Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[S:8][C:9]([Cl:13])=[C:10]([Cl:12])[CH:11]=1)=[O:6])C.Cl.C(Cl)Cl>CC(C)=O.O>[Cl:12][C:10]1[CH:11]=[C:7]([C:5](=[O:6])[C:4]([OH:14])=[O:3])[S:8][C:9]=1[Cl:13]
Reactant: CCOC(=O)C(=O)c1cc(Cl)c(Cl)s1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(O)C(=O)c1cc(Cl)c(Cl)s1
Temperature: 25 °C

Procedure:
A solution of (4,5-dichlorothiophen-2-yl)-oxo-acetic acid ethyl ester (2.53 g, 10.0 mmol) in acetone (15 ml), water (5 ml), and conc. HCl (20 ml) was stirred under reflux for 2 hr. The reaction mixture was then allowed to cool to ambient temperature and was poured into CH2Cl2 and water. The organic layer was dried over Na2SO4 and concentrated under vacuum. Crystallization of the residue from dichloromethane provided pure (4,5-dichlorothiophen-2-yl)-oxo-acetic acid as a yellow solid (557 mg, 25%). MS (M−H)−: 222.78; 1H NMR (300 MHz, DMSO-d6) δ8.06 (s).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][CH:24]([F:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][CH:24]([F:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:1][C@@H:2]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[C@@H:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:36])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(C(F)F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(C(F)(F)F)cc1)[C@H](O)c1ccc(F)cc1)c1ccc(C(F)F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) were added 4-(difluoromethyl)-1-naphthalenecarboxylic acid (213 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the-title compound (410 mg, 83%).
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:20][C:21](OC(C)=O)=[O:22]>N1C=CC=CC=1>[C:21]([O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:22])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1

Procedure:
A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (20 mg) in anhydrous pyridine (200 μl) and Ac2O (100 μl) is kept at 0° C. for 8 hrs. The mixture is evaporated in vacuo and the residue dissolved in EtOAc. This solution is washed with pH 2 phosphate buffer, 5% NaHCO3, and brine, dried with MgSO4, filtered, and evaporated i.v. to provide benzyl 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate. By substituting Ac2O with ##STR25## in Method B, various 3-acyloxy derivatives are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13].C(N(CC)CC)C>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: CC(=O)C(C)Br
Reactant: Cc1cnc(N)c(N)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N)c2nc(C)c(C)n2c1
Yield: 37.5 %

