Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].I[CH:10]([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:10]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)n1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.2 %

Procedure:
4-nitroimidazole (0.500 g, 4.42 mmol), 2-iodopropane (0.553 ml, 5.53 mmol) and powdered K2CO3 (0.917 g, 6.63 mmol) were combined and stirred in DMF (25 ml) at 50° C. After 5 h, the reaction was cooled to RT. The reaction was diluted with EtOAc and filtered to remove inorganic salts, rinsing forward with EtOAc. The filtrate was evaporated to near dryness. The residue was diluted in EtOAc, washed with H2O (2×) and brine (1×), dried (MgSO4) and evaporated to afford 1-isopropyl-4-nitro-1H-imidazole (0.66 g, 96% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1H) 7.98 (s, 1H), 4.52-4.49 (m, 1H), 1.44 (d, 6H); MS (ESI) m/z: 156.0 (M+H+), 178.0 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH2:25](O)[CH3:26]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:25][CH3:26])=[O:5]
Reactant: CCO
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 2-methyl-5-nitrobenzoic acid (27.6 mmol, 5 g) in ethanol (100 mL), sulfuric acid (138 mmol, 7.36 ml) was added slowly and stirred overnight at 80° C. The reaction mixture was neutralized with saturated solution of Na2CO3, extracted with diethyl ether (3×), organic layers were washed with brine, dried and concentrated under reduced pressure to yield crude product ethyl 2-methyl-5-nitrobenzoate 101 (5.4 g, 95%). NMR (400 MHz, CDCl3) 1.44 (t, J=7.0 Hz, 3H), 2.72 (s, 3H), 4.42 (q, J=7.04 Hz, 2H), 7.43 (d, J=8.6 Hz, 1H), 8.23 (dd, J=8.6 Hz and 2.7 Hz, 1H), 8.76 (d, J=2.7 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN(C)C=O>[C:1]1([C:7]2[N:8]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
A solution of 2-phenylindole (4.2 g, 21.7 mmol) and sodium hydride (60% in oil, 0.96 g, 24 mmol) in tetrahydrofuran (90 mL) and N,N-dimethylformamide (10 mL) was stirred under ice-cooling for 20 min. To the reaction mixture was added methyl 4-bromomethylbenzoate (5.0 g, 21.8 mmol), and the mixture was stirred at room temperature for 18 hr. An aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:5-1:2) to give the title compound (2.8 g, yield 38%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@@:26]3([CH2:47][C@H:21]2[C:20](=[O:48])[NH:19][C@:18]2([C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:49][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[O:45][C:30]1[C:31]([C:41]([F:44])([F:43])[F:42])=[N:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][C:38]=2[C:29]=1[C:28](=[O:46])[CH2:27]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:55][Mg+].[Br-]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@@:26]3([CH2:47][C@H:21]2[C:20](=[O:48])[NH:19][C@:18]2([C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:49][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[O:45][C:30]1[C:31]([C:41]([F:44])([F:42])[F:43])=[N:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][C:38]=2[C:29]=1[C:28]([OH:46])([CH3:55])[CH2:27]3)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@]3(CC(=O)c4c(c(C(F)(F)F)nc5ccc(OC)cc45)O3)C[C@H]1C(=O)N2
Reactant: C[Mg+]
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@]3(CC(=O)c4c(c(C(F)(F)F)nc5ccc(OC)cc45)O3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@]3(C[C@H]1C(=O)N2)CC(C)(O)c1c(c(C(F)(F)F)nc2ccc(OC)cc12)O3
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@]3(C[C@H]1C(=O)N2)CC(C)(O)c1c(c(C(F)(F)F)nc2ccc(OC)cc12)O3
Temperature: -25 °C
Reaction time: 0.33 h

