Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[CH2:7]2.BrCC1C=C(C=CC=1CBr)[C:20]([O:22][CH3:23])=[O:21]>>[O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([C:20]([O:22][CH3:23])=[O:21])=[CH:11][C:6]=1[CH2:7]2
Reactant: O=C1C2CCC1Cc1ccccc1C2
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Product: COC(=O)c1ccc2c(c1)CC1CCC(C2)C1=O

Procedure:
Prepared using the procedure described for 11-oxo-5,6,7,8,9,10-hexahydro -6,9-methanobenzocyclooctene (Justus Liebigs Ann. Chem. 1961, 650, 115) using methyl 3,4-bis(bromomethyl)benzoate in place of 1,2-bis(bromomethyl)benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38]([OH:40])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:41]1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>ClCCCl.O>[NH2:41][C:38]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)=[N:23][C:24]([C:27]([CH3:30])([CH3:28])[CH3:29])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:40]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C1
Yield: 91.8 %

Procedure:
A solution of (3R*,5S*)-1-(tert-butoxycarbonyl)-5-[({2-tert-butyl-4-[(2-furylmethyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (1.03 g), 1H-1,2,3-benzotriazol-1-ol ammoniate (420 mg), WSC.HCl (530 mg) and triethylamine (520 μl) in 1,2-dichloroethane (16 ml) was stirred at room temperature for 24 hr. The mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object compound (944 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:13][C@@H:14](O)[CH2:15][CH:16]=[CH2:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH:16]([CH2:15][CH:14]=[CH2:13])[CH3:17])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1O
Reactant: C=CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(C)Oc1ccc(F)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
To a solution of methyl 5-fluoro-2-hydroxybenzoate (1.0 g, 5.88 mmol), (R)-(−)-pent-4-en-2-ol (1.210 ml, 11.76 mmol) and triphenylphosphine (2.004 g, 7.64 mmol) in THF (14 ml) was added dropwise DIAD (1.486 ml, 7.64 mmol) and the resulting solution was stirred at rt. After 20 h, the reaction was diluted with Et2O and washed with 1N NaOH, water (3×'s) and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-40% EtOAc/hexane; 20 CV) to give methyl 5-fluoro-2-(pent-4-en-2-yloxy)benzoate (1.1331 g, 4.76 mmol, 81% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J=8.7, 3.3 Hz, 1H), 7.15 (ddd, J=8.9, 7.7, 3.4 Hz, 1H), 6.96 (dd, J=9.0, 4.2 Hz, 1H), 6.02-5.79 (m, 1H), 5.20-5.06 (m, 2H), 4.50-4.34 (m, 1H), 3.90 (s, 3H), 2.60-2.32 (m, 2H), 1.34 (d, J=6.1 Hz, 3H).
Reaction SMILES: C([NH:8][C:9]([CH3:22])([CH:11]=[CH:12][CH:13]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]1([CH3:21])[CH3:20])[CH3:10])(OC(C)(C)C)=O.O.[OH-].[K+]>FC(F)(F)C(O)=O>[NH2:8][C:9]([CH3:22])([CH:11]=[CH:12][CH:13]1[C:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][C:17]1([CH3:19])[CH3:18])[CH3:10]
Reactant: CC(C)(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C=CC1C(C)(C)CCC1(C)C
Reaction time: 8 h

Procedure:
N-Boc-2-amino-2-methyl-4-(2,2,5,5-tetramethyl-1-cyclopentyl)butene is dissolved in trifluoroacetic acid and the solution is stirred overnight. Water is added and the mixture made basic with 20% KOH. The mixture is extracted with ether, the organic layer dried over NaSO4 and evaporated to yield 2-amino-2-methyl-4-(2,2,5,5-tetramethyl-1-cyclopentyl)butene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N+:19]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 66 h
Yield: 88.6 %

