Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.O.C[O:5][C:6](=[O:36])[C@H:7]([CH2:32][CH2:33][S:34][CH3:35])[NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:12][C:11]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>O>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:36])=[O:5])[CH2:32][CH2:33][S:34][CH3:35])=[O:31])=[C:11]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:12]=2)[CH:19]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1Oc1ccccc1)C(=O)O
Temperature: 60 °C
Yield: 87.4 %

Procedure:
To a solution in 5:1 methanol-H2O (3.5 mL) of [4-(3-pyridyloxymethyl)-2-phenoxybenzoyl]methionine methyl ester (440 mg), prepared as in Example 157G, was added a solution of 50% NaOH (354 mg) in water (0.8 mL) and the reaction mixture was heated at 60° C. for 15 minutes. The reaction mixture was concentrated in vacuo and the residue was taken up in H2O (3, mL). The aqueous solution was acidified with concentrated HCl (415 mg) and 2 drops of ethyl acetate were added. The resulting solid was filtered and dried in a vacuum oven at 60° C. for 3 hours to give [4-(3-pyridyloxymethyl)-2-phenoxybenzoyl]methionine (373 mg). mp 195° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.90 (m, 4H), 2.37 (m, 2H), 4.44 (m, 1H), 5.20 (s, 2H), 7.01 (s, 2H), 7.04 (s, 1H), 7.16 (t, 1H, J=7.4 Hz), 3.66 (m, 5H), 7.70 (d, 1H, J=9.0 Hz), 8.17 (dd, 1H, J=4.4, 1.5 Hz), 8.30 (d, 1H, J=3 Hz). Anal calcd for C24H24N2O5S: C, 63.70; H, 5.35; N, 6:59. Found: C, 63.46; H, 5.11; N, 6.08.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[C:17]3[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=3[N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4].FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)[C:17]3[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=3[N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4]
Reactant: COC(=O)c1nc2n(CCN3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3n2c(=O)c1OC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc2n(CCN3CCNCC3)c3ccccc3n2c(=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Acetoxy-10-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-ethyl]-4-oxo-4,10-dihydro-benzo[4,5]imidazo[1,2-a]pyrimidine-2-carboxylic acid methyl ester (33 mg, 0.064 mmol) was treated with trifluoroacetic acid (0.20 mL) and stirred for one hour at room temperature. After this time, the mixture was concentrated and the crude residue was the desired product (27 mg, 100%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]2[N:16]=[N:17][C:18]([N:21]([CH3:32])[CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)=[CH:19][CH:20]=2)=[C:9]([OH:33])[CH:8]=1)(=O)=O.[CH3:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.CO>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.COCCOC.O>[CH3:14][O:13][C:11]1[C:10]([C:15]2[N:16]=[N:17][C:18]([N:21]([CH3:32])[CH:22]3[CH2:27][C:26]([CH3:28])([CH3:29])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)=[CH:19][CH:20]=2)=[C:9]([OH:33])[CH:8]=[C:7]([C:40]2[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=2)[CH:12]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)cc(O)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: COc1cc(-c2cnn(C)c2)cc(O)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 90 °C
Yield: 63.2 %

Procedure:
A mixture of 3-hydroxy-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (Intermediate 6-2, 100 mg, 0.193 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (120 mg, 0.579 mmol), and sodium carbonate (102 mg, 0.964 mmol) in 3:1 DME/water (1.9 mL) was degassed with a stream of dry nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (16.7 mg, 0.014 mmol) was added and the mixture was heated under microwave irradiation at 90° C. for one hour. The mixture was partitioned between water and dichloromethane and the organic phase acidified with HCl in MeOH (4 equivalents) and concentrated to dryness. The crude material was loaded onto an SCX column (1 g, preconditioned with MeOH), washed with MeOH, and eluted with 7 N ammonia in MeOH. The eluent was concentrated to dryness and purification by flash chromatography (12 g silica, 1-12% 7 N ammonia in MeOH gradient, in DCM) provided 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-phenol as a light yellow solid (55 mg). LCMS Rt=0.44 min [Method Q], MS (M+1)=451.5. 1H NMR (400 MHz, METHANOL-d4) δ 8.25 (d, J=10.11 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.22 (d, J=10.11 Hz, 1H), 6.74-6.85 (m, 2H), 5.05 (t, J=12.38 Hz, 1H), 3.95 (s, 3H), 3.95 (s, 3H), 3.01 (s, 3H), 1.65-1.75 (m, 2H), 1.50-1.64 (m, 2H), 1.39 (s, 6H), 1.24 (s, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9](O)=O)[C:5](C)=[N:6][CH:7]=1.C1C(=O)[N:16](Br)[C:14](=O)[CH2:13]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[O-]CC>C(O)C.N1C=CC=CC=1>[N:16]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:7][N:6]=2)[CH:9]=[CH:13][CH:14]=1
Reactant: Cc1ncc(I)cc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: CC[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCO
Product: c1cnc2ncccc2c1

