treated with 1 M NaOH (5 mL) at 100° C. After 36 h, the MeOH was removed in vacuo, the residue acidified with sat KH2PO4 to pH 4-5 and extracted with EtOAc×3. The organic layer was dried with MgSO4, filtered, concentrated in vacuo to give 180 mg (95% yield) of 4-((1-(4-fluorophenyl)-1H-indazol-5-yl)(hydroxy)methyl)benzoic acid. MS found: (M+H)+=362.
Reaction SMILES: [CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:16][CH2:17][C:18]2[C:19]([OH:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])=[C:6]1[CH3:27])([CH2:3][CH3:4])[CH3:2].[CH3:28][CH2:29]CCCC>C(O)C>[CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:16][CH2:17][C:18]2[C:19]([OH:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])=[C:6]1[CH3:27])([CH2:3][CH3:4])[CH3:2].[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([NH:16][CH2:17][C:18]2[C:19]([OH:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])=[C:6]1[CH3:27])[CH2:2][CH2:28][CH3:29]
Reactant: CCCCCC
Agent: CCC(C)n1c(C)c(C(=O)NCc2c(C)cc(C)nc2O)c2ccccc21
Solvent: CCO
Product: CCCCn1c(C)c(C(=O)NCc2c(C)cc(C)nc2O)c2ccccc21
Yield: 16 %

Procedure:
1-sec-butyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (35 mg, 0.1 mmol) was separated by chiral prep-HPLC (Daicel IA (200 mm×20 mm×5 um), hexane:ethanol (0.2% DEA)=70:30, flow rate: 19 mL/min), then (R or S) 1-sec-butyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (11 mg, 30%) and (S or R)-1-sec-butyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (6 mg, 16%) was obtained. The retention times were 8.030 minutes (“Peak 1”; Compound 147) and 14.126 minutes (“Peak 2”; Compound 148) respectively in chiral HPLC chromatography. LRMS (M+H+) m/z: calcd 365.2. found 365. HPLC purity (214 nm): 99%. 1H.NMR (300 MHz, CD3OD): δ 7.73-7.70 (m, 1H), 7.56-7.53 (m, 1H), 7.12-7.09 (m, 2H), 6.11 (s, 1H), 4.54 (s, 3H), 2.64 (s, 3H), 2.43 (s, 3H), 2.25 (s, 3H), 1.97-1.90 (m, 2H), 1.61 (d, J=6.9 Hz, 3H), 0.73 (t, J=7.5 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:10][CH:9]=1)=[CH:5]OC.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[NH:46][C:45]([NH2:47])=[N:44][CH:43]=2)=[CH:38][CH:37]=1.C[O-].[Na+]>C(O)C>[C:30]([O:29][C:27](=[O:28])[N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[C:3](=[O:2])[N:47]=[C:45]3[NH:46][C:42]([C:39]4[CH:38]=[CH:37][C:36]([Br:35])=[CH:41][CH:40]=4)=[CH:43][N:44]3[CH:5]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])([CH3:32])([CH3:31])[CH3:33]
Reactant: COC=C(C(=O)OC)c1ccc(CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: Nc1ncc(-c2ccc(Br)cc2)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCN(Cc1ccc(-c2cn3cc(-c4ccc(Br)cc4)[nH]c3nc2=O)cc1)C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 52.1 %

Procedure:
To a mixture of 2-(4-{[tert-Butoxycarbonyl-(3-tert-butoxycarbonylamino-propyl)-amino]-methyl}-phenyl)-3-methoxy-acrylic acid methyl ester (5.70 g, 11.92 mmol), 5-(4-bromo-phenyl)-1H-imidazol-2-ylamine (2.84 g, 11.92 mmol) and ethanol (60 mL) was added a solution of sodium methoxide (12 mL, 0.5 M in methanol, 6 mmol). The resulted mixture was refluxed for 18 h, additional 12 mL of sodium methoxide (0.5 M in methanol, 6 mmol) was added and continued to reflex for 20 h. The reaction was concentrated and diluted with EtOAc (300 mL) and washed with water (200 mL), brine (200 mL). The EtOAc solution was concentrated. The crude product was purified by flash chromatography (0%-8% Methanol in dichloromethane) to give desired product (4.05 g, 52%) as brown solid. 1NMR (300 MHz, CDCl3): δ 7.96 (s, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.54 (m, 2H), 7.35(s, 1H), 7.27 (d, J=8.1 Hz, 2H), 5.25 (br.s, 0.5H), 4.70 (br.s, 0.5H), 4.44 (s, 2H), 3.29 (m, 2H), 3.11 (m, 2H), 1.67 (m, 2H), 1.52 (br.d, 9H), 1.44 (s, 9H). LCMS (EI) m/z: 654 (M+H+).
Reaction SMILES: N1([CH:7]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)N2CCCCC2)CCCCC1.[CH3:20][O:21][P:22]([NH:26][CH:27]1[C:34](=[O:35])[N:33]2[CH:28]1[S:29][CH2:30][C:31]([CH3:49])=[C:32]2[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37])([O:24][CH3:25])=[O:23]>C(OCC)(=O)C>[CH3:20][O:21][P:22]([NH:26][CH:27]1[C:34](=[O:35])[N:33]2[CH:28]1[S:29][CH2:30][C:31]([CH:49]=[CH:7][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[C:32]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:24][CH3:25])=[O:23]
Reactant: C1CCN(C(N2CCCCC2)N2CCCCC2)CC1
Reactant: COP(=O)(NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C)CSC12)OC
Solvent: CCOC(C)=O
Product: COP(=O)(NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C=CN3CCCCC3)CSC12)OC
Temperature: 45 °C
Reaction time: 18 h
Yield: 18.4 %