Procedure:
To a pre-cooled (−45° C.) solution of (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 3a) (18.54 g, 69.0 mmol) and 4-nitrobenzohydrazide (12.5 g, 69.0 mmol) in anhydrous THF (400 mL) was added 1-Hydroxybenzotriazole monohydrate (10.57 g, 69.0 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (26.46 g, 138.0 mmol) at −45° C. followed by triethylamine (19.2 mL, 138.0 mmol). The reaction mixture warmed to room temperature and stirred for 66 h, then quenched with 5% aq. citric acid (350 mL). The solution was extracted with EtOAc (300 mL). The organic extract was washed with 5% aq. citric acid (2×300 mL), sat. aq. NaHCO3 (3×300 mL), H2O (2×300 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a yellow solid (26.4 g, 89%): 1H NMR (400 MHz, δ in ppm) 8.37 (dm, J=9.0 Hz, 2H), 8.18 (dm, J=9.0 Hz, 2H), 7.54 (d, J=8.6 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 5.59 (d, J=7.2 Hz, 1H), 4.29 (pentet, J=5.3 Hz, 1H), 4.17 (dd, J=5.1, 7.2 Hz, 1H), 2.36 (s, 3H), 1.40 (d, J=6.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[CH2:10])=[C:6]([OH:11])[CH:5]=[C:4]([OH:12])[C:3]=1[C:13](=[O:15])[CH3:14].C(N(CC)C(C)C)(C)C.[CH3:25][O:26][CH3:27].[O:28]1[CH2:32]CC[CH2:29]1>>[OH:1][C:2]1[C:7]([CH2:8][CH:9]=[CH2:10])=[C:6]([O:11][CH2:25][O:26][CH3:27])[CH:5]=[C:4]([O:12][CH2:29][O:28][CH3:32])[C:3]=1[C:13](=[O:15])[CH3:14]
Reactant: COC
Reactant: C=CCc1c(O)cc(O)c(C(C)=O)c1O
Reactant: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCc1c(OCOC)cc(OCOC)c(C(C)=O)c1O
Reaction time: 1 h
Yield: 94.7 %

Procedure:
In 160 ml of anhydrous tetrahydrofuran were dissolved 18.4 g of the so-obtained 2',4',6'-trihydroxy3'-(2-propenyl)acetophenone and 57.1 g of N,N-diisopropylethylamine, and 28.4 g of chrolomethyl methyl ether was added to the solution under ice cooling and the reaction mixture was stirred under ice cooling for 1 hour, and further, stirred at room temperature for 4 hours to effect a reaction. The reaction mixture was extracted with diethyl ether and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography [eluting solvent=n-hexane/ethyl acetate (7/1)] to obtain 24.8 g (yield=94.7%) of 2'-hydroxy-4',6'-bismethoxymethoxy-3'-(2-propenyl)acetophenone in the form of a colorless oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]([CH:22]([CH3:24])[CH3:23])=[C:9](CCOC)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1[CH2:38][O:37][CH2:36][CH2:35]1>>[CH:25]([C:6]1[C:5]([CH2:3][OH:4])=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:9]([CH:36]([O:37][CH3:38])[CH3:35])=[C:8]([CH:22]([CH3:23])[CH3:24])[N:7]=1)([CH3:27])[CH3:26]
Reactant: C1CCOC1
Reactant: COCCc1c(C(C)C)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COC(C)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
The intermediate obtained in Step A (359 mg, 0.961 mmol) was dissolved in 40 mL of dry THF, for a dropwise addition of a solution of LAH (1M/THF, 1.92 mL, 2 eq.). The reaction mixture was stirred at reflux for 24 hours then cooled to room temperature and quenched with water (80 μL), 20% NaOH (80 μL), and water (160 μL). After filtration, the solvent was evaporated to afford a residue which was filtered through to a pad of silica (10% ethyl acetate/hexane) to afford the title compound as a white solid (281 mg, 0.72 mmol, 85%). 1H NMR (300 MHz, CDCl3): δ 7.13 (m, 4 H), 4.32 (dq, J=5.2 J=11.4 Hz, 1 H), 4.11 (q, J=6.3 Hz, 1 H), 3.77 (septet, J=6.6 Hz, 1 H), 3.42 (septet, J=6.6 Hz, 1 H), 3.10 (s, 3 H), 1.29 (m, 16 H). FAB-MS: calcd for (C21H28FNO2) 345, found 346 (M+H). Anal. Calcd for C21H28NO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 151-153° C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].ClCCCl.[S:13](=O)(=[O:16])([OH:15])[OH:14].C(C(CCCC)C([O-])=O)C.[K+:28]>C(OCC)(=O)C>[K+:28].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:13]([O-:16])(=[O:15])=[O:14]
Reactant: Oc1ccc(O)cc1
Reactant: O=S(=O)(O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 87.6 %