Procedure:
5-Hydroxy-[1,7]naphthyridine-6-carboxamides. Preparation of specific examples of heterocycle W3.6 follows established precedent for 5-hydroxy--[1,7]naphthyridine ring synthesis (Just. Liebigs. 1979, 443-445.), Chart P. 5-Iodo-2-methylpyridine-3-carboxylic acid (P.1) (J. Am. Chem. Soc. 1953, 75, 737) is brominated under radical conditions (e.g. NBS, benzoylperoxide) to afford pyridine P.2. P.2 is treated with ethyl 2-N-toluenesulfonylaminoacetate to provide P.3. Upon treatment of P.3 with ethoxide in ethanol, ring cyclization and elimination occurs to afford naphthyridine P.4. The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature to afford the corresponding amides of the general formula P.5 or, alternatively, ester P.4 is saponified to afford the corresponding acid which is then coupled with a benzylamine employing standard amide coupling protocols (e.g. HOBT/EDC or other suitable carboxylic acid activating agent) to likewise provide amides of the general formula P.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>S(Cl)(Cl)=O.CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:20][CH:19]=1
Reactant: OC(c1cccnc1)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.6 %

Procedure:
The 3-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (87 mg, 0.39 mmol) obtained in Referential Example 11 was dissolved in thionyl chloride (1.0 ml). A catalytic amount of dimethylformamide was added to the resulting solution and the resulting mixture was stirred for 14 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane and the resulting mixture was concentrated further. The residue thus obtained was dissolved in dimethylformamide (5 ml), followed by the addition of 4-chlorobenzenethiol (84 mg, 0.58 mmol) and potassium carbonate (323 mg, 2.34 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (131 mg, 96%) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH2:22][C@H:21]3[CH2:24][O:25][CH3:26])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[ClH:29]>C(Cl)Cl.O1CCOCC1>[CH3:26][O:25][CH2:24][C@@H:21]1[CH2:22][CH2:23][N:20]1[C:13]1[N:14]2[C:18]([N:19]=[C:11]3[CH2:10][CH2:9][NH:8][CH2:28][CH2:27][C:12]=13)=[CH:17][CH:16]=[N:15]2.[ClH:29]
Reactant: COC[C@@H]1CCN1c1c2c(nc3ccnn13)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC[C@@H]1CCN1c1c2c(nc3ccnn13)CCNCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 60.1 mg (0.155 mmol) (S)-10-(2-methoxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 3 mL DCM was added 2 mL (3.1 mmol) HCl in dioxane (4 M) and the reaction was stirred at room temperature for 5 hours. The solvent was evaporated to give the desired product as a HCl salt.
Reaction SMILES: CCO[C:4](/[N:6]=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19]O)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(O)C#N>C(OCC)C>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][C:4]#[N:6])=[CH:16][CH:15]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: N#CCCc1ccc(Br)cc1
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
Diethylazodicarboxylate (5.2 g) is added dropwise to a solution of 4-bromo-phenethylalcohol (2.01 g), and triphenylphosphine (7.9 g) in diethyl ether (16 mL) at 0° C. The reaction mixture is stirred for 10 minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether (10 mL) is added. The clear orange solution is stirred for 5 minutes at 0° C. and then at 25° C. for 12 hours. The reaction mixture is then filtered, and washed with diethyl ether. The filtrate is concentrated under reduced pressure and chromatographed over silica gel (10% ethyl acetate-hexanes is used as the eluant) to provide the desired product as a pale yellow oil (2.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].S(=O)(=O)(O)O>[Zn].CCOCC>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[C:12]([CH3:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:18]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)C(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of 2-chlorobenzoyl chloride (52.2 g, 0.298 mol), ethyl 2-bromoisobutyrate (58.2 g, 0.298 mol) and ether is added in portions to zinc foil (19.5 g, 0.298 mol) and the resultant mixture stirred at reflux for three hours and overnight at room temperature. The mixture is poured into cold, dilute sulfuric acid and the organic layer is washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a yellow oil. The oil is chromatographed on silica gel with hexanes:ethyl acetate to afford the title compound as a colorless oil (41.8 g, 55.1%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:15]I>CN(C)C=O>[F:3][C:4]1[CH:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:15])=[O:7]
Reactant: O=Cc1ccc(C(=O)O)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (69 mg, 1.7 mmol) was added portionwise to a solution of 2-fluoro-4-formylbenzoic acid (0.30 g, 1.4 mmol) in N,N-Dimethylformamide (5.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred for 30 minutes. Methyl iodide (0.18 mL, 2.9 mmol) was introduced dropwise. After 2 hours, the mixture was quenched with 1 N HCl, and extracted with EtOAc. The extracts were washed with water (twice), brine (once), dried over sodium sulfate and concentrated. Flash column chromatography, eluting with a gradient from 0-15% ethyl acetate in hexanes afforded product as a white solid (190 mg, 72%). 1H NMR (300 MHz, CDCl3): δ 10.05 (d, 1H), 8.11 (dd, 1H), 7.73 (dd, 1H), 7.65 (dd, 1H), 3.98 (s, 3H); LCMS (M+H)+: 183.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].[O:41]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[O:44][CH2:43][CH:42]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([C:49]3[CH:48]=[CH:47][C:46]4[O:41][CH2:42][CH2:43][O:44][C:45]=4[CH:50]=3)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Reactant: OB(O)C1COc2ccccc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCCO4)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 96 °C
Reaction time: 15 h
Yield: 51.3 %

