Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]([O:13]CC)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:30]#[N:31].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:29][N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]3[C:18](=[C:30]([NH2:31])[C:10]([C:11]([N:16]=3)=[O:13])=[C:2]3[NH:1][C:5]4[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:3]3)[CH:19]=2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Reactant: CN1CCN(c2ccc(N)c(C#N)c2)CC1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CN1CCN(c2ccc3c(c2)=C(N)C(=C2Nc4ccccc4N2)C(=O)N=3)CC1
Temperature: 80 °C

Procedure:
Ethyl 2-benzimidazol-2-ylacetate (1.1 eq) and 2-amino-5-(4-methylpiperazinyl)benzenecarbonitrile (1.0 eq) were dissolved in 1,2-dichloroethane, and then SnCl4 (11 eq) was added. The mixture was heated at reflux overnight. Upon cooling, the mixture was concentrated in vacuo. NaOH (3 M) was added to the solid, and the mixture heated at 80° C. for 0.5 hours. The solid was filtered and washed sequentially with H2O, CH2Cl2, and acetone. LC/MS indicated that the product was present in the acetone layer and the solid. These fractions were combined and purified by silica gel chromatography (5-10% MeOH in CH2Cl2 with 1% Et3N) to give the desired product. LC/MS m/z 375.4 (MH+), Rt 1.65 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:15][S:16][CH3:17].[OH-].[Na+].CC(OC)(C)C>O>[CH2:1]([O:8][C:9]([NH:12][CH:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCCC(N)C(N)=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CSCCC(NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
51 ml benzyloxycarbonyl chloride was dripped into a solution of 50 g (0.34 mole) DL-methionine amide in 200 ml water at 5-20° C., during which the pH was maintained at 7-9 with sodium hydroxide solution. A slimy precipitate formed immediately which became finely crystalline upon the addition of 200 ml MTBE. After the end of the addition the mixture was agitated 30 min further at room temperature. The precipitated, colorless crystals were then filtered off, washed with a little MTBE and recrystallized out of 700 ml toluene. After filtering off, washing with toluene and drying, 67 g (69%) Nαbenzyloxycarbonyl-DL-methionine amide with a melting point of 120-122° C. was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10]Br.[C-:12]#[N:13].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:12]#[N:13]
Reactant: [C-]#N
Reactant: Fc1cc(Br)c(CBr)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cc(Cl)c(F)cc1Br
Temperature: 25 °C

Procedure:
A mixture of 1 mmol of 1-bromo-2-bromomethyl-4-chloro-5-fluoro-benzene and 4 mmol of sodium cyanide in 3 ml of dry N,N-dimethylformamide is stirred at room temperature till complete conversion is observed. The reaction mixture is quenched by the addition of water and the mixture is extracted with tert-butyl-methyl ether. The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH:55][C@H:56]([CH3:61])[CH2:57][C:58](O)=[O:59]>CN(C)C=O>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:58](=[O:59])[CH2:57][C@H:56]([OH:55])[CH3:61])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)=[CH:27][N:28]=1
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@@H](O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@@H](C)O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 16 h
Yield: 35.8 %

Procedure:
5-(9-Isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (150 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (128 mg, 0.67 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and (R)-3-hydroxybutyric acid (70 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (62 mg, 36%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:17])=[CH:10][C:9]=1[OH:25].Cl[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1.C(O)(C(F)(F)F)=O>C(#N)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:17])=[CH:10][C:9]=1[O:25][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Reactant: CN1CCCC(CCl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NCc1ccc(Cl)c(OCC2CCCN(C)C2)c1)c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 78.6 %