Procedure:
Tripiperidinomethane (1.06 g) is added to a solution of 7-dimethoxyphosphorylamino-3-methyl-2-(4-nitrobenzyloxycarbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.9 g) in ethyl acetate (40 cc) at 45° C., and the reaction mixture is stirred for 18 hours at 45° C. and diluted with ethyl acetate (20 cc). The organic solution is washed with distilled water (3×20 cc) and then with a saturated solution of sodium chloride (2×15 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue obtained is recrystallised from ethyl acetate (5 cc), and 7-dimethoxyphosphorylamino-2-(4-nitrobenzyloxycarbonyl)-8-oxo-3-(2-piperidinovinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E isomer) (0.2 g) is obtained in the form of an orange-yellow crystalline powder, m.p.=220°-221° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(c3ccc(Cl)cc3)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccc(Cl)cc1)Oc1ccc(Br)cc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A mixture of 6-bromo-2-(4-chlorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (600 mg, 1.48 mmol) and Lawesson's Reagent (596 mg, 1.48 mmol) in 1,4-dioxane (25 mL) was stirred at 110° C. overnight. The solvent was removed in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(4-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (450 mg, 69%). 1H-NMR (MeOD): 2.24 (m, 1H), 2.45 (m, 1H), 6.82 (m, 1H), 6.91 (m, 1H), 7.20 (m, 1H), 7.44 (m, 5H).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:60]\[H])/[C:50]1[CH:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[N:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:7]1([C:6]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:22][N:60]=[C:49]([C:50]4[CH:51]=[N:52][CH:53]=[C:54]([C:56]([F:59])([F:57])[F:58])[CH:55]=4)[N:48]=3)[C:2]2=[O:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [H]/N=C(\NO)c1cncc(C(F)(F)F)c1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3cncc(C(F)(F)F)c3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxy-5-(trifluoromethyl)nicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 9.41 (d, J=1.7, 1H), 9.02 (d, J=1.2, 1H), 8.51 (s, 1H), 7.49-7.19 (m, 10H), 4.93 (s, 2H), 3.59 (t, J=6.5, 2H), 2.91 (t, J=6.5, 2H); MS (DCI) m/z 465.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[F:17])[N:5]=[C:4]([C:18]([O:20]C)=[O:19])[C:3]=1[Cl:22].O.[OH-].[Li+].CO.O>O1CCCC1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc(C#N)cc2F)c(F)c(N)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nc(C(=O)O)c(Cl)c(N)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
In a 50-mL round bottom flask, equipped with a stir bar, methyl 4-amino-3-chloro-6-(4-cyano-2-fluorophenyl)-5-fluoropicolinate (351 mg, 1.084 mmol) and lithium hydroxide hydrate (100 mg, 2.383 mmol) were dissolved in tetrahydrofuran (2.0 mL), methanol (2.0 mL) and H2O (1.0 mL). The reaction was stirred at room temperature for 2 hours. The solvent was then removed by rotary evaporator. The resulting solid was treated with H2O, which was then adjusted to pH-3.0 with 1 N HCl, and extracted with ethyl acetate (3× 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by reverse phase chromatography (150 g C18, 0-100% acetonitrile in H2O), as needed, to afford the title compound as a white solid (0.058 g, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[ClH:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(CN2CCN(c3ccc(O)cc3)CC2)cc(OC)c1OC
Product: Cl
Yield: 54.2 %

