Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[C:13]([O-:16])(=[S:15])[CH3:14].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:13]([S:15][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:16])[CH3:14]
Reactant: Clc1ccc(OCCCBr)cc1
Reactant: CC([O-])=S
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SCCCOc1ccc(Cl)cc1
Yield: 93.5 %

Procedure:
A solution of Intermediate 2 (6.0 g) in DMF (50 ml) was treated with potassium thioacetate (5.7 g) at room temperature for 3 h, then the brown solution was added to 5% sodium bicarbonate solution and extracted with ether (3×200 ml). The solvent was washed with water (200 ml) and brine, dried over MgSO4 and evaporated to give the title compound (5.50 g) as a beige solid.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23](Cl)(Cl)=[O:24].C1(C)C=CC=CC=1>ClCCl>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]=[C:23]=[O:24])[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=C=O)CC1
Reaction time: 0.25 h

Procedure:
To a solution of trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamine (500 mg, 2.20 mmol) (from Example 20a supra) and triethylamine (1.52 mL, 10.90 mmol) (Aldrich) in dichloromethane (15 mL) was added a 20% phosgene in toluene solution (3.2 mL, 6.50 mmol) (Fluka) at 0° C. The resulting mixture was stirred for 15 minutes, then filtered and the filtrate was concentrated to a residue that was distilled at 110° C. under high vacuum using a Kugelrohr apparatus to give trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl isocyanate (485 mg) as a colorless liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[O:9])[CH:2]=1.[F:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=O)=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]2[O:18][C:16]([CH:13]3[CH2:12][CH2:11][N:10]([C:8]([O:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:9])[CH2:15][CH2:14]3)=[N:27][N:26]=2)=[CH:22][CH:21]=1
Reactant: O=C(O)C1CCN(C(=O)Oc2cccnc2)CC1
Reactant: NNC(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Oc1cccnc1)N1CCC(c2nnc(-c3ccc(F)cc3)o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a mixture of 1-[(pyridin-3-yloxy)carbonyl]piperidine-4-carboxylic acid (300 mg), 4-fluorobenzohydrazide (222 mg), HOBt (170 mg), and DCM (6 mL) was added WSC hydrochloride (299 mg), followed by stirring at room temperature overnight. The reaction liquid was purified directly by silica gel column chromatography (chloroform/methanol=99/1 to 90/10). The residue was dissolved in THF (6 mL), and toluenesulfonyl chloride (686 mg) and triethylamine (1.0 mL) were added thereto, followed by stirring at 50° C. for 8 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 0/100). To the purified product were added isopropanol/water, and the resulting solid was collected by filtration and dried to obtain pyridin-3-yl 4-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (224 mg) as a colorless solid.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[O:23][CH3:24].Cl>ClCCCl>[CH3:24][O:23][C:17]1[C:16]([O:15][CH3:14])=[CH:21][C:20]([C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:12])=[C:19]([F:22])[CH:18]=1
Reactant: COc1ccc(F)cc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(F)c(C(=O)c2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
12.7 g (95 mmol) of aluminium trichloride in 80 ml of 1,2-dichloroethane are stirred under nitrogen and cooled to 3°. 13.35 g (95 mmol) of benzoyl chloride are added. At 3°, this red solution is added dropwise over a period of 25 minutes to a solution of 12.55 g (80.3 mmol) of 1,2-dimethoxy-4-fluorobenzene (4-fluoroveratrole) in 80 ml of 1,2-dichloroethane. The reaction mixture is stirred for a further 3 hours at 3°, then for 31/2 hours at room temperature and then poured onto a mixture of 250 ml of ice and 20 ml of concentrated hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted several times with ether. Organic phase and ether solutions are combined, washed with 1 N sodium hydroxide solution, water and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The resulting yellow oil is stirred with 50 ml of ether in an ice bath until crystallisation takes place, yielding the desired (4,5-dimethoxy-2-fluorophenyl)-phenylmethanone in the form of white crystals having a melting point of 102°-103°.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13](=[O:28])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:17]=2)[C:3]1=[O:29].[CH3:30]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].S(OC)(OC)(=O)=O>O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:30])=[C:4]([C:13](=[O:28])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:17]=2)[C:3]1=[O:29]
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)c3ccccc3n(C)c2=O)c1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)COc1cccc(C=CC(=O)c2c(OC)c3ccccc3n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.55 g of 1-methyl-4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone and 5 ml of hexamethylphosphoramide was added 67 mg of sodium hydride (60% oily) under ice-cooling. After stirred at room temperature for 1 hour, 0.2 ml of dimethyl sulfate was added, and this was stirred at room temperature for 3 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. After dried over anhydrous sodium sulfate, the extract was concentrated under reduced pressure, and the resulting residue was subjected to silica column gel chromatography to obtain 0.21 g of 1-methyl-4-methoxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone [Compound No. (60e)] as a yellow crystal.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.C[C:22]([CH3:27])([CH3:26])[CH2:23]CN.C([O-])([O-])=O.[K+].[K+].[CH3:34][N:35](C=O)C>>[CH2:23]([N:35]([CH3:34])[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1)[CH:22]([CH3:26])[CH3:27]
Reactant: CN(C)C=O
Reactant: CC(C)(C)CCN
Reactant: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1=Cc2ccc(N(C)CC(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of ethyl 7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 612a, Step 2) (0.45 g, 1.54 mmole) and 3,3-dimethylbutylamine (0.13 g, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil (0.55g, 98%). No further purification was performed. LCMS m/z 358.00 (M+H).
