Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].Cl.[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>O1CCOCC1>[ClH:1].[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:26][CH2:25]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CN(C)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)C1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 19.8 %

Procedure:
First, 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (7.0 g, 0.0243 mol) is suspended in anhydrous dioxan (150 ml) and refluxed for 3 hours after the addition of 4-(dimethylamino)piperidine hydrochloride (4.9 g, 0.0298 mol) and triethylamine (10.0 g, 0.099 mol). Then the mixture is concentrated in vacuo. The residue is made alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and concentrated. The highly viscous residue is taken up in dioxan, clarified with activated charcoal and mixed with ethereal hydrochloric acid solution. The colorless crystals (2.0 g) obtained melted 258° C. after recrystallization from methanol.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30].[NH4+].[Cl-]>ClCCl>[CH:1]1([O:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:28]([O:29][CH3:30])=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCNC(COC2CCCCC2)C1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(COC2CCCCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Methyl 2-(cyclohexyloxymethyl)piperidine-4-carboxylate (2.13 g, 8.34 mmol) was dissolved in dichloromethane (50 mL). DIPEA (2.034 mL, 11.68 mmol) and methyl carbonochloridate (0.788 mL, 10.01 mmol) were added and the mixture was stirred at room temperature for 3 h. 0.1 M NH4Cl was added and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. Dimethyl 2-(cyclohexyloxymethyl)piperidine-1,4-dicarboxylate (2.54 g, 97%) was isolated. MS m/z 314 (M+H)+
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH3:8].[Li]CCCC.CN([CH:17]=[O:18])C>C(OCC)C>[CH2:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH:17]=[O:18])[CH3:8]
Reactant: CCc1sccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1sccc1C=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
A solution of 3-bromo-2-ethylthiophene, A7, (8.9 g, 0.0465 mol) in 50 mL of diethyl ether was cooled to -78° C., and a solution of n-BuLi (29.0 mL, 1.6M) in hexanes was added dropwise. When the addition was complete, the reaction was stirred at -78° C. for 5 min. Then DMF (5.1 g, 0.070 mol) was cannulated into the reaction mixture which was allowed to warm to ambient temperature and was stirred overnight. The reaction was quenched with water and extracted twice with diethyl ether. The organic extracts were combined, washed with twice with water and then brine and dried (MgSO4). The solution was filtered and concentrated to provide an oil which was purified on flash silica gel with 97.5:2.5 hexanes:diethyl ether to give 1.66 g (25%) of 2-ethylthiophene-3-carboxaldehyde, B7. The 1H NMR in CDCl3 supported the desired product structure. ##STR55##
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[CH3:34][O:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Cl.[OH-].[Na+]>CN(C=O)C.C(O)C>[CH3:34][O:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:30])([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]([OH:31])=[O:3])=[CH:12][CH:11]=2)[N:17]([CH3:22])[C:18]1=[O:21]
Reactant: COc1ccccc1CCl
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccccc1CN1CC(CCOc2ccc(CC(C)(Oc3ccccc3)C(=O)O)cc2)N(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
A solution of 2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (0.12 g, 0.281 mmol) in DMF (7 mL) is treated with NaH (60% oil suspension, 0.023 g, 0.575 mmol) and stirred at room temperature under N2 for 20 minutes. The reaction is treated with 2-methoxybenzyl chloride (0.066 g, 0.421 mmol) and then warmed to room temperature and stirred for 3 h. The reaction is quenched with 1 N HCl (10 mL) and worked up extractively with Et2O and water. The organic layer is dried (MgSO4) and the solvent removed in vacuo to afford crude product that is dissolved in ethanol (20 mL) is treated with aqueous 5 N NaOH (1.5 mL) and heated to ref lux 1 h. The reaction mixture is cooled, the solvent removed in vacuo. The resultant residue is acidified with aqueous 1 N HCl (20 mL) and extracted with CH2Cl2. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to afford crude acid that is purified by preparative HPLC to give 0.077 g (53%) of 3-(4-{2-[1-(2-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid. 1H NMR. HRMS (ES+) m/z exact mass calc'd for C30H35N2O6 (M+1) 519.2495. Found m/z 519.2515.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:22])[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 80 %