Procedure:
A small vial was charged with 2 mL of acetonitrile, cesium carbonate (50 mg, 0.15 mmol), (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 83 (30 mg, 0.10 mmol), and 3-(chloromethyl)-1-methylpiperidine (16 mg, 0.11 mmol). The vial was placed in a reaction block and it was heated to 85° C. and stirred for 14 h. The vial was allowed to cool to room temperature and the solution was filtered through a syringe filter into a well of a 24 well plate. This plate was concentrated down in a Genevac vacuum instrument. The plate was by preparatory HPLC. The desired fractions were combined and lyophilized. The final product, (1R)—N-(4-chloro-3-((1-methylpiperidin-3-yl)methoxy)benzyl)-1-(3-chlorophenyl)ethanamine 84 (32 mg, 75% yield) was isolated as a white solid of the TFA salt. 1H NMR (400 MHz, d4-methanol) δ ppm 1.44-1.56 (m, 1H) 1.72 (m, 2H) 1.99 (m, 1H) 2.07 (m, 1H) 2.40 (m, 1H) 2.91-3.00 (m, 4H) 3.55 (m, 1H) 3.67-3.74 (m, 1H) 3.93-4.01 (m, 2H) 4.10 (dd, J=9.00, 4.11 Hz, 1H) 4.18 (d, J=13.11 Hz, 1H) 4.48 (q, J=6.85 Hz, 1H) 5.50 (s, 1H) 7.00 (d, J=8.22, 1H) 7.15 (s, 1H) 7.43-7.52 (m, 3H) 7.57 (s, 1H). Mass spectrum: calculated for C22H28C12N2O 407.4. found 408.4 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH:7][C:19]([NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20])=[O:5]
Reactant: NNC(=O)c1ccccc1Br
Reactant: O=C=Nc1ccccc1
Solvent: CO
Product: O=C(NNC(=O)c1ccccc1Br)Nc1ccccc1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
To a solution of 2-bromobenzohydrazide (500 mg, 2.3 mmol) in methanol (5 mL) was added phenyl isocyanate (280 mg, 2.4 mmol) at room temperature, and then the mixture was refluxed for one hour. The reaction mixture was cooled to room temperature. The precipitated solid was filtered off and dried under a reduced pressure to give 370 mg (48%) of the titled compound as a colorless solid.
Reaction SMILES: [NH2:1][C@@:2]1([C:11]([OH:13])=[O:12])[CH2:7][CH2:6][C@@H:5]2[C@H:3]1[C@H:4]2[C:8]([OH:10])=[O:9].O1CCOCC1.Cl[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22]>C(=O)(O)[O-].[Na+].O>[CH2:24]([O:23][C:21]([NH:1][C@@:2]1([C:11]([OH:13])=[O:12])[CH2:7][CH2:6][C@@H:5]2[C@H:3]1[C@H:4]2[C:8]([OH:10])=[O:9])=[O:22])[CH:25]=[CH2:26]
Reactant: N[C@@]1(C(=O)O)CC[C@H]2[C@H](C(=O)O)[C@H]21
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCOC(=O)N[C@@]1(C(=O)O)CC[C@H]2[C@H](C(=O)O)[C@H]21
Reaction time: 8 h
Yield: 67.3 %

Procedure:
(1S,2S,5R,6S)-2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (15.0 g, 73.9 mmol) was slowly dissolved in 250 mL of saturated sodium bicarbonate. After complete solution, dioxane (100 mL) and allyl chloroformate (15.7 mL, 147.8 mmol) were added at room temperature and the mixture was stirred overnight. The reaction mixture was diluted with water (100 mL) and washed with three portions of ethyl acetate. The organic layer was extracted once with saturated sodium bicarbonate. The combined aqueous layers were acidified to pH 1 with 4N hydrochloric acid and extracted with two portions of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide the title compound as an oil (13.4 g, 67% yield).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([N+:22]([O-])=O)[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[K+].[H][H]>CO.O.[Pd]>[C:1]1([S:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([NH2:22])[CH:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1N
Yield: 57.8 %