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][N:11]3[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]4[C:13](=[CH:14][C:15]([N+:23]([O-])=O)=[CH:16][CH:17]=4)[CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(O)C.[Zn]>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][N:11]3[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]4[C:13](=[CH:14][C:15]([NH2:23])=[CH:16][CH:17]=4)[CH2:12]3)=[CH:26][CH:27]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1(C)CN(Cc2ccc(-n3ccnc3)cc2)Cc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)CN(Cc2ccc(-n3ccnc3)cc2)Cc2cc(N)ccc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of Example 163A (1.45 g, 4.00 mmol) in 95% ethanol (20 mL) were added zinc (2 g, 30.6 mmol) and acetic acid (4 mL, 69.9 mmol). The reaction mixture was stirred for 4 hours at 50° C. Aqueous saturated NaHCO3 solution (200 mL) and CH2Cl2 (200 mL) were added to the reaction mixture and the suspension was filtered. The aqueous layer was extracted with CH2Cl2 (200 mL). The combined organic layers were washed with saturated NaCl (1×300 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified using the Chemflash system using a 120 g C18 column eluting with 40-80% methanol in water (0.8 g (NH4)2CO3 in 1 L of water) to provide the title compound. LC-MS: m/e=333 (M+H)+. 1H NMR (400 MHz, DMSO-d6), δ 8.25 (s, 1H), 7.73 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.11 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.41 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.16 (d, J=2.0 Hz, 1H), 4.76 (s, 2H), 3.62 (s, 2H), 3.43 (s, 2H), 2.31 (s, 2H), 1.15 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([C:26]1[C:27]([N:38]=[CH:39][N:40]([CH3:42])C)=[N:28][C:29]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:30][CH:31]=1)#N.NC1C=C(OCC2C=CC(OC)=CC=2)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([S:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:2]([NH:1][C:42]2[C:26]3[CH:31]=[CH:30][C:29]([CH:32]4[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[N:28][C:27]=3[N:38]=[CH:39][N:40]=2)[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CN(C)C=Nc1nc(C2CCCCC2)ccc1C#N
Agent: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: Oc1ccc(Sc2ccc(OCc3ccccc3)cc2Nc2ncnc3nc(C4CCCCC4)ccc23)cc1

Procedure:
The product from Example 27A was reacted with the product from Example 135A using the procedure from Example 10F substituting the product from Example 27A for the product from Example 10E and substituting the product from Example 135A for the product from Example 10B to provide the title product. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.23-1.51 (m, 4H), 1.53-1.79 (m, 4H), 1.80-2.00 (m, 2H), 2.77-3.02 (m, 1H), 5.10 (s, 2H), 6.67 (d, J=8.46 Hz, 2H), 6.88-7.01 (m, 1H), 7.11 (d, J=8.82 Hz, 2H), 7.22-7.31 (m, 1H), 7.32-7.49 (m, 6H), 7.56 (d, J=7.72 Hz, 1H), 8.55 (s, 1H), 8.73 (d, J=8.09 Hz, 1H), 9.94 (s, 1H); MS (APCI) m/z 535 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH2:12])=[C:4]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:3]=1.[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27](Cl)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27]([NH:12][C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[O:28])[CH3:23]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1c(C#Cc2ccccc2Cl)cc(Cl)cc1C(F)(F)F
Product: CCOC(=O)CC(=O)Nc1c(C#Cc2ccccc2Cl)cc(Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 29 step A from 4-chloro-2-(2-chloro-phenylethynyl)-6-trifluoromethyl-phenylamine and chlorocarbonyl-acetic acid ethyl ester. Off white solid (1.2 g, 45%) LC-MS (ESI): 444 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:21]=[O:22]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH:21]=[O:22])=[C:4]([F:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Cl)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C=O)c1F