Procedure:
A mixture of 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (646 mg, 0.94 mmol), 1,4-benzodioxaneboronic acid (337 g, 1.87 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (103 mg, 0.14 mmol), and cesium carbonate (617 mg, 1.87 mmol) was added dimethoxyethane (15 mL) at room temperature under nitrogen atmosphere. The resulting brown reaction mixture was heated to 96° C. and stirred for 15 h at which time the TLC of the reaction mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with water (50 mL) and ethyl acetate (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic extracts were washed with water (100 mL) and brine solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent under reduced pressure gave the colored residue which was purified by using an ISCO 80 column, eluting with 5-25% ethyl acetate in hexanes to afford 4-(3-{6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-methanesulfonyl-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (336 mg, 51%) as a light brown viscous oil: ES(+)-LRMS m/e calcd for C38H48O10S (M+H)+ 697.3, found 697.23.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].CCN(CC)CC.[F:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CN(C)C=O.C(OCC)(=O)C>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([S:19]([F:18])(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Cl)c1ccc(S(=O)(=O)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(S(=O)(=O)F)cc1
Yield: 95.2 %

Procedure:
A solution of glycine tert-butyl ester hydrochloride (300 mg, 1.79 mmol) (Aldrich), Et3N (250 μL, 1.79 mmol), and 4-(fluorosulfonyl)benzoyl chloride (400 mg, 1.79 mmol) (Aldrich) in 9 mL of dry N,N-dimethylformamide was stirred at room temperature under a nitrogen atmosphere for 12 h. The reaction mixture was diluted with ethyl acetate. The organic phase was washed with distilled water, dried over sodium sulfate, filtered, and concentrated in vacuo to provide crude (4-fluorosulfonyl-benzoylamino)-acetic acid tert-butyl ester (541 mg, 95%) as an oil that solidified upon sitting at room temperature. The crude (4-fluorosulfonyl-benzoylamino)-acetic acid tert-butyl ester was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:29]([O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(O)CO>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:40][C:39]4[CH:38]=[CH:37][C:36]([O:35][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:42][CH:41]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: CCCCCCOc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCOc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1
Temperature: 170 °C
Yield: 23.1 %

