Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:27].[Na+].[CH3:29]O>>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([O:27][CH3:29])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(F)c3)nc2N1C1CCCC1
Reactant: [OH-]
Agent: [Na+]
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(OC)c3)nc2N1C1CCCC1
Yield: 60 %

Procedure:
To a solution of (R)-8-cyclopentyl-7-ethyl-2-(2-fluoropyridin-4-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 16, 200 mg, 0.56 mmol) in 3 mL of CH3OH, aqueous NaOH (1.4 mL of 2N, 2.8 mmol) was added, the mixture was heated to reflux overnight, concentrated under reduced pressure, then extracted with EtOAc. The combined organic phase was dried with Na2SO4, concentrated under reduced pressure and chromagraphed (PE:EA=1:1) to give the title compound as a yellow solid (120 mg, 60% yield). 1H NMR (CDCl3) δ: 8.25 (d, 1H), 7.97 (s, 1H) 7.76 (m, 1H), 7.64 (s, 1H), 4.47 (m, 1H), 4.31 (m, 1H), 4.0 (s, 3H), 3.39 (s, 3H), 2.2-1.6 (m, 10H) and 0.88 ppm (t, 3H); LCMS: 368.2 m/z (M+H)+; ret. Time: 1.77 min (Analytical Method E).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.[CH3:45][Si:46]([C:49]#[CH:50])([CH3:48])[CH3:47]>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.[Cu]I.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:50]#[C:49][Si:46]([CH3:48])([CH3:47])[CH3:45])=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1C#C[Si](C)(C)C

Procedure:
Microwave vial was charged with 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (103 mg, 0.368 mmol), Pd(PPh3)2Cl2 (0.06 eq), CuI (0.06 eq), PPh3 (0.2 eq), Et3N (15 eq), (trimethylsilyl)acetylene and DMF (0.25 ml). The vial was irradiated in microwave synthesizer at 120° C. for 25 min. The contents of the vial were filtered through a Celite pad, which was washed out thoroughly with EtOAc. The filtrate was evaporated, and the residue was purified by column chromatography to 3-(6-trifluoromethyl-2-trimethylsilanylethynyl-pyridin-3-yl)-acrylic acid ethyl ester (58 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[N:17]([O-])=O.[Na+].[OH-].[Na+]>Cl>[F:16][C:3]1[C:2]([NH:1][NH2:17])=[CH:15][C:6]2[N:7]([CH2:12][C:13]#[CH:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: O=N[O-]
Reactant: C#CCN1C(=O)COc2cc(F)c(N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#CCN1C(=O)COc2cc(F)c(NN)cc21
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A suspension of 6-amino-7-fluoro-4-propargyl-2H1,4-benzoxazin-3(4H)-one (13.0 g) in conc. hydrochloric acid (70 g) was cooled to 0° to 5° C., and a saturated solution of sodium nitrite (5.1 g) was dropwise added thereto at 0° to 5° C., followed by stirring for 2 hours. The resultant mixture was cooled to -30° C., and a solution of anhydrous stannous chloride (28.1 g) in conc. hydrochloric acid (30 g) was added thereto at once, followed by stirring at 0° to 5° C. for 3 hours. Celite (50 g) was added to the reaction mixture, which was neutralized with 10 % aqueous sodium hydroxide solution below 10° C. The resulting mixture was filtered, and the filtrate was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-on-6 -ylhydrazine (8.2 g).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([C:27]([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:2]([O-:1])=[N:3]2)=[O:28])[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCOCc1cccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCOCc1cccc(C(=O)n2n[n+]([O-])c3ccccc32)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
To a suspension of 1-Hydroxybenzotriazole (0.283 g) and 6-octyloxymethylpicolinic acid (0.505 g) in dichloromethane (15 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.473 g), and stirred for 3 hours at ambient temperature. The reaction mixture was poured into water. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-(6-Octyloxymethylpicolinoyl)benzotriazole 3-oxide (737 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[CH2:15]([NH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26].[OH-:28].[K+]>C(Cl)CCl>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:27][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:28][C:2]([F:1])([F:13])[F:14])=[CH:5][CH:6]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: [OH-]
Reactant: NCCCCCCCCCCCN
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCCCCCCCNC(=O)c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
m.p. 141.5°-142.5° C., 22.2 g., was prepared as in Example 1 using 24.8 g. of 4-trifluoromethoxybenzoyl chloride in 100 ml. of ethylene dichloride, 9.3 g. of 1,11-undecanediamine, 120 ml. of 10% aqueous potassium hydroxide solution, 400 ml. of ethylene dichloride and recrystallization from acetonitrile.
Reaction SMILES: C(OC([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.[Cl:28]CCl>>[ClH:28].[ClH:28].[NH2:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1ccc(OCCN2CCCC2)cc1
Reactant: ClCCl
Product: COC(=O)C(N)c1ccc(OCCN2CCCC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of methyl [(tert-butoxycarbonyl)amino]{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate was dissolved in dichloromethane, hydrogen chloride gas was bubbled in for 5 minutes. The reaction was then stirred at room temperature for 0.5 h. The solvent was removed to provide 1.80 g of methyl amino{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate dihydrochloride as a light pink solid Yield 100%. mp 80° C. (d). Electrospray Mass Spec 279.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][CH:15]=[N:14][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]1([C:7]2[N:6]=[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]3=[N:3][C:2]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1nc2cccnc2nc1-c1ccccc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc3cccnc3nc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
2-Chloro-3-phenylpyrido[2,3-b]pyrazine (step 3) (175 mg, 0.724 mmol) in dry dioxane (4 ml) under nitrogen was treated with p-tolylboronic acid (108 mg, 0.797 mmol), potassium carbonate (200 mg, 1.448 mmol) in water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (41.8 mg, 0.036 mmol). The resulting mixture was heated using microwave radiation at 150° C. for 1 hour. After cooling to RT, the mixture was diluted with water (100 ml) and extracted with DCM (×3). The combined organic extracts were washed with brine, dried over MgSO4 and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica eluting with 0-30% EtOAc/iso-hexane to afford the title compound as a yellow solid;
Reaction SMILES: [CH:1](Cl)(Cl)Cl.[OH-:5].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].Cl>O>[C:7]([C:11]1[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=1[OH:17])[CH:1]=[O:5])([CH3:10])([CH3:8])[CH3:9]
Reactant: ClC(Cl)Cl
Reactant: [OH-]
Reactant: CC(C)(C)c1ccccc1O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(C=O)ccc1O
Reaction time: 1 h