Procedure:
N-benzenesulfonyl-4-acetylamino-3-nitrobenzamide (12.67 g) was dissolved in 200 ml of methanol and 30 ml of water, and 7.59 g of potassium hydrogencarbonate were further added thereto. The mixture was hydrogenated in a hydrogen atmosphere using 2.53 g of 5% palladium on carbon as catalyst at 40° C. for 24 hours. The solid material was separated through filtration, and the filtrate was concentrated. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 4:1) to give 6.72 g of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O>[Cl:12][C:11]1[C:2]([NH:19][S:16]([CH2:13][CH2:14][CH3:15])(=[O:18])=[O:17])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CCCS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1Cl
Temperature: 150 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
In DMSO were dissolved 2,3-dichloroquinoxaline (5.00 g, 25.1 mmol) and propane-1-sulfonamide (3.09 g, 25.1 mmol). Potassium carbonate (3.47 g, 25.1 mmol) was added and the mixture was stirred at 150° C. for 1 hour. A 1% aqueous acetic acid solution was added to the reaction mixture and the mixture was stirred at room temperature for 3 hours. The resulting solid was separated by filtration, washed with water, and purified by slurrying in diisopropyl ether to give Compound A1 (6.01 g, 84% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:13][CH2:12]2)[CH:26]=[CH:25][N:24]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ccnc(Cl)n3)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2,4-dichloro-pyrimidine (18.6 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.9 mg (23%) of the title compound. MS (ISP): 377.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22](B(O)O)=[CH:23]3)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[CH:25][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:17][CH:18]=3)[CH:23]=2)=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: OB(O)c1ccc2ccc(-c3ccccc3)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cnc(-c2ccc3ccc(-c4ccccc4)cc3c2)c(C)n1
Yield: 65 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were placed 0.62 g of 2-chloro-3,5-dimethylpyrazine, 1.07 g of 7-phenylnaphthalene-2-boronic acid, 0.46 g of sodium carbonate, 0.020 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), 10 mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was irradiated with microwaves (2.45 GHz, 100 W) for 15 minutes, so that heating was performed. Then, the reaction container was cooled to 50° C. or less. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled, and the obtained residue was purified by silica gel column chromatography with a developing solvent of dichloromethane, whereby Hdm7p2npr, which is the pyrazine derivative to be produced, was found to be obtained (as a white powder in 65% yield). Note that the microwave irradiation was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). The synthesis scheme of Step 4 is illustrated in the following (d-5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].CN(C)C=O.[Br:23]N1C(=O)CCC1=O>O>[Br:23][C:7]1[C:2]([Cl:1])=[C:3]([C:16]#[N:17])[C:4](=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(Cl)ccn(-c2ccccc2Cl)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(Cl)c(Br)cn(-c2ccccc2Cl)c1=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a mixture of 4-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step D of Example (16.4 g) and N,N-dimethylformamide (124 mL) was added N-bromosuccinimide (16.5 g) at 60° C., and the mixture was stirred for 40 hr. The reaction mixture was cooled to room temperature, and poured into water. The resulting solid was collected by filtration, and washed with water to give the title compound (20.9 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8]>[Cl-].[Zn+2].[Cl-]>[CH2:11]([O:10][C:6]([CH:7]1[CH2:8][CH:2]2[O:1][CH:5]1[CH:4]=[CH:3]2)=[O:9])[CH3:12]
Reactant: C=CC(=O)OCC
Reactant: c1ccoc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCOC(=O)C1CC2C=CC1O2
Temperature: 3 °C
Reaction time: 27 h