Procedure:
Hydroquinone (10 g, 0.09 mol) and 1,2-dichloroethane (30 mL) was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 8.9 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. Temperature was slowly raised to 40° C. then stirred for 3-8 h. The reaction mass was then cooled to 25-35° C. and ethyl acetate (100 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (18.2 g, 0.099 mol) in ethyl acetate (100 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 18 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:17]#[N:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.Cl.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:17]#[N:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([C:10]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=3)[CH2:22][CH2:21]2)=[O:12])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C#N)nc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(C#N)nc1Cl
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 3-(4-chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 234.5, 60 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 61 mg, 0.27 mmol), HBTU (131 mg, 0.35 mmol), DIEA (123 μL, 0.69 mmol) were added to the reaction. The reaction mixture was stirred for 30 min at 15° C. The reaction mixture was diluted with 40 mL of EtOAc, then was washed with 2×30 mL of brine and 2×30 mL of NH4Cl (sat.), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (160 mg) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and MeCN (49.0% MeCN up to 62.0% in 7 min, up to 100.0% in 3 min, down to 49.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 25.1 mg (25%) of the title compound as a white solid. m/z (ES+) 430 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C@@H:7]2[CH2:9][C@H:8]2[CH:10]([NH:12][O:13][CH3:14])[CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][N:23]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[C:25]([C:31]([F:34])([F:33])[F:32])=[N:24]1>ClCCl.O>[Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:9][CH:8]2[CH:10]([N:12]([O:13][CH3:14])[C:28]([C:26]2[C:25]([C:31]([F:34])([F:33])[F:32])=[N:24][N:23]([CH3:22])[CH:27]=2)=[O:29])[CH3:11])=[CH:4][CH:3]=1
Reactant: CONC(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)(F)F)C(C)C1CC1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To a stirred solution of trans N-{1-[2-(5-chloro-thiophen-2-yl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine (0.19 g; 0.83 mmol) prepared as described in example P18 and triethylamine (0.16 ml; 1.08 mmol) in dichloromethane (5.0 ml) at ambient temperature was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.18 g; 0.83 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (3 ml) and extracted with dichloromethane (3×1 ml). Combined organic layers were washed with water (1 ml) and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 30:70) to afford 0.26 g (79% of theory) of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {1-[2-(5-chloro-thiophen-2-yl)-cyclopropyl]-ethyl}-methoxy-amide as a resin.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=2)=[N:3][CH:4]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2[nH]ccc2c1
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc4[nH]ccc4c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[(1H)-indol-5-yl]-4-pyrimidineamine and 3-hydroxyaniline were reacted to provide 5-fluoro-N2-(3-hydroxyphenyl)-N4-[(1H)-indol-5-yl]-2,4-pyrimidinediamine.
Reaction SMILES: [I-].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]2[C:19]([CH:20]=[C:21]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:22]=[C:23]2[Cl:29])=[S+:18]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([O-:39])=[O:38].[Cl:29][C:23]1[C:24]2[C:19](=[S+:18][C:17]3[C:26]([N:25]=2)=[CH:27][CH:28]=[C:15]([N:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[CH:16]=3)[CH:20]=[C:21]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:22]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(CC)c1cc(Cl)c2nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3[s+]c2c1
Agent: [I-]
Solvent: ClCCl
Product: CCN(CC)c1cc(Cl)c2nc3ccc(N4CCNCC4)cc3[s+]c2c1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C

Procedure:
The 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-chloro-3-(diethylamino)phenothiazin-5-ium iodide was dissolved in CH2Cl2 (4 mL) and trifluoroactic acid (4 mL) and heated at 70° C. overnight. The mixture was allowed to cool to RT and the solvent was evaporated to give a residue. The residue was purified by Prep TLC to give 2.2 mg of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]O.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)ccc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClCc1cc(Br)ccc1Cl
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (10.66 g) in toluene (100 ml) solution were added thionyl chloride (10 ml), and pyridine (2 drops), and the mixture was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzyl chloride as pale yellow crystals, which was used in the subsequent step without further purification.
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C.C1(C)C=CC=CC=1>[I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(I)cc(I)c1I
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)cc(I)c1I
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 15.0 g (30.0 mmol) of 2,3,5-triiodobenzoic acid and 19.0 g (150 mmol) of oxalyl chloride in 60 ml of dry dichloromethane was placed under nitrogen and cooled to 0° C. Two drops of dry DMF were added, the ice bath was removed and the resulting suspension was stirred at room temperature for 1.5 hrs. The resulting brown solution was concentrated in vacuo to produce a tan solid. The solid was dissolved in 30 ml of dry toluene and was concentrated in vacuo. The toluene concentration was repeated two more times to yield 2,3,5-triiodobenzoyl chloride as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH-].[Na+].O.Cl[CH2:14][CH:15]([OH:19])[CH2:16][CH2:17][Cl:18]>C(O)(C)C>[Cl:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1O
Reactant: OC(CCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: COc1ccccc1OCC(O)CCCl