Procedure:
Chloroform (95 gm) was added dropwise with mechanical stirring to a mixture of sodium hydroxide (120 gm), water (120 gm) methanol (50 ml) and o-tert-butylphenol (100 gm) over 2 hours at 50° C. The mixture was stirred at 50° for 1 hour and then poured into water (600 ml) and acidified to pH5 with concentrated hydrochloric acid. The oily layer that formed was collected and steam distilled. The residue from the steam distillation was taken into chloroform (200 ml) and extracted with 2N sodium hydroxide. The basic extracts were acidified and the product formed was crystallised from petroleum ether to give 3-tert-butyl-4-hydroxybenzaldehyde as colourless prisms m.p. 142°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:25].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>C1COCC1>[Br:25][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 1.5 h

Procedure:
The ketone from step 1 (0.32 g, 0.868 mmol) was dissolved in THF (9 ml), and phenyltrimethylammonium tribromide (PTT) (0.368 g, 0.868 mmol) was added as a solid leaving an orange solution which began to deposit a white solid immediately. Stirring for 1.5 hours leaves a colorless mixture to which water (5 ml) was added. THF was then evaporated and the resulting aqueous mixture was extracted with ethyl acetate. Drying over Na2SO4 and evaporation leaves a white crystalline solid (90% desired mono-brominated material by LC-MS, 5% starting material, 5% dibrominated) suitable for the next step. LC-MS (ES−): 436, 438 m/e.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:1]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#Cc1cccc(N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N(c1cccc(C#N)c1)[Si](C)(C)C
Yield: 96.8 %

Procedure:
About 5.87 g of 3-aminobenzonitrile, 11.57 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 25.41 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 12 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 3-[bis(trimethylsilyl)amino]benzonitrile (3-BTMSABZN) as a brown oil (12.62 g, 97% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.00 (multiplet, 1H, aromatic proton), 6.81 (multiplet, 1H, aromatic proton), 6.67 (multiplet, 1H, aromatic proton), 6.59 (multiplet, 1H, aromatic proton), −0.10 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:17][CH2:18]C(C1C=CC=CC=1)=O.C[O:28]C1C=CC(C=O)=CC=1.[OH-].[K+]>C(O)C>[OH:28][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH:7]=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: O=C(CO)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.6 %

