Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:7][CH:6]=1)([O-])=O.C(O)C.[OH-].[Na+]>[Fe].C(Cl)(Cl)Cl.O>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:9][CH:10]=1
Reactant: Nc1nccc(C=Cc2ccc([N+](=O)[O-])cc2)n1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C=Cc2ccnc(N)n2)cc1
Temperature: 65 °C

Procedure:
Hydrochloric acid (100 ml of 4N) is added dropwise to a stirred mixture of 4-[2-(p-nitrophenyl)-ethenyl]-2-aminopyrimidine (21.8 g), ethanol (250 ml) and iron filing (22 g). During the addition the reaction temperature is increased to 65° C., and stirring is continued (2 hours) at 65° C. Water is added, followed by an aqueous 30% sodium hydroxide solution (200 ml) and chloroform (1 liter). The chloroform layer is then separated and dried over sodium sulfate. After evaporation and addition of ether, 4-[2-(p-aminophenyl)-ethenyl]-2-aminopyrimidine is obtained (13.5 g), which is used as the starting compound without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)=O)C.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:13][O:12][C:10]1[CH:11]=[C:6]([CH2:4][OH:3])[N:7]=[N:8][CH:9]=1
Reactant: CCOC(=O)c1cc(OC)cnn1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Product: COc1cnnc(CO)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
5-Methoxy-pyridazine-3-carboxylic acid ethyl ester (8.1 g, 44.5 mmol) was dissolved in ethanol (105 ml) under argon. The reaction mixture was cooled to 0° C. and treated with NaBH4 (3.5 g, 89 mmol). After 10 minutes, the reaction mixture was warmed to room temperature, stirred for 1 hour and treated successively with 2N HCl and saturated sodium bicarbonate to adjust the pH at 8. The solvent was removed in vacuo and the residue was stirred with MeOH (100 ml). The suspension was filtered and the filtrate was concentrated. The residue was chromatographed over silica gel (CH2Cl2—MeOH 19:1) to provide (5-methoxy-pyridazin-3-yl)-methanol (5.2 g, 83%) as a light brown solid, MS: m/e=140 (M+).
Reaction SMILES: C(O[CH:4]1[CH2:12][C:11]2[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]=2[O:5]1)C.[NH3:14]>>[O:5]=[C:6]1[CH2:7][CH2:8][CH2:9][C:10]2[NH:14][CH:4]=[CH:12][C:11]1=2
Reactant: CCOC1CC2=C(CCCC2=O)O1
Reactant: N
Product: O=C1CCCc2[nH]ccc21
Temperature: 100 °C
Yield: 54 %

Procedure:
96.5 mg of 2-ethoxy-4-oxo-2,3,4,5,6,7-hexahydrocoumarone and 1.5 ml of 28% aqueous ammonia were admixed in a glass tube which was sealed and heated at 100° C. for 14 hours. The reaction mixture was treated in the same manner as Example 11 to give 38.4 mg of 4-oxo-4,5,6,7-tetrahydroindole (yield 54%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].[C:16](=[O:18])=[O:17].CC(C)=O.C([Li])CCC.C(=O)=O.[OH-].[Na+]>C(OCC)C.O>[C:1]([O:5][C:6]([NH:7][C:8]1[C:13]([C:16]([OH:18])=[O:17])=[CH:12][N:11]=[CH:10][C:9]=1[Cl:14])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1c(Cl)cncc1C(=O)O
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
(3-Chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (1.50 g) was dissolved in dry diethyl ether (35 mL), N,N,N′,N′-tertamethylenethylendiamine (2.35 mL) was added and the reaction mixture was cooled in a dry ice/acetone cool bath to −78° C. n-Butyl lithium (9.9 mL, 1.59M in hexane) was added to the suspension, the cool bath was replaced by a sodium chloride/ice mixture and the reaction mixture was stirred at −10° C. for 1.5 h. The suspension was slowly poured on crushed dry ice (2.0 g) in dry diethyl ether (20 mL) and stirred for 1 h. Water was added and the pH was adjusted to −12 by addition of 2N sodium hydroxide solution. The aqueous layer was washed 2× with MTB-ether, 2 M hydrochloric acid was added to the aqueous layer and the pH was adjusted to −2 and the aqueous layer was 3× extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum to afford 1.03 g of the title compound of the formula
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C@H:10]([CH2:17][CH2:18][CH2:19][CH2:20][O:21]CC2C=CC=CC=2)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:2]=1.C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@@H:10]([CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC[C@@H](CCCCOCc1ccccc1)CCCc1cccnc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COC(=O)CC[C@@H](CCCCO)CCCc1cccnc1

