Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[CH3:22][NH:23][CH:24]([CH3:26])[CH3:25]>>[CH:24]([N:23]([CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[CH2:8][OH:10])[CH3:22])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Reactant: CNC(C)C
Product: CC(C)N(C)Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO

Procedure:
Prepared using intermediate 44 and N-methylisopropylamine. This compound was used directly without collection of analytical data for the preparation of Example 75.
Reaction SMILES: [O:1]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[C@H:2]1[O:10][C@@H:9]([CH3:11])[C@@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[CH2:21]([Sn](=O)CCCC)CCC>CO>[CH3:21][O:6][C@@H:5]1[C@H:7]([OH:8])[C@H:9]([CH3:11])[O:10][C@H:2]([O:1][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C@H:3]1[OH:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: C[C@@H]1O[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@@H](O)[C@H](O)[C@@H]1O
Solvent: CO
Product: CO[C@H]1[C@H](O)[C@@H](Oc2ccc([N+](=O)[O-])cc2)O[C@@H](C)[C@H]1O
Temperature: 70 °C
Reaction time: 40 h
Yield: 60.8 %

Procedure:
6 g (21 mmol) of p-nitrophenyl β-L-fucopyranoside in 300 ml of absol. methanol are treated with 7.84 g (31.5 mmol) of dibutyl tin oxide and heated under reflux for 2 h. The mixture is then concentrated, and the residue is dried and then taken up in 300 ml of DMF. After addition of 15.7 ml of methyl iodide, the batch is stirred at 70° C. for 40 h. The solvent is removed under reduced pressure and the residue is taken up in 300 ml of dichloromethane. The suspension is filtered, and the solution that remains is concentrated again and subjected to flash chromatography (dichloromethane/methanol 99:1). The concentration gives 3.82 g (61%) of the target product.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)=[O:20])[CH2:15]1>>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:38])[C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:35])([F:37])[F:36])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-phenyl-cyclohexanone (Aldrich) and N-(azetidin-3-ylcarbamoylmethyl)-3,5-bistrifluoromethyl-benzamide (as prepared in the previous step) using the procedure described in Step C of Example 4.
Reaction SMILES: OP([O-])(O)=O.[K+].[C-:7]#[N:8].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][CH:19]=[C:20]([CH:22]=[O:23])[N:21]=2)=[CH:13][CH:12]=1>CN(C=O)C.O.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:18][CH:19]=[C:20]([CH:22]([OH:23])[C:7]#[N:8])[N:21]=2)=[CH:15][CH:16]=1
Reactant: [C-]#N
Reactant: O=Cc1coc(-c2ccc(F)cc2)n1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(O)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
KH2PO4 (712 mg, 5.23 mmol) and NaCN (251 mg, 5.12 mmol) were added to a solution of 2-(4-fluorophenyl)oxazole-4-carbaldehyde (500 mg, 2.62 mmol) in DMF-H2O (10 mL, 4:6, v/v). The resulting reaction mixture was stirred at room temperature for 1 h, then diluted with water and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyacetonitrile (500 mg, yield 87%). 1H NMR (400 MHz, CDCl3) δ 8.07-8.02 (m, 2H), 7.88 (s, 1H), 7.20-7.16 (t, J=8.8 Hz, 2H), 5.62 (s, 1H), 4.38 (br s, 1H). MS (ESI) m/z: Calculated for C11H7FN2O2: 218.05. found: 218.8 (M+H)+.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1.[OH:19][CH2:20][CH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.[H-].[Na+]>>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][CH2:20][OH:19])[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCc1ncc[nH]1
Reactant: ICCCc1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Product: OCCc1nccn1CCCc1cccc(OCc2ccccc2)c1
Yield: 78.9 %

Procedure:
Using benzyl 3-(3-iodopropyl)phenyl ether (3.53 g), 2-(2-hydroxyethyl)imidazole (1.46 g) and 65% oily sodium hydride (0.48 g), the same reaction as Reference Example 11-(iv) was carried out to yield the titled compound (2.66 g) as a colorless oily substance.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:21])[N:11]([CH2:19][CH3:20])[C:12](=[O:18])[N:13]([CH2:16][CH3:17])[C:14]=1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22]Br>C(Cl)(Cl)Cl>[C:1]([C:9]1[C:10](=[O:21])[N:11]([CH2:19][CH3:20])[C:12](=[O:18])[N:13]([CH2:16][CH3:17])[C:14]=1[CH2:15][Br:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(C)c(C(=O)c2ccccc2)c(=O)n(CC)c1=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(CC)c1=O
Temperature: 60 °C