Procedure:
To a solution of 2,3-diamino-5-methylpyridine (2.0 g, 16 mmol) in ethanol (100 ml) was added 3-bromo-2-butanon (2.4 g, 16 mmol). The reaction mixture was refluxed for 16 h. An additional amount of 3-bromo-2-butanon (1.0 g 6.7 mmol) and triethylamine (1.0 g, 9.9 mmol) were added and the mixture was refluxed for 2 h. The ethanol was evaporated under reduced pressure and the residue was treated with methylene chloride and a solution of bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The oily residue was purified by column chromatography on silica gel, using methanol:methylene chloride (1:20) as eluent to give the desired product (1.05 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[N-:11]=[N+:12]=[N-:13].[Na+].C(O)(=O)C.[OH-].[Na+]>CCOCC.C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([C:7]2[NH:13][N:12]=[N:11][N:8]=2)[CH:9]=1
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CCOCC
Solvent: CC(=O)O
Product: Fc1ccc(Cl)cc1-c1nnn[nH]1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A mixture of 5-chloro-2-fluoro-benzonitrile (2.84 g, 0.01823 mol), butanol (15 mL), sodium azide (1.543 g, 0.0237 mol), acetic acid (1.36 mL, 0.0237 mol) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, additional 1.543 g sodium azide added, and the reaction mixture refluxed for additional 24 hours. After cooling to room temperature, Et2O (100 mL) and 10% aqueous NaOH (200 mL) were added sequentially. The mixture was vigorously stirred. The aqueous layer was separated, cooled with ice-methanol bath (−15° C.) and acidified to pH 1 with conc. HCl. A gray solid precipitated. The solid was dried in vacuum at 50° C. to give 1.76 g (49%) of 5-(5-chloro-2-fluoro-phenyl)-1H-tetrazole: mp partial melt at 110° C., complete melting at 124° C.);
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.O1CCCC1CO.O.[NH2:28][NH2:29]>O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:28][NH2:29])=[O:15])=[CH:12][CH:11]=1
Reactant: COCCCCCCOc1ccc(C(=O)OC)cc1
Reactant: NN
Solvent: OCC1CCCO1
Solvent: O
Product: COCCCCCCOc1ccc(C(=O)NN)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-(6-methoxy-n-hexyloxy)benzoate (17.05 g) in 1:1 tetrahydrofuran-methanol (300 ml) was treated with hydrazine monohydrate (66 ml) and refluxed for 15 hours then cooled to room temperature. The reaction mixture was poured into water and the resulting precipitate collected by filtration, washed thoroughly with water then dried under hi-vacuum at 50° C. to give 4-(6-methoxy-n-hexyloxy)benzohydrazide (15.63 g) as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)=[NH:4].Cl.N([O-])=O.[Na+].[F:23][C:24]1[CH:30]=[CH:29][C:27](N)=[CH:26][C:25]=1[CH3:31]>O1CCOCC1.O.C(O)C>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])=[CH:26][C:25]=1[CH3:31]
Reactant: CS(=O)(=O)NCCNc1nonc1C(=N)NO
Reactant: Cc1cc(N)ccc1F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=NO)c2nonc2NCCNS(C)(=O)=O)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
N-Hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (35 mg, 0.13 mmol) was stirred in 1,4-dioxane (2 mL) and 6 N hydrogen chloride solution (4 mL) was added. The solution was cooled to 0° C. and a solution of sodium nitrite (11 mg, 0.16 mmol) in water (3 mL) was slowly added. The mixture was stirred for 1 hour at 0° C. and evaporated. Dry 1,4-dioxane (2 mL) was added and the mixture evaporated two more times. A solution of 4-fluoro-3-methylaniline [Aldrich, product #559415] (25 mg, 0.20 mmol) in ethanol (2 mL) was added and the mixture was stirred for 1 hour. Purification by preparative LCMS (pH 2) gave the desired compound (17 mg, 27%). LCMS calculated for C13H18FN6O4S (M+H)+: m/z=373.1. 1H NMR (400 MHz, DMSO-d6): δ 11.25 (s, 1H), 8.61 (s, 1H), 7.18 (m, 1H), 6.91 (m, 1H), 6.72 (m, 1H), 6.58 (m, 1H), 6.24 (s, 1H), 3.32 (m, 2H), 3.11 (m, 2H), 2.89 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C@:5]12[O:12][C@:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=4)[CH:14]=3)([O:10][CH2:11]1)[C@H:8]([O:30]CC1C=CC=CC=1)[C@@H:7]([O:38]CC1C=CC=CC=1)[C@@H:6]2[O:46]CC1C=CC=CC=1)[OH:4].ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[NH2:1][CH2:2][CH:3]([C@:5]12[O:12][C@:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=4)[CH:14]=3)([O:10][CH2:11]1)[C@H:8]([OH:30])[C@@H:7]([OH:38])[C@@H:6]2[OH:46])[OH:4]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CN)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CN)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.6 %

Procedure:
To a solution of 2-amino-1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 10b (205 mg, 0.28 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 25 mL) were added o-dichlorobenzene (0.16 mL, 1.42 mmol) and 10% Pd/C (32 mg, 0.03 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filter cake was washed with a tetrahydrofuran/methanol mixture (v/v=1/4, 10 mL×2) and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 10 as colorless oil (36 mg, 25.7%, HPLC: 98.0%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 466.0[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.73 (s, 2H), 7.42 (m, 2H), 7.31 (m, 1H), 7.09 (m, 2H), 6.82 (m, 2H), 5.52 (d, 2H), 5.02 (d, 2H), 3.95 (m, 5H), 3.72 (d, 1H), 3.61 (d, 1H), 3.48 (m, 2H), 3.14 (m, 1H), 2.69 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.O.CO>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CSc1ccc(B(O)O)c(F)c1
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: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CSc1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 100 °C
Yield: 54.2 %