Procedure:
To the solution of (2S,6S,13aS,14aR,16aS,Z)-ethyl 6-((tert-butoxycarbonyl) amino)-9′-methoxy-1′,5,16-trioxo-5′-(trifluoromethyl)-1′,2′,3,5,6,7,8,9,10,11,13a,14,14a,15, 16,16a-hexadecahydro-1H-spiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3′-pyrano[2,3-c]quinoline]-14a-carboxylate (2923 mg, 3.85 mmol) in THF (26 ml) was added 1.4M of MeMgBr solution in THF (11.01 ml, 15.41 mmol) at −25° C. and stirred at −25° C. for 20 min. TLC and LC-MS indicated that the major was product (about 50%) and starting material. Then the reaction was quenched with 1N HCl to pH=5-6 (about 12 ml 1N HCl), and diluted with EtOAc (40 ml). The layers were separated, and the aq. layer was extracted again with EtOAc (25 ml×2). The organic layers were combined and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (120 g, gold column), eluting with 100% hexane for 400 ml, gradient to 35% of acetone to give 1430 mg of starting material and 1130 mg of (2S,6S,13aS,14aR,16aS,Z)-ethyl 6-((tert -butoxycarbonyl)amino)-1′-hydroxy-9′-methoxy-1′-methyl-5,16-dioxo-5′-(trifluoromethyl)-1′,2′,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydro-1H-spiro[cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2,3′-pyrano[2,3-c]quinoline]-14a-carboxylate as a light yellow solid. m/z=775.4 (M+1)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[NH2:8][C:9]1[C:10]([C:16](O)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:16]([NH:7][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1
Reactant: Cn1cc(N)cn1
Reactant: Nc1ccc(Br)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(NC(=O)c2nc(Br)ccc2N)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 100 mL round bottom flask containing 1-methyl-1H-pyrazol-4-amine (700 mg, 7.0 mmol), 3-amino-6-bromopicolinic acid (1.86 g, 8.5 mmol) and PyBop (4.12 g, 8.0 mmol) was added methylene chloride (30 mL) and diisopropylethylamine (3.8 mL, 21.6 mmol). The reaction mixture was stirred for 24 hr at room temperature and the reaction was monitored by LCMS. Upon completion of the reaction, the solvent was distilled off and the crude material was purified via flash chromatography, heptane/ethyl acetate 0% to 100% to afford a yellow solid. A fraction of it was purified via reverse phase HPLC to afford 317. 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.02 (br, 2H), 3.81 (s, 3H). MS (ESI) m/z: 296.0/298.0 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5]>CCOC(C)=O.CCO.[Pd]>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)C#Cc1cccc(N)c1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)CCc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A suspension of 2-amino-6-(3,3-dimethylbut-1-ynyl)benzonitrile (Example 21c, 690 mg, 3.48 mmol) and 10% Pd/C (100 mg) in EtOAc/EtOH (1:1, 20 mL) was stirred under an atmosphere of H2 with a balloon at room temperature overnight. The Pd/C was removed by filtration, the filtrate was concentrated, and purified by chromatography on silica gel eluting with 20% EtOAc in hexanes to give the title compound as a light yellow oil (620 mg, 88%). 1H NMR (400 MHz, DMSO-d6) δ 0.92 (s, 9H), 1.36-1.40 (m, 2H), 2.52-2.56 (m, 2H), 5.88 (s, 2H), 6.45 (d, J=7.6 Hz, 1H), 6.57 (d, J=7.6 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H). MS 203 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>ClCCl.CN(C1C=CC=CN=1)C>[C:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
13.8 Grams (0.1 mol) of 4-hydroxybenzoic acid was dissolved in 140 ml of dichloromethane. To this mixture were consecutively added 16 ml of triethylamine, 20.1 g (0.11 mol) of n-decanoic acid chloride and 0.97 g (0.0079 mol) dimethylaminopyridine, and the mixture was stirred at room temperature over 1 day and night. To this reaction mixture was added 50 ml of 10% hydrochloric acid, and the mixture was extracted with 100 ml of ether three times. An organic layer was washed with 100 ml of sodium chloride aqueous solution three times, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was washed with 400 ml of hexane to give 25.5 g (yield 82%) of 4-decanoyloxybenzoic acid as an end product.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([N:28]=1)[C:24]1[CH:23]=[C:22]([OH:25])[CH:21]=[C:20]([F:26])[C:19]=1[O:18][C:17]1[C:12]2=[CH:13][C:14](Br)=[CH:15][CH:16]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([N:28]=1)[C:24]1[CH:23]=[C:22]([OH:25])[CH:21]=[C:20]([F:26])[C:19]=1[O:18][C:17]1[C:12]2=[CH:13][C:14]([C:35]2[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
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: CN(C)C=O
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Temperature: 85 °C

