Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH2:7][C:8]#[N:9].C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7](=[N:14][OH:15])[C:8]#[N:9]
Reactant: O=N[O-]
Reactant: CN1CCN=C1CC#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN=C1C(C#N)=NO
Reaction time: 2 h

Procedure:
12.3 g (0.1 mol) of 1-methyl-2-cyanomethyl-2-imidazoline are initially introduced into 50 ml of glacial acetic acid. A solution of 7.8 g (0.1 mol) of NaNO2 in 20 ml of water is added dropwise at about 15°, with cooling. The mixture is stirred for 2 hours, cooled and filtered and the residue is washed with a little cold water. This yields 11 g (=73% of theory) of end product, which is recrystallised from methanol; melting point 216.5° C.
Reaction SMILES: [CH2:1]([O:14][C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]C)=[CH:23][CH:22]=2)=[N:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(OC1C=NC(C2C=CC(CCCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCCC.C(OC1C=NC(C2C=CC(CCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCCC>>[CH2:1]([O:14][C:15]1[CH:20]=[N:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=2)=[N:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCCCC)cc2)nc1
Product: CCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCC)cc2)nc1

Procedure:
5-tridecyloxy-2-(4-hexylphenyl)pyrimidine ##STR35## 5-tridecyloxy-2-(4-heptylphenyl)pyrimidine 5-tridecyloxy-2-(4-octylphenyl)pyrimidine ##STR36## 5-tridecyloxy-2-(4-nonylphenyl)pyrimidine ##STR37## 5-tridecyloxy-2-(4-decylphenyl)pyrimidine 5-tridecyloxy-2-(4-undecylphenyl)pyrimidine
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12](Br)=[CH:13][C:8]=3[S:7](=[O:16])(=[O:15])[C:6]=2[CH:17]=1.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C@@H:20]([OH:26])[CH2:19]2.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[O:15]=[S:7]1(=[O:16])[C:6]2[CH:17]=[CH:2][CH:3]=[CH:4][C:5]=2[C:9]2[CH:10]=[CH:11][C:12]([O:26][C@@H:20]3[CH:21]4[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]4)[CH2:19]3)=[CH:13][C:8]1=2
Reactant: O=S1(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: O[C@H]1CN2CCC1CC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=S1(=O)c2ccccc2-c2ccc(O[C@H]3CN4CCC3CC4)cc21
Temperature: 110 °C
Reaction time: 30 h
Yield: 38.3 %

Procedure:
A mixture of 3,7-dibromodibenzothiophene-5,5-dioxide (0.60 g, 1.75 mmol; see J. Med. Chem. 1978, 21, 1084), (R)-(−)-quinuclidin-3-ol (280 mg, 2.2 mmol; Acros), copper (I) iodide (33 mg, 0.17 mmol; Aldrich), 1,10-phenanthroline (63 mg, 0.35 mol; Aldrich) and powdered cesium carbonate (0.86 g, 2.64 mmol; Aldrich) in toluene (2 mL) was heated to 110° C. with vigorous stirring for 30 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, rinsing with ethyl acetate and dichloromethane, and the residue purified by flash chromatography (80 g silica gel, 1:10:89 NH4OH-MeOH—CH2Cl2) to afford the title compound (0.23 g, 0.67 mmol; 38% yield): MS (DCI/NH3): m/z 342 (M+1)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:5][CH:4]=1.Br.C1(C)C=CC=CC=1>[Br-].C([P+](CCCC)(CCCC)CCCCCCCCCCCCCCCC)CCC.O>[CH2:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCc1ccc(OC)cc1
Agent: Br
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCc1ccc(O)cc1
Temperature: 135 °C
Reaction time: 5 h

Procedure:
The alkyl anisole of Example 1 (40 g) was transferred to a dry 3-neck 1-litre flask under nitrogen. To this was added tributylhexadecylphosphonium bromide (12.69 g) and HBr (48% aq., 71.4 ml). The resulting thick suspension was warmed to 135° C. and stirred for five hours. Toluene was added and the reaction was transferred to a separating funnel. The organic layer was shaken with water and then the aqueous extract shaken with fresh toluene. The organic extracts were combined and dried with MgSO4. The solvent was removed in vacuo to give the title compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH3:15])[OH:9]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:15][C:14]1[CH:13]=[CH:12][S:11][C:10]=1[C:8](=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccccc1C(O)c1sccc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1sccc1C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
2-Methylphenyl-(3-methyl-2-thienyl)methanol (36.0 g, 0.165 mole) was dissolved in dichloromethane (400 ml) and manganese dioxide (58 g, 0.667 mole) was added. The reaction mixture was heated at reflux for 18 h, cooled and further manganese dioxide (30 g, 0.34 mole) was introduced; reflux was continued for a further 18 h. The mixture was filtered and evaporated to a residue (32 g) which was distilled in vacuo (0.2 mm Hg). Fractions boiling at 100°-120° C. (4.8 g) and 120°-132° C. (21.0 g) were collected, giving the title compound as an oil (25.8 g, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O)([O-:15])=[O:14]>C(O)C>[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[N:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][CH:7]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Yield: 86.3 %