Procedure:
A mixture of [2-fluoro-4-(methylthio)phenyl]boronic acid (5 g, 26.9 mmol), 5-bromo-2-pyrazinamine (4.7 g, 26.9 mmol), Pd(PPh3)4 (0.62 g, 0.54 mmol), 2M Na2CO3 (25 mL), 1,4-dioxane (50 mL), and methanol (25 mL) was stirred and heated at 100° C. for 5 h, then at 25° C. overnight. The reaction was charged with water (300 mL) and extracted with EtOAc (100 mL). The organic extracts were dried over MgSO4, filtered, and concentrated to dryness to give a tan solid. The solid was triturated with CH2Cl2, filtered, and the solid air-dried to afford 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinamine (3.43 g, 54% yield) as a tan solid. The filtrate was concentrated to dryness to give additional solid (2.5 g) that was purified by SiO2 chromatography (0-25% EtOAc/hexanes, 20 min. gradient; then 25% EtOAc/hexanes, 60 min.; 100 g column) to afford additional product (940 mg, 15% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.10 (d, 1H, J=1.4 Hz), 7.83 (t, 1H, J=8.3 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.9 Hz), 7.00 (dd, 1H, Ja=12.1 Hz, Jb=1.9 Hz), 4.80 (bs, 2H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20][Si](C(C)(C)C)(C)C)=[C:13]([O:18][CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:20])=[C:13]([O:18][CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CN(C(=O)OC(C)(C)C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1O)CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C

Procedure:
A 6.0 g portion of 3,4-dihydro-7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-methoxy-2(1H)-isoquinolinecarboxylic acid-1,1-dimethylethyl ester is dissolved in 30 mL tetrahydrofuran and cooled to 0° C. To this is added 22.8 mL of a 1.0M solution of tetrabutylammonium fluoride, while stirring. The reaction mixture is brought to room temperature, and stirred for three hours. The reaction is quenched with 10 mL saturated sodium bicarbonate solution and 10 mL water, followed by the addition of 20 mL diethyl ether. After separating the layers, the aqueous phase is extracted with 2×20 mL diethyl ether. The combined organic layers are washed with 20 mL brine, and dried over magnesium sulfate. Following removal of the solvent, the product is purified by silica gel chromatography (eluting with 2:1 hexane/ethyl acetate) to produce 4.15 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][S:3]1.Cl.[NH2:15][OH:16].N1C=CC=CC=1>C(O)C>[CH3:1][C:2]1([CH3:13])[C:11](=[N:15][OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][S:3]1
Reactant: CC1(C)SCc2ccccc2C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC1(C)SCc2ccccc2C1=NO
Yield: 55.7 %