Procedure:
5-Benzoyl-1,3-diethyl-6-methylpyrimidine-2,4(1H,3H)-dione (step 2)(800 mg, 2.79 mmol) was dissolved in chloroform (Volume: 60 mL) and bromine (0.288 mL, 5.59 mmol) was added. The mixture was heated at 60° C. for 1 h. A further portion of bromine (0.288 mL, 5.59 mmol) was added. The mixture was heated for 30 mins and further bromine (0.288 mL, 5.59 mmol) was added. The reaction mixture was cooled to RT and washed with aqueous sodium metabisulfite. The organic phase was separated, passed through a hydrophobic frit and evaporated under vacuum. The residue was dissolved in DCM and evaporated onto silica. The silica was deposited onto a 10 g silica cartridge and the system eluted with 20% EtOAc/hexane, 30% EtOAc/hexane, and 40% EtOAc/hexane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[CH3:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)Cc1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (10 g, 0.05 mol) in acetonitrile (100 mL) were added K2CO3 (15.3 g, 0.11 mol) and dimethyl sulfate (8.4 g, 0.06 mol) under an inert atmosphere. The reaction mixture was stirred at 80° C. for 2 h and then extracted with EtOAc (2×300 mL), The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-(4-methoxyphenyl)acetate (8 g, 74%) as a white solid.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14](Cl)=[O:15].[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>ClCCl>[CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:15]
Reactant: O=C(Cl)c1cn2c(n1)COc1ccccc1-2
Reactant: OCCN1CCOCC1
Solvent: ClCCl
Product: O=C(OCCN1CCOCC1)c1cn2c(n1)COc1ccccc1-2
Temperature: 50 °C
Yield: 42.4 %

Procedure:
1.0 g (0.0043 mole) of 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carbonyl chloride was suspended in dry dichloromethane and 1.31 g (0.01 mole) of N-(2-hydroxyethyl)-morpholine was added thereto. The mixture was warmed at 50° C. for two hours and thin layer chromatography then indicated only a small quantity of starting material remained. The mixture was then washed with water, dried and evaporated. The residue was chromatographed on a silica column using ethyl acetate as eluant. The product thus obtained was finally crystallized from ether to obtain 0.6 g (43% yield) of 2-morpholinoethyl 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 142°-3° C.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].N.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([N+:33]([O-])=O)=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19]>C1COCC1.O>[NH2:33][C:29]1[CH:30]=[C:31]([CH3:32])[C:26]([N:23]2[CH2:22][CH2:21][N:20]([C:18]([C:12]3[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])=[O:19])[CH2:25][CH2:24]2)=[N:27][CH:28]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCN(C(=O)c2c(F)cccc2F)CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N)cnc1N1CCN(C(=O)c2c(F)cccc2F)CC1
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
Add Na2S2O4 (10 equiv.) and aqueous ammonia (3 mL/mmol, 32%) to a solution of (2,6-difluoro-phenyl)-[4-(3-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone (3 g, 8.29 mmol) in THF/H2O (166 mL, 1:1). Stir for 30 min., then separate layers. Extract the aqueous layer with DCM, EtOAc and isopropyl alcohol/EtOAc. Combine organic layers and dry over Na2SO4, filter and remove solvent under reduced pressure. Subject crude to a Varian™ SCX column and wash the column with MeOH and then flush off the product with 2 M NH3 in MeOH to obtain 1.2 g of [4-(5-amino-3-methyl-pyridin-2-yl)-piperazin-1-yl]-(2,6-difluoro-phenyl)-methanone (44% yield). ES+(m/z): 333 [M+1]
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][N:12]=[N+:13]=[N-:14])[CH2:5][CH2:4]1)=O.C(Cl)(=O)C(Cl)=O.[NH2:21][CH:22]1[C:41](=[O:42])[N:24]2[C:25]([C:30]([O:32][CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:31])=[C:26]([CH3:29])[CH2:27][S:28][C@H:23]12>C(N(CC)CC)C>[N:12]([CH2:11][CH2:10][CH2:9][CH:6]1[CH2:7][CH2:8][N:3]([CH:1]=[N:21][CH:22]2[C:41](=[O:42])[N:24]3[C:25]([C:30]([O:32][CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:37])([CH3:38])[CH3:39])=[O:31])=[C:26]([CH3:29])[CH2:27][S:28][C@H:23]23)[CH2:4][CH2:5]1)=[N+:13]=[N-:14]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: [N-]=[N+]=NCCCC1CCN(C=O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N=CN3CCC(CCCN=[N+]=[N-])CC3)[C@H]2SC1
Temperature: -10 °C