Procedure:
Sodium carbonate (saturated, 2 mL), Pd(PPh3)4 (0.237 g, 0.205 mmol), (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (0.75 g, 2.054 mmol), and 2-fluoropyridine-3-boronic acid (310 mg, 2.18 mmol) were combined in DMF (5 mL). The solution was heated at 85° C. overnight before being cooled to rt. The solution was diluted with water (25 ml) and filtered. The solids were triturated with MeOH and dried under vacuum to afford (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a tan solid. MS m/z=382.0 [M+H].
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([N:9]3[CH2:41][CH2:40][C:12]4[N:13]=[C:14]([C:19]5[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]6[C:20]=5[C:21]([CH3:39])=[N:22][N:23]6[S:29]([C:32]5[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[N:15]=[C:16]([O:17][CH3:18])[C:11]=4[CH2:10]3)[N:6]([CH3:42])[N:5]=2)[CH2:3][CH2:2]1.[Cl:43]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:43][C:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]([CH3:42])[C:7]=1[N:9]1[CH2:41][CH2:40][C:12]2[N:13]=[C:14]([C:19]3[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]4[C:20]=3[C:21]([CH3:39])=[N:22][N:23]4[S:29]([C:32]3[CH:33]=[CH:34][C:35]([CH3:36])=[CH:37][CH:38]=3)(=[O:31])=[O:30])[N:15]=[C:16]([O:17][CH3:18])[C:11]=2[CH2:10]1
Reactant: COc1nc(-c2c(C)ccc3c2c(C)nn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C3CC3)nn1C)CC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1nc(-c2c(C)ccc3c2c(C)nn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1c(Cl)c(C3CC3)nn1C)CC2
Reaction time: 8 h

Procedure:
To a solution of 6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (7.0 g, 11.99 mmol) in DCM (120 mL) was added N-chlorosuccinimide (1.76 g, 13.19 mmol) at room temperature, and the reaction mixture was stirred overnight. The mixture was then concentrated and the residue was directly purified by FCC (20-100% EtOAc/heptane) to provide 6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 619.9 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([S:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=2)=[CH:11][N:12]=1.[NH2:23][CH2:24][C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[OH:26][C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:20](=[O:22])[C:16]1[CH:15]=[C:14]([S:13][C:10]2[S:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:12][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NCC(O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(Sc2cnc(Nc3ccccn3)s2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(O)(c1ccccc1)c1ccccc1)c1cc(Sc2cnc(Nc3ccccn3)s2)ccn1
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 0 %