Procedure:
A mixture of 10.0 g of 3,3-dimethylisothiochroman-4-one, 8.0 g of hydroxylamine hydrochloride, 18 ml of pyridine and 60 ml of ethanol is heated at reflux for 60 hours. The cooled reaction mixture is concentrated by evaporation, then toluene is added and the mixture is again concentrated by evaporation. The residue is boiled up in dichloromethane, cooled and filtered. The filtrate is concentrated by evaporation and the residue is chromatographed with silica gel (eluant: ethyl acetate/hexane 1:12). Concentration of the eluate by evaporation yields 6.0 g of 3,3-dimethylisothiochroman-4-oneoxime in the form of yellow crystals having a melting point of 83°-84° C.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C.[CH2:8]([C:15]#[N:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:9]1([CH2:8][C:15]([NH2:2])=[NH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [NH4+]
Reactant: N#CCc1ccccc1
Agent: C
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)Cc1ccccc1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
Ammonium chloride (2.9 g, 54 mmol) was suspended in 20 mL of anhydrous toluene, stirred under argon, and cooled to 0° C. To this suspension was added 25 ml (50 mmol) of a 2M solution of trimethylaluminum in toluene. The reaction was allowed to warm to room temperature and stirring continued until the evolution of methane ceased (˜1 hour). Then, 3.46 mL (30 mmol) of benzyl cyanide in 10 mL of anhydrous toluene was added and the reaction was heated to 80° C. for 18 hours. The reaction was then cooled to room temperature and slowly poured into a slurry of 15 g of silica gel in 50 mL of chloroform and stirred for 5 minutes. The silica was filtered and washed with methanol. The filtrate and washings were combined and reduced to a volume of ˜15 mL and refiltered. Then, 18 mL (54 mmol) of a 3N solution of methanolic HCl was added to the filtrate followed by 400 mL of diethyl ether. After 16 hours of stirring at room temperature, a white precipitate formed and was subsequently filtered. This crude solid was then added to 150 mL of a 4:1 mixture of isopropanol-acetone and stirred for an additional 16 hours at room temperature. Undissolved ammonium chloride was then removed by filtration and the filtrate reduced to ˜15 mL, and 300 mL of diethyl ether was added and the mixture stirred for ˜1 hour. The white precipitate was then filtered and dried to yield 3.7 g (72%) of the objective compound as the hydrochloride salt. MS: (ESI, Pos) m/z 157.9 (M+23) 1H NMR (500 MHz, DMSO-d6): δ (ppm) 9.06 (br.d, 3H), 7.49 (d, 2H), 7.36 (t, 2H), 7.31 (t, 1H), 3.74 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:24]([O:26][CH:27]1[CH:34]2[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:36][CH:28]1[CH2:29]3)[CH2:33]2)=[O:25].C(Cl)Cl.Cl>>[C:9]([O:8][C:7]([NH:6][CH2:5][CH:3]1[CH2:4][N:1]([C:24]([O:26][CH:27]2[CH:28]3[CH2:36][CH:32]4[CH2:31][CH:30]([CH2:35][CH:34]2[CH2:33]4)[CH2:29]3)=[O:25])[CH2:2]1)=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Reaction time: 0.08 h
Yield: 23 %

Procedure:
A vial was charged with tert-butyl azetidin-3-ylmethylcarbamate (25 mg, 0.12 mmol), i-Pr2NEt (31 μL, 0.17 mmol) and a flea stir bar. A solution of 2-adamantyl chloroformate in CH2Cl2 (1.5 mL, 17 mg mL−1, 0.12 mmol) was added. The mixture was stirred overnight at rt. A 10-mL ChemElut cartridge (Varian Inc. catalog number 12198007) was wetted with 5% aq HCl (5 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford the title compound (10 mg, 23%). 1H NMR (CDCl3) δ 1.42 (s, 9H), 1.5-2.0 (14H), 2.76 (m, 1H), 3.35 (m, 2H), 3.67 (m, 2H), 4.03 (m, 2H), 4.68 (m, 1H), 4.78 (s, 1H); LC-MS Method 1 tR=2.08 min, m/z=387, 365, 309.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]([CH3:9])[CH3:8])[N:3]=1.Cl.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH:20]([C:25](OC)=O)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-:29].[NH4+]>C(O)(=O)C>[CH2:11]([N:18]1[CH2:23][C:22](=[O:29])[C:21]2[N:1]=[C:2]3[N:3]=[C:4]([N:7]([CH3:9])[CH3:8])[NH:5][N:6]3[CH2:25][C:20]=2[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)c1n[nH]c(N)n1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: [OH-]
Agent: Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: CN(C)C1=NC2=NC3=C(CN(Cc4ccccc4)CC3=O)CN2N1
Reaction time: 2 h
Yield: 58 %