Procedure:
8.3 g of 3,4,5-trimethoxybenzyl chloride and 3.5 g of N-(4-hydroxyphenyl)-piperazine and 3.5 g of K2CO3 are reacted and processed according to example 2. 4.2 g of N-(3,4,5-trimethoxy-benzyl)-N'-(4-hydroxyphenyl)-piperazine hydrochloride is obtained. Mp.: 268° C. (decomposition).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C@H:11]([CH2:16][OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14].Cl[C:19]1[C:20]2[S:36][C:35]([NH2:37])=[N:34][C:21]=2[N:22]=[C:23]([S:25][C@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])[N:24]=1.O>CN1C(=O)CCC1>[NH2:37][C:35]1[S:36][C:20]2[C:19]([NH:10][CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:16][OH:17])=[N:24][C:23]([S:25][C@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])=[N:22][C:21]=2[N:34]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)CC(CO)Nc1nc(S[C@@H](C)c2ccccc2)nc2nc(N)sc12
Temperature: 120 °C
Yield: 55.1 %

Procedure:
DIPEA (400 mg, 3 mmol) and D -leucinol (400 mg, 3.4 mmol) were added to 7-chloro-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-2-amine (300 mg, 0.9 mmol) in NMP (6 mL) and the mixture was heated to 120° C. for 24 h. The mixture was poured into water and extracted with ethyl acetate. The organic phase was dried (MgSO4), evaporated and the residue was purified by flash column chromatography (EtOAc) to give the title compound (200 mg, 54% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH:7]([Br:38])[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30]C3CCCCO3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23]C3CCCCO3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1>O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH:7]([Br:38])[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([OH:30])[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1O
Reaction time: 1 h
Yield: 80.3 %

Procedure:
360 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-Bromo-6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Example 1) were dissolved in a mixture of 0.7 ml of tetrahydrofuran and 7 ml of 65% aqueous acetic acid and the mixture was stirred at 40° to 45° C. for one hour. The reaction mixture was then diluted with ethyl acetate, washed with water and an 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 cyclohexane and ethyl acetate (1:3) as eluent to give 210 mg of the title compound having the following physical characteristics:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][N:17]=1>O1CCOCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[C:21]([F:22])[C:16]([F:15])=[N:17][CH:18]=2)=[N:3][CH:4]=1
Reactant: CC1(C)OB(c2cnc(F)c(F)c2)OC1(C)C
Reactant: Clc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(-c2ccc(Cl)cn2)cnc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a pressure vessel was added 2-bromo-5-chloropyridine (3.0 g, 16 mmol), cesium carbonate (15 g, 47 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (2.5 g, 3.1 mmol), and 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.5 g, 19 mmol) in 1,4-dioxane (120 mL) and water (22 mL). The mixture was flushed with argon, sealed and stirred at 90° C. for three hours. The mixture was concentrated, diluted with dichloromethane and washed with water. Organic extracts were concentrated and purified by MPLC (eluted with 0-10% methanol in dichloromethane) to yield 5-(5-chloropyridin-2-yl)-2,3-difluoropyridine as a yellow solid (2.4 g, 68%). MS m/z=227.2 [M+1]+. Calc'd for C10H5ClF2N2: 226.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH3:10]
Reactant: Oc1c(Br)cccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COc1c(Br)cccc1Br
Reaction time: 4 h
Yield: 58.9 %

Procedure:
A mixture of 2,6-dibromophenol (25 g, 0.099 mol), powder potassium carbonate (28 g, 0.2 mol, 2 equiv) and dimethyl sulfate (12.6 g, 0.099 mol) in acetonitrile (400 mL) was kept at reflux with good stirring for 4 hr. After cooling, the solids were removed by filtration and the solvent was removed in a rotary evaporator. The residue was taken in 2:1 heptane/ethyl acetate mixture (800 mL) and washed with water (2×400 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in a rotary evaporator, leaving almost pure 1 (15.5 g, 96%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2([CH:16]3[O:20][CH2:19][CH2:18][O:17]3)[O:15][CH:10]([C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=32)[CH2:9]1)[C:2]1C=CC=CC=1.C(O)(=[O:27])C>C(O)C.[Pd]>[C:1]([N:8]1[CH2:14][C:13]2([CH:16]3[O:20][CH2:19][CH2:18][O:17]3)[O:15][CH:10]([C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=32)[CH2:9]1)(=[O:27])[CH3:2]
Reactant: CC(=O)O
Reactant: c1ccc(CN2CC3OC(C4OCCO4)(C2)c2ccccc23)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CC2OC(C3OCCO3)(C1)c1ccccc12
Reaction time: 6 h
Yield: 88 %