Procedure:
To a solution of 4-(2-(pyridine-2-ylamino)thiazol-5-ylthio)picolinic acid (0.063 g, 0.19 mmol) and 2-amino-1,1-diphenylethanol (0.060 g, 0.28 mmol, 1.5 eq, described in Example D) in NMP (3 mL), was added EDAC (0.055 g, 0.28 mmol, 1.5 eq), HOBt (0.026 g, 0.19 mmol, 1 eq) and diisopropylethylamine (0.100 mL, 0.57 mmol, 3 eq). The resulting mixture was stirred at 23° C. for 3.5 h. The mixture was purified on preparative HPLC (ammonium acetate/water/acetonitrile) and freeze dried to give the title compound as a solid (0.024 mg, 24%). The product was converted to the HCl salt by dissolving it in ethyl acetate (2 mL) and tetrahydrofuran (2 mL) and treating the mixture with a solution of HCl (4.0 M in dioxane, 0.011 mL, 0.045 mmol, 1 eq). The mixture was concentrated, then diluted with water and lyophilized to give the HCl salt of the title material (0.029 g) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.10 (2H, d, J=5.56 Hz), 6.30 (1H, s), 7.01 (1H, dd, J=6.69 and 5.43 Hz), 7.11-7.20 (3H, m), 7.28 (4H, t, J=7.71 Hz), 7.37 (1H, dd, J=5.31, 2.02 Hz), 7.42-7.48 (4H, m), 7.66 (1H, d, J=1.52 Hz), 7.79 (1H, ddd, J=9.22, 6.32 and 1.89 Hz), 8.31 (1H, dd, J=5.43 and 1.39 Hz), 8.40 (1H, t, J=4.80 Hz), 8.41 (1H, d, J=4.8 Hz), 11.86 (1H, s). LC/MS (M+H)+: 526. Ret. time: 2.00 (Condition D). HRMS: calcd: 526.1371; found: 526.1387.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][CH:19]=2)[C:13](=[O:27])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.CC(O)=O.[Pd]>[O:27]=[C:13]1[CH2:12][NH:11][CH2:16][CH2:15][N:14]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=[NH:25])=[CH:20][CH:19]=1
Reactant: N=C(N)c1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1ccc(CN2CCNCC2=O)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-(4-carbamimidoylbenzyl)-3-oxopiperazine-1-carboxylic acid benzyl ester (2.0 g, 5.0 mmol) in 40 mL of MeOH and 4 mL of AcOH is added 10% Pd/C (0.4 g). The atmosphere above the reaction is replaced by hydrogen. After 4 hours, the solution is filtered through a pad of Celite. The organic layer is concentrated. The resulting crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1%TFA) to 40% CH3CN/H2O (0.1% TFA). The title compound is obtained as a white foam. 1H NMR (d6-DMSO, 300 MHz) δ9.3 (bs, 4H), 9.1 (bs, 2H), 7.83 (d, 2H), 7.42 (d, 2H), 4.78 (s, 2H), 3.80 (s, 2H), 3.44 (m, 2H), 3.32 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([C:10]1[N:11]=[C:12]([CH3:16])[O:13][C:14]=1[CH3:15])(=[O:9])[CH3:8]>>[CH3:16][C:12]1[O:13][C:14]([CH3:15])=[C:10]([C:7]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:9])[CH3:8])[N:11]=1
Reactant: CC(=O)c1nc(C)oc1C
Reactant: Brc1ccsc1
Product: Cc1nc(C(C)(O)c2ccsc2)c(C)o1

Procedure:
Starting with 3-bromothiophene and 4-acetyl-2,5-dimethyloxazole and following the general method of Example 4 the title compound was prepared. M.p. 83°-84° C.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1([CH3:18])[CH2:13][CH2:12][CH:11]([CH:14]([CH3:16])[CH3:15])[CH:10](O)[CH2:9]1.S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([O:7][CH:10]1[CH:11]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:13][CH:8]([CH3:18])[CH2:9]1)(=[O:6])[CH2:2][C:3]([O:5][CH:10]1[CH:11]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:13][CH:8]([CH3:18])[CH2:9]1)=[O:4]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)CC(=O)OC2CC(C)CCC2C(C)C)C1
Yield: 76.2 %

Procedure:
Malonic acid (22.2 g, 0.213 mol) and menthol (70 g, 0.448 mol) are brought to reflux for 6 hours in 100 ml of toluene in the presence of 2 ml of concentrated sulfuric acid in a reactor surmounted by a Dean & Stark apparatus. The water formed is removed by azeotropic distillation. The organic phase is washed 3 times with water and is dried over sodium sulfate. The excess menthol is removed by distillation under vacuum (140° C. under 0.6 hPa). The residue is treated with animal charcoal in isopropanol at reflux. After filtering, rinsing and evaporating the solvent, 61.8 g (Yield 76%) of dimenthyl malonate are obtained in the form of a yellow oil which is used as is in the following stage.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[NH2:14]>C(OCCOCCOCC)C>[CH3:10][C:11]1[CH:12]=[C:13]([NH:14][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: CSc1nccc(=O)[nH]1
Reactant: Cc1cc(C)cc(N)c1
Solvent: CCOCCOCCOCC
Product: Cc1cc(C)cc(Nc2nccc(=O)[nH]2)c1
Temperature: 170 °C