Procedure:
To a solution of methyl 4(R)-[3-(3-pyridyl)propyl]-8-(benzyloxy)octanoate (1.67 g, 4.2 mmol) in ethanol (30 ml) is added 20% palladium hydroxide on carbon (0.43 g) followed by cyclohexene (15.6 ml). The mixture is refluxed for 25 hours and then filtered to remove the catalyst. The catalyst is washed with ethanol, the combined filtrate is evaporated, and the residue is purified by flash chromatography on silica gel using 9:1 ethyl acetate/hexane to obtain methyl (R)-8-hydroxy-4-[3-(3-pyridyl)propyl]octanoate; IR (CH2Cl2): 3617, 1732, 1197, 1174, 1027 cm- 1.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([C:5]2[S:6][C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(Br)s2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(-c3ccc(N)nc3)s2)n1

Procedure:
The title compound was prepared from 2-(5-bromo-thiophen-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.86) (0.27 g, 0.678 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.164 g, 0.745 mmol) according to the general procedure VI. Obtained as a light brown solid (0.100 g, 35%). MS (ISP) 412.2 [(M+H)+]; mp 196° C.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:20]1([C:19]2[NH:26][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccccn1
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)[nH]c1-c1ccccn1
Yield: 23.4 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(2-pyridyl)propionate (6.0 g) and benzylamine (5.7 g) were dissolved in acetonitrile (100 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-phenyl-5-(2-pyridyl)imidazole-4-carboxylate (1.8 g), melting point 211-213° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CO)CC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(C)CC1CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a cooled (0° C.), stirred solution of 2-methyl-3-cyclohexylpropanol (40.3 g., 0.26 mol.), dimethylaminopyridine (2.5 g., 0.02 mol.), and triethylamine (38.4 g., 0.38 mol.) in 200 ml of toluene was added acetic anhydride (39.4 g. 0.39 mol) over 30 minutes. The resulting solution was allowed to warm to room temperature and stirred for an additional 1.5 hours. The reaction mixture was washed twice with 125 ml portions of 2 N aqueous sodium chloride, dried over magnesium sulfate and concentrated to a colorless oil which was distilled to obtain 72 g. 98% yield; bp 67-71° C. at 0.6 mm. Odor: very pleasant fruity, rosy, floral. Mass Spectrum from 5508-36. MS (El) m/z (relative intensity) 155 (M+−C2H3O, 2), 138 (M+−C2H4O2, 15).
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[C:27]([CH3:33])=[N:28][CH:29]=[C:30]([CH3:32])[N:31]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:29]3[C:30]([CH3:32])=[N:31][CH:26]=[C:27]([CH3:33])[N:28]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Cc1cnc(C)c(Cl)n1
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cnc(C)c(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 3-chloro-2,5-dimethyl-pyrazine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.44 min; Mass spectrum (ESI+): m/z=418 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.N1C=CC=CC=1.[C:26]1([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[N:7]=[C:6]([NH:8][S:33]([CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:35])=[O:34])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc2[nH]cc(Cc3ccc(NS(=O)(=O)Cc4ccccc4)nc3F)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
In a vial, 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 157 mg, 0.614 mmol) was mixed with 4 mL of dichloromethane and pyridine (149 μL, 1.84 mmol) and cooled to 0° C. in an ice water bath. Phenyl-methanesulfonyl chloride (139, 0.234 g, 1.23 mmol) was added and the reaction stirred at 0° C. for 1 hour, then warmed to room temperature and stirred overnight. Aqueous saturated sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 0-10% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (P-2181, 39 mg). MS (ESI) [M+H]+=411.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2ccc(Cl)cc2NC1=O
Product: CC(C)(CC(=O)NC1CCc2ccc(Cl)cc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step F by the procedure described in Example 1, Step F. 1H NMR (300MHz, CDCl3): 1.35 (s,6H), 1.42 (s,9H), 1.95 (m,1H), 2.4-2.8 (m,5H), 4.51 (m,1H), 5.22 (br s,1H), 6.73 (d,7Hz,1H), 7.02 (s,1H), 7.14 (br s,2H), 8.21 (br s,1H). FAB-MS: calculated for C20H28C1N3O4 409; found 410 (M+H,55%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]([CH3:34])[CH2:20][CH2:21][N:22]([CH3:33])[C:23]1[S:24][C:25]2[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:26]=2[N:27]=1>>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:32][C:30]3[CH:29]=[CH:28][C:26]4[N:27]=[C:23]([N:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:34])[CH3:33])[S:24][C:25]=4[CH:31]=3)=[O:15])=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(OCC2CCCCC2)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(OCC4CCCCC4)cc3)cc2s1