Procedure:
As described for example 163c, 3-((3-(5-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methylamino)-1-methyl-1H-pyrazole-5-carboxylic acid (76 mg, 0.23 mol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (95 mg, 80%) which was obtained as a white solid. MS: m/e=415.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[N:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][CH2:20][CH2:19][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=1
Reactant: COCCBr
Reactant: COCOc1ccc(O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(OCOC)cn1
Temperature: 60 °C
Yield: 26.9 %

Procedure:
To a mixture of 5-(methoxymethoxy)pyridin-2-ol (1.35 g, 8.71 mmol, 1 eq.) and K2CO3 (6.01 g, 43.6 mmol, 5.0 eq.) in DMF (30.0 mL) was added 1-bromo-2-methoxyethane (3.61 g, 26.1 mmol, 3 eq.). The mixture was heated at 60° C. for 2 h, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (500 mg, 27%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=3.0 Hz, 1H), 7.35 (ddd, J=8.9, 3.0, 1.0 Hz, 1H), 6.76 (dd, J=8.9, 1.0 Hz, 1H), 5.11 (s, 2H), 4.48-4.40 (m, 2H), 3.79-3.71 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H). MS (ESI) m/z 214.1 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:19])=[C:15]([NH2:18])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[CH2:34][C:33](=[O:35])[NH:32][CH:31]=[C:30]2[C:36](Cl)=[O:37])=[CH:25][CH:24]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.Cl>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:19])=[C:15]([NH:18][C:36]([C:30]3[C@H:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH2:34][C:33](=[O:35])[NH:32][CH:31]=3)=[O:37])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1N
Reactant: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)Cl)=CN1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1NC(=O)C1=CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine (89 mg, 0.29 mmol) and (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride (74 mg, 0.29 mmol, prepared as described in Example 1) were dissolved in pyridine (2 ml) together with a crystal of DMAP and sealed in a tube. The mixture was heated to 90° C. with stirring for 18 hours. Upon cooling the mixture was diluted with dilute aqueous HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give 46 mg (30.3%) of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-yl}-amide as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[CH:32]=[CH:31][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=5)[N:17]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:5][CH2:4][O:3]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[F:52][C:53]1([F:59])[CH2:55][CH:54]1[C:56](O)=[O:57]>CN(C=O)C>[F:52][C:53]1([F:59])[CH2:55][CH:54]1[C:56]([NH:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:16]=[C:15]2[C:13]1[NH:12][C:11]2[CH:31]=[CH:32][C:8]([N:6]3[CH2:5][CH2:4][O:3][CH:2]([CH3:1])[CH2:7]3)=[CH:9][C:10]=2[N:14]=1)=[O:57]
Reactant: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(N)cc45)nc3c2)CCO1
Reactant: O=C(O)C1CC1(F)F
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.8 %

Procedure:
3-(5-(2-Methylmorpholino)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.046 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (9.37 mg, 0.069 mmol), EDC (13.30 mg, 0.069 mmol) and sodium bicarbonate (3.88 mg, 0.046 mmol) was added to a solution of 2,2-difluorocyclopropanecarboxylic acid (5.64 mg, 0.046 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (16 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.51 (s, 1H), 7.75-7.65 (m, 2H), 7.56 (m, 1H), 7.04 (m, 2H), 5.84 (dd, 1H, J=2.4 and 9.6 Hz), 3.98 (m, 2H), 3.80 (m, 3H), 3.51 (m, 1H), 3.43 (m, 1H), 2.77 (m, 2H), 2.60 (m, 1H), 2.11 (m, 3H), 1.85 (m, 2H), 1.70 (m, 2H), 1.23 (d, 3H, J=6.0 Hz); ESI-MS [M+H]+: 537.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (311 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (400 mg, 75%).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:9])(C)(C)C.[CH3:28]C(O)=O>>[F:18][C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[C:10]([C@@H:8]([NH:7][C:6](=[O:5])[CH3:28])[CH3:9])[N:19]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:13]=2[CH:14]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cccnc1
Reactant: CC(=O)O
Product: CC(=O)N[C@@H](C)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 100 °C
Yield: 57 %

Procedure:
A solution of {(S)-1-[4-fluoro-2-(pyridin-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (47 mg, 0.126 mmol) in AcOH (1 mL) was heated at 100° C. for 28 h in a sealed tube. In a separate vial, {(S)-1-[4-fluoro-2-(pyridin-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (228 mg, 0.61 mmol) was dissolved in AcOH (2 mL) and heated at 100° C. for 17 h. After cooling to RT, the two reaction mixtures were combined and the volatiles were removed in vacuo. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as an orange oil (126 mg, 57%). LCMS (Method C): RT 2.16 min [M+H]+ 299.3. 1H NMR (CDCl3, 400 MHz): δ 8.84 (1H, dd, J=4.82, 1.02 Hz), 8.75 (1H, s), 7.95 (1H, s), 7.72-7.57 (2H, m), 7.47 (1H, s), 7.07 (1H, td, J=9.15, 2.31 Hz), 6.80 (1H, d, J=8.61 Hz), 5.21-5.09 (1H, m), 1.96 (3H, s), 1.50 (3H, d, J=6.99 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:25][C:26]1[N:31]=[C:30]([O:32][CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:29]=[CH:28][CH:27]=1)(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[N:13]([CH2:25][C:26]4[N:31]=[C:30]([O:32][CH2:33][C@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:29]=[CH:28][CH:27]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncc2cc(-c3ccc(Cl)cc3)sc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(COS(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(Cn2ncc3cc(-c4ccc(Cl)cc4)sc3c2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(4-Chlorophenyl)thieno[2,3-d]pyridazin-7(6H)-one (285 mg, 1.1 mmol) was added to dry DMF (5 mL) and NaH (71 mg, 55% in mineral oil, 1.6 mmol) was added in small potions and stirred 10 min. tert-butyl (2R)-2-{[(6-{[(methylsulfonyl)oxy]methyl}pyridin-2-yl)oxy]methyl}pyrrolidine-1-carboxylate (420 mg, 1.1 mmol) dissolved in dry DMF (3 mL) was added drop wise and the reaction mixture was stirred at ambient temperature for 3 h. Water was added and the aqueous phase was extracted three times with DCM. The organic phase was evaporated and purified by flash chromatography using a gradient of EtOAc/heptane to give the title compound as a yellow solid. Yield: 380 mg (63%). 1H NMR (399.961 MHz, CDCl3) δ 8.22 (s, 1H), 7.64 (d, J=8.7 Hz, 2H), 7.53-7.42 (m, 4H), 6.72 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 5.48 (s, 2H), 4.41-4.01 (m, 3H), 3.43-3.25 (m, 2H), 1.97-1.74 (m, 4H), 1.42 (s, 9H). MS (ESI+) 553.3 (M+1H+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:13]([C:12]2[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[F:1])=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Reactant: Cc1onc(-c2ccncc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccncc2F)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 3-(3-fluoro-pyridin-4-yl)-5-methyl-isoxazole-4-carboxylic acid (0.41 g, 0.0019 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.55 g, 0.0019 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.36, 0.0019 mol), 1-hydroxy-7-azabenzo-triazole (0.25 g, 0.0019 mol), and N,N-diisopropylethyl amine (0.96 mL, 0.0055 mol), in N,N-dimethylformamide (10 mL). Stir the mixture overnight at ambient temperature. Concentrate in vacuo and take up the residue in water and extract with ethyl acetate. Concentrate and elute over silica gel using methanol/dichloromethane resulting in the isolation of 0.66 g (76%) of the desired amide as a light yellowish solid. MS(ES): (M+1)+ 467.0, 468.1 m/z.