Procedure:
To a solution of ethyl-4-aminobenzoate (5.0 g, 30.3 mmol) in ethanol was added 2-nitrobenzaldehyde (5.03, 33.3 mmol) at room temperature. The reaction mixture was stirred at reflux for 3 h LC-MS showed ester was consumed nearly. The reaction mixture was concentrated in vacuo. The residue was washed by diethyl ether to give ethyl 4-(2-nitrobenzylideneamino)benzoate as yellow solid (7.8 g, yield 86.4%). LC/MS m/e obsd. (ESI+) [(M+H)+] 299.2.
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Cl:29].Cl>C1COCC1.[Cl-].[Na+].O.O>[Cl:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: ClCCCCCBr
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(C)(C)OC(=O)C1(CCCCCCl)CC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Under an Ar atmosphere at 0° C., BuLi (2.5M in hexanes, 80 mL, 0.20 mol) was added dropwise to a solution of iPr2NH (27.2 mL, 194 mmol, distilled from NaOH) in dry THF (200 mL) in 30 min. The reaction mixture was stirred for 30 min, cooled to −70° C. and then, tert-butyl cyclopropanecarboxylate (prepared according to Kohlrausch, K. W. F.; Skrabal, R., Z. Elektrochem. Angew. Phys. Chem, 1937, 43, 282–285, 25.0 g, 176 mmol) was added dropwise in 30 min. The resultant mixture was allowed to warm up to −35° C., cooled again to −70° C. and then 1-bromo-5-chloropentane (36 mL, 50.7 g, 273 mmol) was added dropwise in 15 min. The reaction mixture was allowed to reach −5° C., stirred for 3 h, poured into a mixture of ice (100 mL), H2O (100 mL), brine (200 mL) and aqueous HCl (2M, 200 mL) and extracted with Et2O (2×300 mL). The combined organic layers were washed with a mixture of brine and saturated aqueous NaHCO3 (10:1, 300 mL), dried (Na2SO4) and evaporated in vacuo. The remaining oil was purified by fractional distillation under reduced pressure to give tert-butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (31.5 g 73%) as a colorless liquid. bp: T=67–74° C. (p=0.001 mbar). 1H NMR (CDCl3): δ=3.52 (t, J=6.6 Hz, 2H), 1.77 (quintet, J=6.8 Hz, 2H), 1.48–1.38 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J=6.5 Hz, 3.8 Hz, 2H), 0.59 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=174.1, 79.9, 45.2, 34.2, 32.7, 28.2 (3×), 27.20, 27.17, 24.3, 15.4 (2×). HRMS calcd for C13H24ClO2 (MH+): 247.1465, found: 247.1465.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][C:15]([C:17]3[N:18]=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:16])[N:10]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].CO.[Li+].[OH-]>C1COCC1>[CH2:27]([N:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=[C:11]1[NH:14][C:15]([C:17]1[N:18]=[CH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc2c1nc(NC(=O)c1cc3ccccc3cn1)n2Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1nc2c(C(=O)O)cccc2n1Cc1ccccc1)c1cc2ccccc2cn1
Temperature: 65 °C
Yield: 100 %

Procedure:
To a solution of 45 mg (0.12 mmol) of (1-benzyl-2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester (Example 134) in THF (1 mL) was added methanol (1 mL) and 1 N LiOH solution (1 mL). The reaction was heated at 65° C. for 45 min., and the conversion was monitored by TLC. After cooling to room temperature, the organic solvents were removed under reduced pressure, the reaction residue was acidified (pH=2) by addition of 1 N HCl solution. The solid product was collected by filtration and further dried to afford 43 mg (100%) 1-benzyl-2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid. LCMS: 423 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH3:23][O:24][CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:36]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([CH2:25][O:24][CH3:23])=[CH:27][CH:28]=2)=[O:37])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: COCc1ccc(C(=O)O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: COCc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (300 mg, 0.96 mmol) in acetonitrile (30 ml) were added 4-((methyloxy)methyl)-1-naphthalenecarboxylic acid (207 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg, 1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) and recrystallized from ethyl acetate-hexane to give the title compound (340 mg, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:16][NH2:17].[OH-].[K+].Cl>>[CH3:16][NH:17][S:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)(=[O:14])=[O:13]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CNS(=O)(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C