Procedure:
A solution of N-formyl-4-(3-azidopropyl)-piperidine (1.13 g) in alcohol-free chloroform (2.5 ml) was cooled to -20° C. and oxalyl chloride (0.44 ml) in alcohol-free chloroform (2.5 ml) was added dropwise. After 1 hour at -20° C. the solution was added dropwise at -60° C. to -70° C. to a stirred solution of pivaloyloxymethyl 7-amino-3-methyl-3-cephem-4-carboxylate (1.72 g) in alcohol-free chloroform (12 ml). Triethylamine (1.46 ml) was added and within the next hour the temperature was gradually raised to -10° C. The solvent was evaporated and the residue was extracted with ether. The ether extract was evaporated to leave an oil, which was purified by column chromatography on Sephadex to yield the desired compound as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C@H:10]([CH2:17][CH2:18][CH2:19][CH2:20][O:21]CC2C=CC=CC=2)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:2]=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@@H:10]([CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC[C@@H](CCCCOCc1ccccc1)CCCc1cccnc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COC(=O)CC[C@@H](CCCCO)CCCc1cccnc1

Procedure:
To a solution of methyl 4(R)-[3-(3-pyridyl)propyl]-8-(benzyloxy)octanoate (1.67 g, 4.2 mmol) in ethanol (30 ml) is added 20% palladium hydroxide on carbon (0.43 g) followed by cyclohexene (15.6 ml). The mixture is refluxed for 25 hours and then filtered to remove the catalyst. The catalyst is washed with ethanol, the combined filtrate is evaporated, and the residue is purified by flash chromatography on silica gel using 9:1 ethyl acetate/hexane to obtain methyl (R)-8-hydroxy-4-[3-(3-pyridyl)propyl]octanoate; IR (CH2Cl2): 3617, 1732, 1197, 1174, 1027 cm- 1.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1.CN1CCCC1=O>ClCCl>[Br:8][C:6]1[N:7]=[C:2]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Nc1ccc(CCO)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cn1cc(Br)nc(Nc2ccc(CCO)cc2)c1=O
Temperature: 120 °C
Yield: 84.5 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (2.0 g; 7.5 mmol), 2-(4-Amino-phenyl)-ethanol (1.0 g; 7.3 mmol), and 1-methyl-2-pyrrolidinone (1 mL) was heated at 120° C. for 1 hr. The mixture was cooled to room temperature, diluted with dichloromethane and filtered to give a dull brown oil. This was dissolved in CH2Cl2 and washed with 0.01N NaOH, and dried over solid sodium sulfate. After filtration and evaporation of the CH2Cl2 layer, the resulting brown solid was chromatographed on silica using methanol/CH2Cl2 (1:9) as eluent to provide 2.0 g of 5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one (1) as a light tan solid. MS 324.23 (M+H).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[N:22]1([C:2]2[CH:19]=[CH:18][C:5]([C:6]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COC(=O)c1ccncc1C(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccncc1C(=O)c1ccc(-n2ccnc2)cc1
Temperature: 120 °C

Procedure:
A solution of 3-(4-fluorobenzoyl)-4-carbomethoxypyridine (2.25 g, 8.68 mmol) in 10 mL of DMF is added dropwise to a solution of NaH (0.25 g, 10.21 mmol) and imidazole (0.59 g, 8.68 mmol) in 26 mL of DMF. The mixture, after heating at 120° C. for 1 day, is allowed to cool, quenched with ice water, and extracted with EtOAc (3×75 mL). The combined organic layers are dried (Na2SO4) and evaporated to produce crude product. Chromatographic purification on silica gel (using EtOAc-MeOH, 9:1 as the eluent) gives pure 3-[4-(1H-imidazol-1-yl)benzoyl]-4-carbomethoxypyridine as a light brown solid. M.P. 125°-128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34]>O1CCCC1>[CH2:33]([O:32][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1)=[O:35])[CH3:34]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(N)cc3)cs2)c1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc(-c2csc(Cn3cc(C(=O)OCC)cn3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
In an ice-bath, to a solution (4 mL) of the crude compound (0.84 mmol) obtained in Example 36b in tetrahydrofuran were added triethylamine (0.15 ml, 1.1 mmol) and ethyl chlorocarbonate (79 ml, 1.0 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (hexane-ethyl acetate) to give the title compound (180 mg, 54% in 2 steps) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31](=[O:32])/[CH:30]=[CH:29]/[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[O:20][CH3:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Product: COc1cccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1OC

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid.
Reaction SMILES: [NH:1]([C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19]>CN(C=O)C.C(Cl)(Cl)Cl>[NH:1]([C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18](=[O:20])[CH3:19])=[C:10]([Cl:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1nc(Nc2ccccc2)nc2nc[nH]c12
Reactant: CC(=O)OCCCCBr
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)OCCCCn1cnc2c(Cl)nc(Nc3ccccc3)nc21
Yield: 45 %