Procedure:
The synthesis of the chalcone compounds of the present invention was carried out by a Claisen-Schmidt condensation. Taking chalcone compound 1 as the example, a mixture of 2-hydroxyacetophenone (273.6 mg, 2.01 mmol), 4-methoxybenzaldehyde (279.1 mg, 2.05 mmol), potassium hydroxide (KOH, 50% w/v, 2 ml) and ethanol (100% v/v, 20 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and then partitioned with ethyl acetate (EtOAc) and H2O. The organic layer was then evaporated, and the residue was purified using column chromatography (silica gel: 70-230, Merck; n-hexane-EtOAc, 15:1, Rf=0.2) to give 2-hydroxy-4′-methoxychalcone (chalcone compound 1, 273.6 mg; yield, 53.6%). The purity of compound 1 was greater than 95%, which was determined by high-performance liquid chromatography (HPLC).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C@@H:10]1[O:11]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][CH:10]1[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: OC1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
Methyl 2,3,6-tri-O-benzyl-α-D-galactopyranoside (5 g, 10.775 mmol) was dissolved at 0° C. in a 9:1 mixture of trifluoroacetic acid and water (50 mL) [N. Morishima, S. Koto, M. Oshima, A. Sugimoto and S. Zen, Bull Chem. Soc. Jpn 56, 2849 (1983)]. The mixture was stirred overnight at 0° C. The solvents were evaporated under reduced pressure without heating. The residue was dissolved in ethyl acetate and washed successively with sodium bi-carbonate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a graded mixture of ethyl acetate and hexane afforded 2,3,6-tri-O-benzyl-D-galactopyranose (3.927 g, 81%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:5][CH:4]=1.[Br:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[Br-:14].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]2[CH:13]=[CH:12][N:11]([CH2:15][CH2:16][CH3:17])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCBr
Reactant: COc1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Product: CCCn1cc[n+](-c2ccc(OC)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure; 4.48 mmol (0.700 g) 1-(4-methoxyphenyl)imidazole and 4.93 mmol (0.606 g, 0.45 ml) 1-bromopropane are dissolved in 5 ml THF and heated for 5 h to 80° C.
Reaction SMILES: Cl.[CH:2]1([NH2:5])[CH2:4][CH2:3]1.[Na].[C:7]([NH:9][C:10](N)=[NH:11])#[N:8]>C(O)CCC.O>[C:7]([NH:9][C:10]([NH:5][CH:2]1[CH2:4][CH2:3]1)=[NH:11])#[N:8]
Reactant: NC1CC1
Reactant: N#CNC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCCCO
Solvent: O
Product: N#CNC(=N)NC1CC1
Yield: 62 %

Procedure:
9.36 g (0.1 mole) of cyclopropylamine hydrochloride and 8.9 g (0.1 mole) of the sodium salt of cyanoguanidine are suspended in 100 ml of n-butanol and 8 ml of water. The mixture is heated under reflux for 2 hours. The suspension is filtered and the filter cake is washed with 100 ml of n-butanol. The filtrate is evaporated under reduced pressure. The residual oil is taken up in 300 ml of acetonitrile. The mixture is heated to reflux, filtered hot and the filter cake is washed with acetonitrile. The filtrate is evaporated off and the oil obtained crystallizes slowly. 7.7 g of N-cyano-N'-cyclopropylguanidine are obtained. Yield: 62%. M.P.: 106° C. (isopropyl alcohol/diethyl ether).
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](F)[C:8]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.[H-].[Na+]>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:8]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1
Reactant: CC1(C)COC(c2c(F)cccc2F)=N1
Reactant: CC(C)(C)S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)COC(c2c(F)cccc2SC(C)(C)C)=N1
Yield: 82.9 %