Procedure:
6-Bromonaphthalene-2-sulfonyl chloride (576 mg) was added portionwise to 40% methylamine solution (5 ml, WAKO), added with 3.6 N aqueous potassium hydroxide (5 ml), stirred at room temperature, then heated to 60° C. and further stirred for 3 hours. The reaction mixture was cooled to room temperature, then added with 2 N hydrochloric acid (15 ml) and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (Intermediate 30, 484 mg).
Reaction SMILES: O[C@@H](C1C=CC=CC=1)C(O)=O.[NH2:12][C@@:13]([CH3:29])([CH2:18]/[CH:19]=[CH:20]/[CH2:21][N:22]1[C:26](=[O:27])[O:25][N:24]=[C:23]1[CH3:28])[C:14]([O:16][CH3:17])=[O:15]>>[NH2:12][C:13]([CH3:29])([CH2:18]/[CH:19]=[CH:20]/[CH2:21][N:22]1[C:26](=[O:27])[O:25][N:24]=[C:23]1[CH3:28])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@](C)(N)C/C=C/Cn1c(C)noc1=O
Agent: O=C(O)[C@@H](O)c1ccccc1
Product: COC(=O)C(C)(N)C/C=C/Cn1c(C)noc1=O

Procedure:
(2S)-hydroxy(phenyl)ethanoic acid salt of methyl (2S,4E)-2-amino-2-methyl-6-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)hex-4-enoate
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][C@@:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[N:28][C:27]=1[CH3:33]>>[Cl:25][C:26]1[CH:31]=[C:30]([N:13]2[CH2:14][CH2:15][CH2:16][C@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:24])[CH3:23])([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:9][C:8]3=[O:10])[CH2:12]2)[N:29]=[N:28][C:27]=1[CH3:33]
Reactant: Cc1nnc(Cl)cc1Cl
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCNC2)C(=O)O1
Product: Cc1nnc(N2CCC[C@H](N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)C2)cc1Cl

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one and 4,6-dichloro-3-methylpyridazine following a procedure analogous to that described in Example 1. LC-MS Method 1 tR=1.37 min, m/z=459, 461(M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:32])[CH3:31])=[C:9]2[N:8]=1)[CH2:4][CH3:5].N[C@@H](CC)CO>>[OH:1][CH2:2][C@@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:19][CH:20]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:31])[CH3:32])=[C:9]2[N:8]=1)[CH2:4][CH3:5]
Reactant: CC[C@H](CO)Nc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Agent: CC[C@H](N)CO
Product: CC[C@@H](CO)Nc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Yield: 48 %

Procedure:
According to the same conditions resulting in the preparation of the compound 2, the compound 4 is prepared from IIa.2 by oxidation reaction of the sulfur atom and then introduction of commercial (S)-(+)-2-aminobutanol. Yield=48%. Foam. 1H NMR (300 MHz, CDCl3): δ 8.69 (d, 1H, J=4.1 Hz, Harom), 7.96 (d, 2H, J=7.9 Hz, Harom), 7.78-7.69 (m, 2H, Harom), 7.62 (s, 1H, Harom), 7.42 (d, 2H, J=7.9 Hz, Harom), 7.26-7.21 (m, 1H, Harom), 6.91 (bs, 1H, NH), 5.10 (s, 1H, H exchangeable), 4.75 (d, 2H, J=6.0 Hz, CH2), 3.93 (bs, 1H, CH), 3.83-3.62 (m, 2H, CH2), 3.02 (hept, 1H, J=6.8 Hz, CH), 1.70-1.52 (m, 2H, CH2), 1.27 (d, 6H, J=6.8 Hz, 2 CH3), 1.02 (t, 3H, J=7.4 Hz, CH3). MS (EST): m/z 432 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]C)=[O:11])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:3]=1[F:22].O.O.[OH-].[Li+]>C1COCC1.CO>[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:3]=1[F:22]
Reactant: COC(=O)c1nc(-c2ccc(OC)nc2)c(F)c(N)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc(C(=O)O)c(OC)c(N)c2F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of methyl 4-amino-3-fluoro-5,6′-dimethoxy-[2,3′-bipyridine]-6-carboxylate (100 mg, 0.325 mmol) in THF (1.0 mL), MeOH (1.000 mL), and Water (0.500 mL), lithium hydroxide hydrate (60 mg, 1.430 mmol) was added as a solid. The solution was stirred at room temperature for 18 hrs. The reaction solution was then concentrated under vacuum to dryness. The resulting solid was suspended in H2O and the pH was adjusted to 3.8, forming a ppt. The suspension was extracted with EtOAc (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to yield 4-amino-3-fluoro-5,6′-dimethoxy-[2,3′-bipyridine]-6-carboxylic acid (80.1 mg, 0.273 mmol, 84% yield).). ESIMS for m/z 294 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 3.78 (s, 3H), 3.92 (s, 3H), 6.47 (s, 2H), 6.95 (dd, J=8.7, 0.8 Hz, 1H), 8.15 (ddd, J=8.7, 2.4, 1.1 Hz, 1H), 8.61 (t, J=2.1 Hz, 1H), 13.02 (s, 1H). 19F NMR (376 MHz, DMSO-d6) δ −141.78.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:14]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:15][C:16]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17]>C1COCC1>[C:30]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:27]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]
Reactant: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCN
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1