Procedure:
A mixture of 300 g of furan (4.32 mol) and 611 g (6.05 mol) of ethyl acrylate was cooled to 3° C. in an ice bath under an inert atmosphere. 706 g (5.2 mol) of zinc chloride were added portionwise to the solution during 30 min, maintaining the temperature at between 10° C. and 20° C. After completed addition, the cooling bath was removed and the mixture was allowed to gradually heat up during 30 min to 50° C. by exothermy. It was subsequently kept at 50° C. during 27 h by means of an oil bath, then cooled to 40° C. and diluted with 200 ml of dichloromethane in order to reduce its viscosity. The solution was subsequently cooled to room temperature, poured on a mixture of 1.0 kg of crushed ice and 1.5 l of water and extracted. The aqueous phase was extracted with 2.5 l of ethyl acetate, and the combined organic phases were subsequently washed with 2.5 l of water, a solution of 109 g sodium bicarbonate in 2.5 l water, and 250 ml of brine. The organic phase was dried over sodium sulfate, filtered, evaporated at 45° C./1 mbar and dried at 40° C./0.06 mbar for 45 min, to yield 580 g (80%) of a 87:13 exo/endo mixture of product. Purity: 98% (HPLC; ISTD).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.O.O=[C:13]([CH3:16])[CH:14]=[O:15]>C(O)(=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[C:13](\[CH3:16])/[CH:14]=[O:15])=[CH:5][CH:4]=1
Reactant: CC(=O)C=O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: C/C(C=O)=N\Nc1ccc(F)cc1
Reaction time: 4 h

Procedure:
A mixture of (4-fluorophenyl)hydrazine HCl salt (2.0 g, 12.30 mmol), water (10 mL), and acetic acid (10 mL) was added with stirring to a 40% aqueous solution of 2-oxopropanal (9.41 mL, 61.5 mmol) for 20 minutes. Stirring was continued for 4 hours and the mixture was then filtered. The precipitate was washed with water and dried to afford the desired products. The crude was purified by silica gel flash column chromatography (1:50 to 1:10=EtOAc:CH2Cl2) to afford 2.05 g (93%) along with byproduct. 1H-NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.09 (br. s, 1H), 7.24 (m, 2H), 7.06 (t, 2H), 1.98 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −121.0.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][C:43]=1[OH:44])[C:8]([NH:10][C@H:11]([B:28]1[O:36][CH:35]2[C:30]([CH3:40])([CH:31]3[CH2:37][CH:33]([CH2:34]2)[C:32]3([CH3:39])[CH3:38])[O:29]1)[CH2:12][C:13]1[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:52][CH2:53][NH:54]C(=O)OC(C)(C)C.O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][C:43]=1[O:44][CH2:52][CH2:53][NH2:54])[C:8]([NH:10][C@H:11]([B:28]1[O:36][CH:35]2[C:30]([CH3:40])([CH:31]3[CH2:37][CH:33]([CH2:34]2)[C:32]3([CH3:39])[CH3:38])[O:29]1)[CH2:12][C:13]1[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1c(C[C@H](NC(=O)c2ccc(O)c(OC(C)=O)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C[C@H](NC(=O)c2ccc(OCCN)c(OC(C)=O)c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-((2R)-2-(3-acetoxy-4-hydroxybenzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (100 mg from step 1) in DMF (3 mL) was added K2CO3 (100 mg) followed by tert-butyl 2-bromoethylcarbamate (100 mg). The resulting reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with EtOAc three times. The combined organic phases were dried and concentrated to afford the product which was carried on to the next step without further purification.
Reaction SMILES: [CH:1]1[N:2]=[C:3]([NH2:22])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@@H:13]4[CH2:15][O:16][P:17]([OH:20])([O:19][C@H:12]4[C@H:11]3[OH:21])=[O:18])[C:5]=2[N:6]=1.[CH2:23]([N:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>O.C(O)C>[CH2:32]([NH+:27]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:33][CH2:34][CH3:35].[CH:1]1[N:2]=[C:3]([NH2:22])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@@H:13]4[CH2:15][O:16][P:17]([OH:20])([O:19][C@H:12]4[C@H:11]3[OH:21])=[O:18])[C:5]=2[N:6]=1
Reactant: CCCCN(CCCC)CCCC
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Solvent: CCO
Solvent: O
Product: CCCC[NH+](CCCC)CCCC