Procedure:
A mixture of 5.09 g (0.04 mole) of 5-amino-3-dimethylamino-1H-1,2,4-triazole, 11.35 g (0.04 mole) of 1-benzyl-3-carbomethoxy-4-piperidone-hydrochloride and 40 ml of acetic acid is heated to boiling for 2 hours. The reaction mixture is allowed to stand at room temperature for 16 hours. To the mixture 70 ml of a 25% ammonium hydroxide solution are added, the precipitated crystals are filtered and washed with hot methanol. The product is heated to boiling with 20 ml of methanol for 10 minutes and filtered again. The crystals are dried and dissolved in hot dimethyl formamide. The product is precipitated by adding acetonitrile, filtered and washed with acetone. Thus 12.179 g of 7-benzyl-2-dimethylamino-6,7,8,9-tetrahydro-pyrido[4,3-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained, yield 58%, m.p.: 279°-281° C.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9][C:2]=12.C([NH2:19])(C)(C)C.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:19][C:6]1[N:1]=[C:2]2[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[C:3]2=[CH:4][CH:5]=1
Reactant: COC(=O)C1CCc2c1ccc[n+]2[O-]
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCc2nc(N)ccc21
Temperature: 0 °C

Procedure:
To a solution of methyl 6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxylate 1-oxide (700 mg, 3.6 mmol) in CF3-toluene (20 mL) and CHCl3 (20 mL) was added tert-butylamine (3.8 mL, 36 mmol). The solution was cooled to 0° C. in an ice bath. To the solution was added p-toluenesulfonic anhydride (3.5 g, 10.9 mmol) in small portions until all SM was consumed according to LC-MS. The volatiles were removed under reduced pressure, and the residue was redissolved in TFA (20 mL). The dark solution was heated to 70° C. for 2 hours. LC showed mostly product, with a little bit SM remaining. The reaction was stopped at that point. TFA was removed on a rotavapor, and the residue was taken up in saturated sodium carbonate, extracted three times with IPA-CHCl3 (1:3, 50 mL each). The extractions were combined, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC (DCM:MeOH with 10% aq NH4OH). After removal of solvent was collected as the desired methyl 2-amino-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxylate. LC-MS (IE, m/z): 193 [M+1]+;
Reaction SMILES: [N:1]1([C:6]2[C:15]3[C:10](=[N:11][C:12](Cl)=[C:13]([Cl:16])[N:14]=3)[N:9]=[C:8](Cl)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C(N(C(C)C)CC)(C)C.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>O1CCOCC1>[Cl:16][C:13]1[N:14]=[C:15]2[C:10](=[N:11][C:12]=1[N:22]1[CH2:23][CH2:24][C@@H:20]([OH:19])[CH2:21]1)[N:9]=[C:8]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[N:7]=[C:6]2[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCCC2)c2nc(Cl)c(Cl)nc2n1
Reactant: O[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O[C@@H]1CCN(c2nc3nc(N4CCNCC4)nc(N4CCCC4)c3nc2Cl)C1
Temperature: 40 °C
Reaction time: 30 h

Procedure:
a)+b) 80 mg (0.26 mmol) 4-pyrrolidin-1-yl-2,6,7-trichloro-pteridine are dissolved in 5 ml dioxane and combined with 72 mg (0.58 mmol) (R)-3-hydroxypyrrolidin and 100 μl (0.75 mmol) diisopropylethylamine The mixture is stirred for approx. 30 h at 40° C. The reaction mixture is then slowly added dropwise to a solution of 113 mg (1 mmol) piperazine in 15 ml dioxane at a temperature of 80° C. The mixture is stirred for approx. 16 h at 80° C., cooled to ambient temperature and then poured onto ice water. It is extracted with dichloromethane, the organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is purified by chromatography. Yield 68.8 mg (65% of theoretical).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].ON1C2C=CC=CC=2N=N1.[NH2:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:34][C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1nccs1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nccs3)(CC1)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.3 %

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg), along with 1-hydroxybenzotriazole, was dissolved in N,N-dimethylformamide (1.0 mL). To this solution, 2-aminothiazole (18.6 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.4 mg) were added, and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the resulting residue was purified by preparative thin-layer chromatography (solvent:dichloromethane:methanol=9:1) to give (2S,4S)-4-fluoro-1-[[N-[4-[N-(thiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (17.4 mg).