Temperature: -55 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A solution of 4-chloro-2-fluoro-1-methoxy-benzene (Aldrich; 10.2 g, 63.5 mmol) in dry tetrahydrofuran (500 mL) was cooled to −78° C. under a nitrogen atmosphere. A solution of lithium diisopropylamide (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 39.9 mL, 70.2 mmol) was added dropwise by syringe. The reaction mixture was warmed to −55° C. and held at this temperature for 1 h. The mixture was then cooled again to −78° C., and dry N,N-dimethylformamide (10.7 mL, 139 mmol) was added by syringe. The cooling bath was removed and the reaction was allowed to warm to −10° C. and quenched by the addition of ice flakes (˜200 mL) and a solution of saturated ammonium chloride (200 mL). Ethyl acetate (200 mL) was added, the layers were separated and the aqueous later was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporated, and purified by silica gel chromatography, eluting with 0-30% ethyl acetate/hexanes to give 6-chloro-2-fluoro-3-methoxy-benzaldehyde (5.6 g, 47% yield) as an oil that solidified upon standing.
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1.CO>[NH2:1][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:11])[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: NS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Dioxane (250 mL) is saturated with ammonia and cooled down to 0° C. A solution of benzyl-4-(chlorosulfonyl)piperidine-1-carboxylate (10 g; 31.5 mmol; 1 eq) in dioxane (25 mL) is added dropwise over 10 min. The reaction mixture is stirred at room temperature for 3 h while keeping ammonia bubbling. The suspension is filtered through a short plug of silica using dioxane as eluent and the resulting solution is concentrated in vacuo to give a colourless oil. The oil is taken up in MeOH and concentrated in vacuo to give a white foam which is crystallised from EtOAc and Et2O to afford 8.1 g (86%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.40-7.29 (m, 5H), 6.79 (s, 2H), 5.08 (s, 2H), 4.10 (br d, J=13.3 Hz, 2H), 3.05 (tt, J=11.9, 3.6 Hz, 1H), 2.95-2.75 (m, 2H), 2.0 (dd, J=1.8, 11.5 Hz, 2H), 1.46 (dq, J=12.5, 4.4 Hz, 2H). HPLC (max plot) 82%; Rt 3.55 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23](OC(ON=C(C#N)C(OCC)=O)=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH2:23]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NOC(=O)OCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of N-benzyloxycarbonylglycine (0.42 g) and triethylamine (0.28 ml) in dioxane (5 ml), ethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate (0.55 g) is added, and the resulting mixture is stirred for 3 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine benzyl ester (0.57 g) as an oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:13][C@:14]4([CH2:22][N:23]=3)[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]4)=[N:10][C:5]2=[N:4][CH:3]=1.Cl>CO>[S:8]1[C:6]2=[N:7][CH:2]=[CH:3][N:4]=[C:5]2[N:10]=[C:9]1[NH:11][C:12]1[O:13][C@:14]2([CH2:22][N:23]=1)[CH:19]1[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]1)[CH2:15]2
Reactant: Brc1cnc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Agent: Cl
Solvent: CO
Product: c1cnc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2n1
Yield: 67.6 %

Procedure:
(R)—N-(6-Bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (44 mg, 0.111 mmol) was suspended in MeOH (50 mL) and 3N HCl was added until all solids had dissolved (˜10 ml). The reaction flask was flushed with nitrogen and then 10% palladium on carbon (35 mg) was added, and the flask was fitted with a hydrogen balloon. The mixture was allowed to react overnight, at which time TLC showed consumption of the starting material. The flask was flushed with nitrogen, filtered through celite and washed with methanol. The combined filtrates were concentrated by ˜90% to remove most of the methanol, and the solution was made basic by the addition of a saturated solution of sodium bicarbonate. The basic aqueous phase was extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(thiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (24 mg, 0.075 mmol, 67.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.50 (br. s., 1 H) 8.41 (d, J=2.76 Hz, 1 H) 8.27 (d, J=2.76 Hz, 1 H) 4.06 (d, J=9.79 Hz, 1 H) 3.72 (d, J=9.79 Hz, 1 H) 3.43 (dd, J=15.06, 1.76 Hz, 1 H) 2.74-3.09 (m, 5 H) 2.12-2.25 (m, 2 H) 1.71-1.86 (m, 1 H) 1.49-1.67 (m, 2 H). MS (LC/MS) R.T.=0.75; [M+H]+=317.13.