Procedure:
One gram of cAMP was dissolved in a mixture of 5 ml of water, 5 ml of ethanol and 1.5 ml of tri-n-butylamine. The solution was concentrated under reduced pressure at 30° to 40° C., and dried under reduced pressure using phosphorus pentoxide to afford tri-n-butylammonium salt of cAMP. The resulting cAMP salt was dissolved in 50 ml of dehydrated dimethyl formamide, and 5 ml of tri-n-butylamine and 2 ml of ethyl iodide were added. The reaction was performed at 80° C. for 3 hours.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:28][CH2:27][NH:26][CH2:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[CH2:28][CH2:27][N:26]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:25]2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: COc1ccc(C2CCNC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)C2)cc1
Temperature: 70 °C
Yield: 56.3 %

Procedure:
A solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (50 mg, 0.22 mmol) in ethanol (1 mL) was added to 3-(4-methoxyphenyl)pyrrolidine hydrochloride (71 mg, 0.33 mmol). The reaction mixture was treated with DIPEA (86 mg, 0.66 mmol) and the mixture was heated at 70° C. for 16 hours. The reaction mixture was evaporated to leave an involatile residue that was purified by preparative reverse phase chromatography to give 6-[3-(4-methoxyphenyl)pyrrolidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (45 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](F)[C:3]=1[Cl:10].[CH3:11][O-:12].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:12][CH3:11])[C:3]=1[Cl:10]
Reactant: C[O-]
Reactant: Fc1cc(Cl)cc(Br)c1Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)cc(Br)c1Cl
Temperature: 25 °C
Yield: 97.7 %

Procedure:
1-Bromo-2,5-dichloro-3-fluorobenzene (40 g, 160 mmol) and sodium methoxide (44.3 g, 820 mmol) were stirred in methanol (500 ml) at reflux for 16 hours. The reaction was cooled to ambient temperature then quenched with water (500 ml). The mixture was extracted with diethyl ether (3×300 ml), dried over Na2SO4 and evaporated to afford the title compound as a white solid (40 g).
Reaction SMILES: C[O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[C:8](=[O:23])[NH:9][C:10](=[O:22])[N:11]([C@H:13]2[O:18][C@@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@@H:14]2[F:21])[CH:12]=1)=[O:4].[OH-].[Na+].CCOCC>O>[C:3](/[CH:5]=[CH:6]/[C:7]1[C:8](=[O:23])[NH:9][C:10](=[O:22])[N:11]([C@H:13]2[O:18][C@@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@@H:14]2[F:21])[CH:12]=1)([OH:4])=[O:2]
Reactant: COC(=O)/C=C/c1cn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2F)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)/C=C/c1cn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2F)c(=O)[nH]c1=O
Yield: 83.7 %

Procedure:
Compound 15 (560 mg, 1.70 mmol) was stirred in a NaOH solution (2 N, 5 mL) at rt for 1.5 h, then diluted with water (20 mL) and neutralized with Dowex 50 w×8 (H+) resin. The mixture was filtered and washed with water and acetone. The combined filtrate was evaporated to dryness to give a pale-white solid, which was trituated with Et2O to give 16 as an off-white solid (450 mg, 84%): UV (MeOH) λmax 298.0,0 267.0 mn (sh); 1H NMR (CDCl3) δ 11.70 (s, 1H, NH, D2O exchangeable), 8.49 (s, 1H, H-6, j=8.1 Hz 7.22 (d, 1H, Ha, J=15.9 Hz), 6.73 (d, 1H, Hb, J=15.9 Hz), 5.89 (d, 1H, H-1′, J1′,F=16.8 Hz), 5.86 (d, 1H, 3′-OH, D2O exchangeable), 5.62 (bs, 1H, 5′-OH, D2O exchangeable), 5.05 (dd, 1H, H-2′, J2′,F=52.9 Hz), 4.18 (dm, 1H, H-3′, J3′,F=24.1 Hz), 3.89 (m, 3H, H-4′), 3.74 (m, 2H, H-5′).