Procedure:
To a magnetically stirred solution of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.89 mmol) in ethylene glycol (3.0 mL) under nitrogen at room temperature was added N,N-diisopropylethylamine (0.12 g, 0.89 mmol) followed by 4-hexyloxyaniline (0.27 g, 1.4 mmol). The reaction mixture was heated to 170° C. for 5.5 h, cooled to room temperature and partitioned between water (20 mL) and chloroform (20 mL). The aqueous layer was extracted with chloroform (20 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude brown solid was purified by chromatography (silica gel, 2:1 hexanes/ethyl acetate) to afford N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-n-hexyloxyphenyl)-2,4-pyrimidindiamine (0.09 g, 23%) as a white solid: Rf 0.53 (silica gel, 4:1 chloroform/ethyl acetate); mp 115-117° C.; 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J=3.2 Hz, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.29 (d, J=2.5 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 6.88-6.82 (m, 3H), 6.61 (s, 1H), 4.29 (d, J=3.1 Hz, 4H), 3.94 (t, J=6.6, 6.7 Hz, 2H), 1.77 (m, 2H), 1.47 (m, 2H), 1.35 (m, 4H), 0.92 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 156.3, 155.1, 150.3, 143.6, 142.7, 140.3, 140.07, 139.4, 133.0, 131.7, 121.9, 117.3, 115.0, 114.7, 110.8, 68.6, 64.6, 31.8, 29.5, 25.9, 22.8, 14.2; IR (ATR) 3357 cm−1; ESI MS m/z 439 [C24H27FN4O3+H]+; HPLC (Method B) 98.5% (AUC), tR=7.9 min. Anal. Calcd for C24H27FN4O3: C, 65.74; H, 6.21; N, 12.78. Found: C, 65.34; H, 6.19; N, 12.96.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:24][NH:25][O:26][CH3:27].Cl>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[CH3:27][O:26][N:25]([CH3:24])[C:3](=[O:4])[C:2]([CH3:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CON(C)C(=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition over 5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in aster (40 mL). Add, by dropwise addition, a solution of N,O-dimethylhydroxylamine hydrochloride (8.9 g, 91.2 mmol) in cater (20 mL) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N. 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer over (Na2SO4), filter, evaporate the filtrate in vacuo and purify by vacuum distillation to give 2-methyl-2-phenyl-propionic acid. N-methoxy-N-methylamide (18.0 g, 95%): by 91-103° C./5 mm Hg. MS (CI, CH4) m/e 208 (M++1, 100), 119.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH2:11]([O:13][C:14](=O)[O:15]CC)[CH3:12]>>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH2:1][C:14]([O:13][CH2:11][CH3:12])=[O:15])=[O:3])=[CH:5][CH:6]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(O)cc1
Product: CCOC(=O)CC(=O)c1ccc(O)cc1

Procedure:
This novel compound was synthesized by the acylation of 4-hydroxyacetophenone with diethylcarbonate to yield ethyl 4-hydroxybenzoylacetate. Treatment with acetic anhydride and subsequent catalytic hydrogenation yielded the desired product. The experimental details are given below:
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[CH:10]1[C:15]([O:16][C:17](Cl)=[O:18])=[CH:14][CH:13]=[C:12]([Cl:20])[CH:11]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:20][C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:18])[N:2]([C@H:3]2[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]2)[CH3:1])=[CH:10][CH:11]=1
Reactant: CN[C@H]1CC[C@H](O)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](O)CC1
Temperature: 25 °C

Procedure:
To a solution of 16.1 g (124.7 mmol) trans-4-methylamino-cyclohexanol in 40 ml CH2Cl2, 18.3 ml (130.9 mmol, 1.05 eq) 4-chlorophenylchloroformate and 22.4 ml (130.9 mmol, 1.05 eq) Huenigs base were added at 0° C. The solution was stirred at RT over night, diluted, and washed with 1M HCl, sat. aqueous NaHCO3 solution. The organic phase was dried over MgSO4. Column chromatography on silica gel with EtOAc:hexane 1:1 yielded 32.2 g (91%) trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester as white solid, MS: 283 (M, 1Cl).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[NH:8])C.[OH-].[Na+]>Cl>[C:10]1([NH:9][C:7]2[NH:8][CH:4]=[CH:5][N:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(CNC(=N)Nc1ccccc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(Nc2ncc[nH]2)cc1
Reaction time: 2 h
Yield: 50 %

Procedure:
The guanidine (b) was dissolved in HCl (5 mL, 6 M) at 0° C. and then stirred for 2 h. After the starting material was consumed, NaOH (25%) was added until a precipitate formed. This mixture was stirred for 30 min. The reaction was then poured into NaOH (0.5 M), extracted with CH2Cl2, dried and concentrated. Flash chromatography afforded (c) (0.95 g, 50%). 1H NMR (500 MHz, DMSO-d6) δ 8.58 (s, br, 1H), 7.34-6.74 (m, 5H), 6.68 (s, 2H), 6.62 (br, 2H), 3.82 (s, 6H), 3.73 (s, 3H). MS: 157.6 (M−H)−; 160.0 (M+H)+.