Procedure:
A mixture of 2-methyl-2-propanethiol (2.7 g, 30 mmol), the compound of example g (3.17 g, 15 mmol), and NaH (0.79 g, 33 mmol) in THF (100 mL) was stirred at RT for 1d, then at reflux for 1d. This was then quenched with sat aq NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 1:4 EtOAc/hexanes to afford 3.5 g of 2-[2-fluoro-6-(1,1-dimethylethylthio)phenyl]-4,4-dimethyl-2-oxazoline as a yellow oil, an 83% yield.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)O1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:29])[C:26]=1[CH:27]=[O:28].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.C(OCC)(=O)C>[F:29][C:25]1[CH:24]=[N:23][CH:22]=[C:21]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)[C:26]=1[CH:27]=[O:28]
Reactant: O=Cc1c(F)cncc1Br
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1c(F)cncc1-c1ccc2c(c1)COC2=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-isobenzofuran-1-one (210 mg, 0.809 mmol) in DMF (4 mL) was added 3-bromo-5-fluoro-pyridine-4-carbaldehyde (150 mg, 0.735 mmol) and 2M aqueous sodium carbonate (0.735 mL, 1.471 mmol). The reaction mixture was flushed and evacuated with N2 twice followed by the addition of PdCl2(dppf).CH2Cl2 adduct (30.0 mg, 0.037 mmol). The reaction mixture was stirred at 100° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with water twice. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford 3-fluoro-5-(1-oxo-1,3-dihydro-isobenzofuran-5-yl)-pyridine-4-carbaldehyde, which was taken into the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)=[O:4].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21])[CH2:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CCN2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Yield: 79.8 %

Procedure:
To a solution of 10 (0.28 g, 1.58 mmol) in pyridine (2 mL), benzenesulfonyl chloride (0.40 ml, 3.16 mmol) was added. The reaction mixture was refluxed overnight. The mixture was then purified by silica gel chromatography (EtOAc:n-hexane=1:3) to afford 11 (0.40 g). 1H NMR (500 MHz, CDCl3): δ 2.99 (t, J=8.6 Hz, 2H), 3.87 (s, 3H), 3.97 (t, J=8.6 Hz, 2H), 7.45-7.48 (m, 2H), 7.56-7.59 (m, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.75 (s, 1H), 7.82 (d, J=7.7 Hz, 2H), 7.90 (d, J=7.9 Hz, 1H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C@H:15]([N:19]2[CH2:22][C:21]4([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH2:20]2)[CH2:14][CH2:13]3)[CH:5]=1.C(N(CC)CC)C.Cl.[CH3:36][C:37]1[S:41][C:40]2=[N:42][C:43]([CH2:45][C:46](O)=[O:47])=[CH:44][N:39]2[CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[CH3:36][C:37]1[S:41][C:40]2=[N:42][C:43]([CH2:45][C:46]([N:25]3[CH2:26][CH2:27][C:21]4([CH2:22][N:19]([C@H:15]5[C:16]6[C:12](=[CH:11][C:10]([C:6]7[CH:5]=[C:4]([CH3:3])[N:9]=[CH:8][N:7]=7)=[CH:18][CH:17]=6)[CH2:13][CH2:14]5)[CH2:20]4)[CH2:23][CH2:24]3)=[O:47])=[CH:44][N:39]2[CH:38]=1
Reactant: Cc1cn2cc(CC(=O)O)nc2s1
Reactant: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)Cc4cn5cc(C)sc5n4)CC3)C2)ncn1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 2-[(R)-5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane dihydrochloride (540 mg, 1.22 mmol) in 10 mL of dichloromethane was added triethylamine (492 mg, 4.90 mmol). Once the mixture became a homogenous solution, it was added to a solution of 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetic acid hydrochloride (251 mg, 1.28 mmol) in 3 mL of dichloromethane. The mixture was stirred for 5 minutes and HBTU (462 mg, 1.22 mmol) in 2 mL of DMF was added. The reaction was stirred at room temperature for 1.5 hours. The reaction was quenched by the addition of 10 mL of NaHCO3 and was diluted with 50 mL of dichloromethane. The organic layer was washed with saturated brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was dissolved in 5 mL of CH3CN and the solution was heated to 100° C. for 1 hour with stirring. The mixture was cooled to room temperature and the resulting solids were vacuum filtered to afford the desired product as an off white powder (428 mg, 69%). MS (ES+) 513.5 (M+H)+. 1H NMR (CD3OD) δ 1.70-1.74 (m, 4H), 1.88-1.96 (m, 1H), 2.27-2.34 (m, 2H), 2.40 (s, 3H), 2.58 (s, 3H), 2.86-2.97 (m, 1H), 3.11-3.15 (m, 1H), 3.31-3.34 (m, 3H), 3.52-3.55 (m, 4H), 3.78 (s, 2H), 4.05-4.09 (m, 1H), 7.33 (s, 2H), 7.55 (d, 1H), 7.78-7.79 (m, 1H), 7.94-8.03 (m, 2H), 8.93 (s, 1H). [α]D20=+45.3 deg (c=2.5 mg/mL, MeOH).