Procedure:
Dodecylamine (924 mg.) in 20 ml. THF is added dropwise to a 0° C. solution of 1.78 g. z-Gly-Phe and 1.02 g. DDC in 30 ml. THF under N2 and stirred at 0° C. for 4 hours. The reaction mixture is filtered, the filtrate evaporated in vacuo to give 3.53 g. crude product, which was chromatographed on 100 g. silica gel in CHCl3 /EtOAc (2:1) to give 890 mg. product (34%). NMR (CDCl3, δ): 7.7m (1H); 7.3 d (10 Hz); 6.6 m (1H); 6.2 (1H); 5.2 s (2H); 4.8 m (1H); 3.9 d, J=6 Hz (2H); 3.1 m (4H); 1.3 bs (20H); 0.9 m (3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3(CCOC[CH2:19]3)[O:10][C:9]2=[O:24])[CH:5]=[CH:4][N:3]=1.[O:25]1CC(=O)[CH2:26]1>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:11]3([CH2:19][O:25][CH2:26]3)[O:10][C:9]2=[O:24])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1OC2(CCOCC2)C(c2ccccc2)N1c1ccnc(Cl)n1
Reactant: O=C1COC1
Product: O=C1OC2(COC2)C(c2ccccc2)N1c1ccnc(Cl)n1

Procedure:
Prepared using similar methods as described above for 3-(2-chloropyrimidin-4-yl)-4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one, but starting with oxetan-3-one. LCMS m/z 318.1 (M+H)+, Rt 0.78 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[N:31]1([C:2]2[N:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH:9]3[C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:14]=3)[N:5]=[C:4]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[CH:3]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N3CCCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 100 °C
Yield: 53.7 %

Procedure:
A mixture of 6-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}pyrimidine (Example 17) (250 mg, 0.59 mmol), pyrrolidine (0.5 ml, 5.98 mmol) and anhydrous 1,4-dioxane (5.0 ml) was heated at 100° C. in a sealed vessel under microwave irradiation for 1 hour. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2). Product containing fractions were combined and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue triturated with diethylether and collected by filtration to give the title compound (145 mg, 54%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][N:4]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>ClC(Cl)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:13][C:14]([S:17](/[N:19]=[CH:9]\[C:6]1[CH:5]=[N:4][C:3]([C:2]([F:12])([F:11])[F:1])=[N:8][CH:7]=1)=[O:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cnc(C(F)(F)F)nc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)S(=O)/N=C\c1cnc(C(F)(F)F)nc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a solution of 2-(trifluoromethyl)pyrimidine-5-carbaldehyde (27.2 g, 99 mmol) in dichloroethane (250 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (13.3 g, 109.0 mmol) and copper(II) sulfate (31.5 g, 197.0 mmol). The mixture was heated to 50° C. After 18 h, the mixture was cooled to ambient temperature and filtered through a pad of silica gel. The filtered cake was washed with dichloromethane and the filtrate was concentrated to give the title compound (27.3 g). MS 224 [(M+1)−56].
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1F
Reactant: CCOC(=O)C1CCCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(F)cc2F)CCC1

Procedure:
using isopropyl 2,4-difluoro-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate in toluene there is obtained isopropyl 2,4-difluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 149°-151° C.,
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1.Cl.C(N=C=N)C.OS1C2C=CC=CC=2N=C1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCN=C=N
Agent: Cl
Agent: O[SH]1C=Nc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)cc1
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a mixture of [4-(1-adamantyl)phenoxy]acetic acid (143.2 mg, 0.5 mmol), 4-aminobenzoic acid methyl ester (113.4 mg, 0.5 mmol), N-3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzothiazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (6 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (97.0 mg, 0.13 mL, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 4-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (108.3 mg, 51.7% yield).