Procedure:
2-(Methylthio)pyrimidin-4(3H)-one (4-1, 2.00 g, 14.1 mmol) and 3,5-dimethylaniline (2.10 ml, 16.9 mmol) were stirred in 14 ml of 2-ethoxyethyl ether and the resulting solution was heated to 170° C. After 3 days the reaction was concentrated in vacuo. The residue was diluted with 95:5 DCM/MeOH. The solid, which did not dissolve, was filtered to afford a sample of pure 2-(3,5-dimethylphenylamino)-3H-pyrimidin-4-one. The filtrate was concentrated in vacuo and the residue was triturated with ether. The mixture was filtered and the solid was washed with ether. The solid sample was combined with the previous precipitate to afford 2-(3,5-dimethyl-phenylamino)-3H-pyrimidin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@H:15]3[C@H:20]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[N:35]([CH3:36])[N:34]=[N:33][N:32]=5)[CH:26]=4)=[O:23])[CH2:19][CH2:18][NH:17][CH2:16]3)=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@H:15]3[C@H:20]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[N:35]([CH3:36])[N:34]=[N:33][N:32]=5)[CH:26]=4)=[O:23])[CH2:19][CH2:18][N:17]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:16]3)=[O:14])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCNC[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCN(S(C)(=O)=O)C[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 0.42 h
Yield: 57.7 %

Procedure:
In a dry flask 1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea (67 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and then triethylamine (65 •L, 0.47 mmol) and methanesulfonyl chloride (9 μL, 0.11 mmol) were added. The reaction mixture was stirred for 25 minutes. The reaction mixture was concentrated in vacuo then was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (38 mg, 60%). 1H NMR NMR (400 MHz, DMSO-d6, 140° C.), δ: 8.37 (s, 1H), 7.89 (t, 1H, J=2), 7.54 (d, 1H, J=6), 7.44 (t, 1H, J=8), 7.35 (m, 1H), 7.14 (m, 2H), 6.99 (t, 2H, J=9), 6.05 (d, 1H, J=8), 4.12 (s, 3H), 4.05 (d, 2H, J=14), 3.85 (m, 1H), 3.63 (m, 2H), 3.16 (td, 1H, J=10, J′=4), 2.90 (m, 3H), 2.88 (s, 3H), 2.66 (m, 1H), 2.56 (dd, 1H, J=14, J′=6), 2.44 (dd, 1H, J=14, J′=8), 2.01 (m, 1H), 1.79 (qd, 1H, J=13, J′=4), 1.65 (bs, 3H), 1.40 (m, 1H), 1.20 (m, 1H). HRMS (ESI), C28H36FN8O4S m+/z: calc. 599.2564, found=599.2586.
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:15][CH2:16][CH3:17])[CH:3]=1.[N+](=[CH2:20])=[N-]>O1CCCC1.CCOCC>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([S:11]([CH3:14])(=[O:12])=[O:13])[C:2]([Cl:1])=[CH:3][C:4]=1[O:15][CH2:16][CH3:17]
Reactant: C=[N+]=[N-]
Reactant: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)OC
Reaction time: 0.17 h

Procedure:
A solution of 4-chloro-2-ethoxy-5-methanesulfonylbenzoic acid (2.5 g, 9.0 mmol) in tetrahydrofuran was cooled to 5° C. and treated with excess diazomethane in ether solution (prepared from N-methyl-N-nitroso-p-toluenesulfonamide, Aldrich) and stirred for 10 min. Solvent and excess diazomethane was removed by rotary evaporation. The resulting residue was dissolved in dichloromethane and filtered through a plug of silica gel and evaporated. The solids were triturated with ether/hexane to give 4-chloro-2-ethoxy-5-methanesulfonyl-benzoic acid methyl ester (2.1 g, colorless solids).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=O)[CH:8](Br)[CH2:7]1)=[O:5])[CH3:2].[C:14]([NH2:20])([NH2:19])=[N:15][C:16]([NH2:18])=[S:17]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2[N:18]=[C:16]([NH:15][C:14]([NH2:20])=[NH:19])[S:17][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: NC(=S)N=C(N)N
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Product: CCOC(=O)C1CCc2nc(NC(=N)N)sc2C1

Procedure:
Analogously to the preparation of Example C-01, 3-bromo-4-oxo-cyclohexane carboxylic acid ethyl ester is reacted with 2-imino-4-thiobiuret to form the title compound.