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])[CH:7]=[N:6][CH:5]=1)=[N+]=[N-].[H][H]>[Pd].[NH4+].[OH-]>[NH2:1][C:4]1[N:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])[CH:7]=[N:6][CH:5]=1
Reactant: COc1ccc(C)cc1NC(=O)Nc1cncc(N=[N+]=[N-])n1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccc(C)cc1NC(=O)Nc1cncc(N)n1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(6-azido-pyrazin-2-yl)-3-(2-methoxy-5-methyl-phenyl)-urea (8 mg, 27 μmol) 95% EtOH (2mL) at room temperature was added concentrated NH4OH (10 μL) and 10% Pd on C (25 mg). The suspension was put through a vacuum/purge cycle three times with hydrogen gas and then held under 50 psi of hydrogen pressure and shaken on a Parr Shaker. After 2 hours the vacuum/purge cycle was repeated and the reaction held under hydrogen for another 2 hours. The suspension was then filtered through GF/F filter paper with EtOH and concentrated to a yellow film (3 mg, 41%). 1H-NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 6.83 (s, 2H), 3.95 (s, 3H), 2.33 (s, 3H). LRMS (ESI, Positive) m/e 274.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)[C:10]2=[O:13])=[CH:5][CH:4]=1>O1CCCC1.CO.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)CC2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)C(Cc1cccc(N)c1)CC2
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A mixture of 626 mg (2.02 mmol) of the product of Example 28 and 125 mg of 10% Pd/C in 15 mL tetrahydrofuran and 15 mL CH3OH was hydrogensted on a Parr (trademark) Hydrogenator under 25 psi H2 at room temperature. After 30 minutes, the reaction mixture was filtered through diatomaceous earth [Celite (trademark)], the filtrate concentrated in vacuo, and the residue purified by silica gel chromatography (5% ethyl acetate-CH2Cl2) to yield 369 mg of pure product, a yellow solid. m.p.: 159°-161° C. MS (LSIMS): 282 M+H, 155 Base; 1H NMR (AC 300, CDCl3): δ3.84 (s, 3H); 3.64 (br s, 2H, NH2); IR (cm31 1): 3360, 6450, 1665. Analysis calculated: C 76.85, H 6.81, N 4.98%; found: C 75.94, H 6.66, N 4.77%.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH2:21][CH3:22])[C:15]=1[CH:23]1[C:28](=[O:29])[CH2:27][CH:26]([CH2:30][CH:31]([S:33][CH2:34][CH3:35])[CH3:32])[CH2:25][C:24]1=[O:36])[CH3:13]>ClCCl>[CH2:21]([C:16]1[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH2:12][CH3:13])[C:15]=1[CH:23]1[C:24](=[O:36])[CH2:25][CH:26]([CH2:30][CH:31]([S:33]([CH2:34][CH3:35])=[O:6])[CH3:32])[CH2:27][C:28]1=[O:29])[CH3:22]
Reactant: CCSC(C)CC1CC(=O)C(c2c(CC)cc(C)cc2CC)C(=O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1cc(C)cc(CC)c1C1C(=O)CC(CC(C)S(=O)CC)CC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 70% 3-chloroperoxybenzoic acid (0.104 g, 0.42 mmol) in dichloromethane (2 ml) is added dropwise to a solution of 2-(2,6-diethyl-4-methylphenyl)-5-[2-(ethylthio)propyl]cyclo-hexane-1,3-dione (0.17 g, 0.47 mmol) in dichloromethane (3 ml) at 0° C. and the reaction mixture is stirred for 1 hour at 0° C. and then left to stand at room temperature overnight. The reaction mixture is diluted with dichloromethane, washed with 15% aqueous sodium metabisulfite solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is purified by column chromatography on silica gel to give 2-(2,6-diethyl-4-methylphenyl)-5-[2-(ethylsulfinyl)propyl]cyclohexane-1,3-dione, m.p. 58-61° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:17](=O)[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(O)(O)(=O)=O.[CH3:25][O:26][C:27](=[NH:29])[NH2:28].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[NH:29][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:28]=1
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A reaction mixture containing 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, ethyl ester (2.62 g, 10.0 mmole), O-methylpseudourea hydrogen sulfate (1.72 g, 10.0 mmole), and sodium bicarbonate (2.52 g, 30.0 mmole) in dimethylformamide (7 ml) was heated at 65°-70° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and filtered. The filtrate was washed with water and brine, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a yellow oil which was purified by flash chromatography (5% ethyl acetate in dichloromethane). The resulting foam was crystallized from isopropyl ether/hexanes to provide 2.41 g of 1, 4-dihydro-2-methoxy-6-methyl -4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester as a colorless crystalline product; melting point 103.5°-105° C. Analysis Calc'd. for C15H17N3O5 :
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[F:15][C:16]([F:36])([F:35])[C:17]1[CH:34]=[CH:33][C:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30](=O)[CH3:31])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:30]([CH3:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:20]3[CH:33]=[CH:34][C:17]([C:16]([F:15])([F:35])[F:36])=[CH:18][CH:19]=3)=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 36, Step 2, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-propan-2-one.