Reaction SMILES: [C:1](=O)([CH3:4])[CH2:2]Cl.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:19](=[O:22])([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:2][CH:1]([CH3:4])[C:19]([N:16]1[CH2:17][CH2:18][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[CH2:14][CH2:15]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)CCl
Agent: [K+]
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Isopropanoyl chloride (112 μL) was added to a mixture of N-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassium carbonate in anhydrous DCM (10 mL) under a nitrogen atmosphere. The mixture was stirred at r.t. for 18 hours, then it was filtered off from inorganics. The organic phase was diluted with Et2O (20 mL) and washed with IN hydrochloric acid solution (10 mL). The aqueous phase was made basic with 1N sodium hydroxide solution and extracted twice with DCM. The combined organic layers were dried and concentrated in vacuo and the residue was purified by flash chromatography (AcOEt 100%) to give the title compound (133 mg) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]3[C:16](=[O:27])[NH:15][C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][CH3:32])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].N12CCCN=C1CCCCC2.Br[CH2:47][C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1[F:57].C(OCC)(=O)C>C(#N)C>[C:1]([NH:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[C:17]3[C:16](=[O:27])[N:15]([CH2:47][C:48]4[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=4[F:57])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][CH3:32])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCn1c(=O)n(Cc2cc([N+](=O)[O-])ccc2F)c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
A solution of 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (104 mg, 0.22 mmol) in acetonitrile (2.0 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mL, 0.24 mmol) and 2-bromomethyl-1-fluoro-4-nitro-benzene (56.6 mg, 0.24 mmol). The resulting solution was heated to 50° C. for 6 h. At this time, another portion of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mL, 0.24 mmol) was added. The reaction was stirred at 25° C. for 18 h. At this time, the reaction was poured into ethyl acetate (200 mL) and was washed with a 1N aqueous hydrochloric acid solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:1 ethyl acetate/petroleum ether) afforded 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-1-(2-fluoro-5-nitro-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (45.3 mg, 33%) as a tan solid: FAB-HRMS m/e calcd for C31H35N6O7F (M+H)+ 623.2630, found 623.2631.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:22]2[CH:26]=[N:25][NH:24][C:23]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.CS(C)=O.[OH-].[K+].Br[CH:35]([CH2:37][CH3:38])[CH3:36]>O>[Br:1][C:2]1[CH:3]=[C:4]([N:22]2[CH:26]=[N:25][N:24]([CH:35]([CH3:36])[CH2:37][CH3:38])[C:23]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3Br)CC2)cc1
Reactant: CCC(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)c(Br)c2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.8 %

Procedure:
To a stirred mixture of 45 parts of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one and 90 parts of dimethyl sulfoxide were added 15 parts of potassium hydroxide (pulverized). Then there were added 6.2 parts of 2-bromobutane and the whole was stirred for 20 hours at room temperature. The reaction mixture was poured into water. The produce was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of methylbenzene and hexane (1:2 by volume). The precipitated product was filtered off and recrystallized from 80 parts of methanol. The product was filtered off and dried in vacuo at 60° C., yielding a first fraction of 14.7 parts (29.8%) of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one; mp. 144.6° C. The less pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography (HPLC) over silica gel using a mixture of ethyl acetate and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from methanol, yielding a second fraction of 4-[3-bromo-4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one; mp. 144.7° C. (int. 35).