Procedure:
A suspension of 10% Pd-C (1.42 g) in a solution of the product from Example 29 (9.75 g, 0.0302M) and glacial acetic acid (12 ml) in absolute ethanol (130 ml) was hydrogenated in a Parr apparatus at an initial pressure of 32 psi. After six hours, the catalyst was removed by filtration through Celite and the solvents. removed in vacuo. The residue was taken up in CH2Cl2 (50 ml) and treated with acetic anhydride (6.0 ml). After 15 minutes, the mixture was evaporated to dryness and the residue crystallized from Et2O to give the titled compound (7.34 g, 88% yield) as white crystals, mp 122°-123° C. NMR (CDCl3) δ 1.73 ppm (s, 3H, COCH3), 3.0-4.60 (m, 8H, ##STR49## and --OCH2CH2O--), 5.17 (m, 2H, ##STR50## 7.25 (m, 4H, aromatic H). IR (KBr): 1653 cm-1 (C=O). MS: 275 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[C:10](=[N:18][OH:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11].[H-].[Na+].O>CN(C=O)C.Cl.C(Cl)Cl>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:19][N:18]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[N:3]=1
Reactant: CC(=NO)c1ccccc1
Reactant: Nc1nc(Cl)ncc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NOc1ncc(F)c(N)n1)c1ccccc1
Temperature: 100 °C
Yield: 34 %

Procedure:
To a magnetically stirred mixture of 4-amino-2-chloro-5-fluoropyrimidine (0.10 g, 0.68 mmol) and acetophenone oxime (0.092 g, 0.68 mmol) in dry DMF (3 mL) in a 5 mL Biotage Iniator microwave vessel was added NaH (0.027 g of a 60 wt. % suspension, 0.68 mmol) under a N2 atmosphere. After gas evolution ceased, the resulting mixture was sealed with a Biotage Initiator microwave septa cap and heated to 100° C. in a Biotage Initiator microwave for 60 min. The contents were poured into a vial with water (5 mL) and CH2Cl2 (5 mL), and neutralized with a few drops of 2N HCl. The phases were separated and the organic extract was dried over MgSO4, filtered, and evaporated under a stream of nitrogen. The crude contents were purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions gave 0.057 g (34%) of 1-phenyl-ethanone-O-(4-amino-5-fluoro-pyrimidin-2-yl)oxime as an off-white solid: mp 163-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.75 (m, 2H), 7.42 (m, 3H), 5.25 (bs, 2H), 2.51 (s, 3H); HPLC-MS (ESI) m/z 247 (M+H)+.
Reaction SMILES: OCC=C(CCC=C(CCC=C(C)C)C)C.N1C=CN=C1.CN(C)C=O.[Si:27]([Cl:44])([C:40]([CH3:43])([CH3:42])[CH3:41])(C1C=CC=CC=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:40]([SiH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[Cl:44])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[SiH](Cl)c1ccccc1
Yield: 99 %

Procedure:
Synthesis was carried out with farnesol as a starting material. A protective group was bonded to the hydroxy group of farnesol using imidazole, anhydrous dimethylformamide, anhydrous dichloromethane, and tert-butyldiphenylsilyl chloride (TBDPS) to obtain a TBDPS-protected form (compound represented by (ei) below) (yield: 99%). Next, this compound was reacted with m-chloroperbenzoic acid in an anhydrous dichloromethane solvent to obtain an epoxy form (compound represented by (eii) below) (yield: 29%). Next, the epoxy was subjected to periodic acid oxidation using orthoperiodic acid in a mixed solvent of ether and tetrahydrofuran to obtain an aldehyde form (compound represented by (eiii) below) (yield: 73%). A Grignard reagent was prepared from ethyl iodide and magnesium in an anhydrous ether solvent and then reacted with the aldehyde to form an alcohol form (compound represented by (eiv) below) (yield: 80%). The secondary hydroxy group of the racemic alcohol form and (S)-MaNP acid were subjected to reaction in the presence of N,N-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, and (+)-10-camphorsulfonic acid in an anhydrous dichloromethane solvent to obtain diastereomers. Then, the diastereomers were optically resolved by HPLC, and the absolute configuration was determined by NMR to optically obtain a compound represented by (ev) below (yield: 84%). The TBDPS protective group was then deprotected using tetra-n-butylammonium hydrate in anhydrous tetrahydrofuran to obtain a diol form (compound represented by (evi) below) (yield: 91%). Next, the primary hydroxy group was replaced by chlorine using N-chlorosuccinimide and dimethyl sulfide in an anhydrous dichloromethane solvent at −40° C. or lower to obtain a chloride (compound represented by (evii) below) (yield: 70%). Next, the chloride was diphosphorylated using tris-tetra-n-butylammonium hydrogen pyrophosphate in anhydrous acetonitrile to obtain a compound represented by (eviii) below (compound represented by the formula (E)) as the substance of interest (yield: 59%).