Procedure:
To a mixture of 2 moles (248.26 g.) of 2-methoxyphenol, 4 moles (160 g.) of sodium hydroxide, 250 ml. of water and 1 liter of isopropanol was added with stirring 2.2 moles (314.64 g.) of 1,4-dichloro-2-butanol. The mixture was refluxed gently overnight. The reaction mixture was extracted with 1 liter of isopropyl ether, dried over sodium sulfate and distilled under reduced pressure. The distillate which was collected at 136°-138° C./0.015 mm. (396.8 g.) solidified to a white crystalline solid which melted at 48°-50° C.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:6]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[CH3:35].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:15]([CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:25])[CH:10]=[CH:9][CH:8]=2)=[CH:29][C:28]=1[CH3:35]
Reactant: Cc1cc(C=O)ccc1F
Reactant: COC(=O)Cc1cccc(OCCCNC[C@H](C)c2ccccc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(CN(CCCOc2cccc(CC(=O)O)c2)C[C@H](C)c2ccccc2)ccc1F
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
To a solution of {3-[3-((R)-2-Phenyl-propylamino)-propoxy]-phenyl}-acetic acid methyl ester (100 mg, 293 mmol) in methanol (1 ml) was added acetic acid (10% by volume) followed by 4-Fluoro-3-methyl-benzaldehyde (121 mg, 879 mmol) and sodium cyanoborohydride (54.5 mg, 879 mmol). After the resulting mixture was stirred for 18 h at RT water was added to quench the reaction. The solution was made basic by the addition of sodium hydroxide and heated for 30 min. The sample concentrated in vacuo and purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: 0.1% trifluoroacetic acid in acetonitrile B: 0.1% aqueous trifluoroacetic acid, A: 10 to 90% during 10 min, UV detection at 254 nm) to give the title compound as a solid (71.6 mg, 54%). MS (ESI) 450.0 (M+H)+.
Reaction SMILES: [N+](=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N-].[S:13]1[C@H:24]2[CH2:25][C@@H:26]([OH:37])[C@H:27](/[CH:28]=[CH:29]/[C@@H:30]([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:23]2[CH2:22][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].CO>C(Cl)Cl>[CH2:3]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[S:13][C@H:24]2[CH2:25][C@@H:26]([OH:37])[C@H:27](/[CH:28]=[CH:29]/[C@@H:30]([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:23]2[CH2:22]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC=[N+]=[N-]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)O)S[C@H]2C[C@H]1O
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)CCCCC1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]2S1

Procedure:
An ethereal solution of diazodecane was added dropwise to a solution of 100 mg of (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15-dihydroxyprost-13-enoic acid (prepared as described in Example 2) in 5 ml of methylene chloride at room temperature with stirring until the starting material was not detected by thin layer chromatography on silica gel using a 2% v/v solution of methanol in ethyl acetate as developing solvent. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:1) as eluent to give 109 mg of the title compound having the following physical characteristics:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:33][CH3:34].O>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:33]([N:28]1[CH:29]=[C:9]2[C:10]([N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:27]1)[CH3:34].[CH2:33]([N:27]1[C:10]2=[N:11][C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]2[CH:29]=[N:28]1)[CH3:34]
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Product: CCn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21
Temperature: 100 °C
Reaction time: 48 h
Yield: 61 %
Yield: 9 %

Procedure:
A suspension of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.39 g, 0.8 mmol, obtained in example 1), KOH (0.05 g, 0.8 mmol) and crown ether 18-C-6 (0.01 g, 0.03 mmol) in toluene (3 mL) was heated to 100° C. for 2 h. A solution of iodoethane (0.18 g, 1.2 mmol) in toluene (1 mL) was added and stirred at 100° C. for 2 days. It was allowed to cool, water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.20 g of 2-ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 61%) and 28 mg of 1-ethyl-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 9%).