Procedure:
Reaction between 2-anilino-6-chloropurine and 4-acetoxybutyl bromide was performed as described in A.a., above, giving 2-anilino-6-chloro-9-(4-acetoxybutyl) purine in a 45% yield (from DMF/chloroform), mp 195°-197° C. 1H NMR δ9.98 (s, 2-NH), 8.32 (s, 8-H), 7.31 (m, C6H5), 4.20 (t, 1'-CH2), 4.02 (t, 4'-CH2), 1.95 (s, CH3), 1.92, 1.58 (m, 2'/3'CH2).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Br:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 122-123° C.; 1H NMR (300 MHz, CDCl3): δ 7.07 (s, 1 H), 6.92 (d, J=2.6 Hz, 1 H), 6.77 (d, J=2.2 Hz, 1 H), 4.95-4.80 (m, 1 H), 4.34 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.66 (dd, J=10.7, 5.5 Hz, 1 H), 3.56 (dd, J=10.3, 3.3 Hz, 1 H), 3.35 (s, 3 H), 3.10 (t, J=7.7 Hz, 2 H), 1.87-1.74 (m, 2 H), 0.93 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C18H22N3O3Br2 (M+H)+: 486.0028; found m/z 486.0018.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[N:4][N:5]2[C:10](O)=[C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8]([CH3:17])=[N:7][C:6]=12.O=P(Cl)(Cl)[Cl:21]>>[Cl:1][C:2]1[C:3]([CH3:18])=[N:4][N:5]2[C:10]([Cl:21])=[C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8]([CH3:17])=[N:7][C:6]=12
Reactant: COC(=O)Cc1c(C)nc2c(Cl)c(C)nn2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1c(C)nc2c(Cl)c(C)nn2c1Cl
Temperature: 0 °C
Yield: 59 %

Procedure:
To a solution of methyl 2-(3-chloro-7-hydroxy-2,5-di-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.160 g, 0.6 mmol) was added POCl3 (1 mL). The reaction mixture was heated at reflux for 1 h. After cooling, the reaction mixture was added drop-wise to ice-water. A brown solid precipitated. The solid were filtered and washed with water, then dissolved in ethyl acetate. The organic solution was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated to give the title compound (0.1 g, 59%). NMR (500 MHz, DMSO-d6) δ ppm 2.44 (s, 3H), 2.57 (s, 3H), 3.68 (s, 3H), 4.00 (s, 2H). Used as is in the next step.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:8]=[CH:9][N:10]=1.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]2[O:32][CH:33]=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:25][CH:24]=1>>[F:39][C:22]([F:21])([F:38])[C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]2[O:32][CH:33]=[C:34]([CH2:36][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH2:5][CH2:4][OH:3])=[CH:19][CH:18]=3)[N:35]=2)=[CH:25][CH:24]=1
Reactant: OCCc1nccn1CCCc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Product: OCCc1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Yield: 66.4 %

Procedure:
Using 65% sodium hydride (40.6 mg), 4-[3-[2-(hydroxyethyl)-1H-imidazol-1-yl]propyl]phenol (246 mg) and [2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]oxazol-4-yl]methyl chloride (316 mg), the same reaction as Example 17 was carried out to yield the titled compound (330 mg) as colorless needles.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH3:12])[NH:7][C:6]=2[C:5]([NH2:13])=[CH:4][CH:3]=1.C(O[C:17](=N)[C@@H:18]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:19])C>CCO>[C:24]([O:23][C:21](=[O:22])[NH:20][C@H:18]([C:17]1[N:7]2[C:6]3[C:11]([O:10][CH2:9][C@@H:8]2[CH3:12])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:13]=1)[CH3:19])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=N)[C@H](C)NC(=O)OC(C)(C)C
Reactant: C[C@H]1COc2c(F)ccc(N)c2N1
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Temperature: 75 °C
Yield: 76.3 %

Procedure:
(S)-8-Fluoro-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamine (160 mg, 0.86 mmol) was added to a solution of (S)-2-tert-butoxycarbonylaminopropionimidic acid ethyl ester (570 mg, 2.64 mmol) in EtOH (10 mL) and the reaction was heated at 75° C. for 60 min. The reaction mixture was concentrated in vacuo, and the residue was partitioned between DCM and sat. NaHCO3. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-40% DCM in cyclohexane) to afford the title compound as an off-white foam (220 mg, 76%). LCMS (Method J): RT=2.50 min, [M+H]+=336.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[S:19][C:20]([C:33]4[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=4[F:41])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[N:22]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[S:19][C:20]([C:33]4[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=4[F:41])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=4)[N:22]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)CC(c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)c(-c3cc(OC)ccc3F)s2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2sc(COc3cccc(C(CC(=O)O)C4CC4)c3)nc2-c2ccc(C(F)(F)F)cc2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((5-(2-fluoro-5-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methoxy)phenyl)propanoate (120 mg) in THF (3.0 mL) and methanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (100 mg) as pale-yellow crystals.