Procedure:
The title compound is prepared by following Method A, using 4-cyclohexylmethoxy-benzoic acid (Crooks, S. L.; Merrill, B. A.; Wightman, P. D. WO 9603983 A1.) (0.20 g, 0.86 mmol), and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.17 g, 0.68 mmol) to afford 0.12 g (38%). LC/MS: Retention time=5.67 min; (m/z): calcd for C26H34N4O2S (M+H)+: 467.7; found: 467.0.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(F)nc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
2,6-Difluoro-3-nitropyridine (3.84 g) was dissolved in ethanol (42 ml). A solution of iron powder (4.03 g) and ammonium chloride (2.57 g) in water (14 ml) was added, and the reaction solution was heated and stirred at 80° C. for one hour. After leaving to cool, the reaction solution was filtered through celite. Ethyl acetate and water were added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.06 g). The property values of the compound are as follows.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([O:8][CH2:9][C@@H:10]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11]1)[CH3:7])[CH3:4].[CH3:17][O:18][C:19](=[O:27])[CH2:20][O:21][CH2:22][C:23]#[C:24][CH2:25]I.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:17][O:18][C:19](=[O:27])[CH2:20][O:21][CH2:22][C:23]#[C:24][CH2:25][N:15]1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C@@H:10]1[CH2:9][O:8][CH:6]([O:5][CH2:3][CH3:4])[CH3:7]
Reactant: CCOC(C)OC[C@H]1CCCC(=O)N1
Reactant: COC(=O)COCC#CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(C)OC[C@H]1CCCC(=O)N1CC#CCOCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
Sodium hydride (60% dispersion in oil, 278 mg, 6.95 mmol) was added to a solution of (R)-6-(1-ethoxyethoxymethyl)-piperidin-2-one (from example 50, step 1, 1.40 g, 6.96 mmol) in DMF (10 mL) at 0° C. After 1 h at 0° C., (4-iodo-but-2-ynyloxy)-acetic acid methyl ester (2.05 g, 7.65 mmol) in DMF (10 mL) was added via cannula and the reaction was allowed to warm to rt. After 15 min at rt, the reaction mixture solidified, so more DMF (3 mL) was added. After 18 h at rt, the reaction was treated with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×70 mL). The combined extracts were washed with water (2×50 mL) and brine (2×50 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20%→50% EtOAc/CH2Cl2, gradient) afforded 500 mg (21%) of {4-[(R)-2-(1-ethoxy-ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:34])[NH:7][C@H:8]1[C:11](=[O:12])[N:10](C2C=CC(OC)=CC=2)[C@H:9]1[CH2:21][O:22][N:23]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])[CH3:3].O.[C:36]([OH:40])(=[O:39])[CH:37]=O>C1COCC1>[CH3:3][C:2]([CH3:4])([O:5][C:6]([NH:7][C@H:8]1[C:11](=[O:12])[NH:10][C@H:9]1[CH2:21][O:22][N:23]=[CH:37][C:36]([OH:40])=[O:39])=[O:34])[CH3:1]
Reactant: O=CC(=O)O
Reactant: COc1ccc(N2C(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H]2CON2C(=O)c3ccccc3C2=O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C(=O)N[C@H]1CON=CC(=O)O
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A solution of the oxyamine produced in Example 1 (637 mg, 2.75 mmol) and glyoxylic acid monohydrate (295 mg, 3.20 mmol) in THF (25 ml) was allowed to stir for 1 hour. The solvent was removed under reduced pressure and the resulting solid triturated with a solution of methanol-methylene chloride (1:20) to afford [[[cis-3-[[(1,1-dimethylethoxy)carbonyl]amino]-4-oxo-2-azetidinyl]methoxy]imino]acetic acid (630 mg, 79%): IR (KBr) 3325, 2960, 1755, 1705, 1685, 1595, 1515, 1330, 1265, and 1155 cm-1 ; NMR (DMSO-d6) δ 1.40 (9H, s), 3.86 (1H, m), 4.25 (2H, m), 4.88 (1H, dd, J=9, 5 Hz), 7.59 (1H, s), 7.65 (1H, d, J=9 Hz, exchangeable), 8.40 (1H, s, exchangeable); FAB HRMS, m/e 288.1194 (M+ calculated for C11H18O6N3 : 288.1195).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1)=[O:5])[CH3:2].[Cl:17]N1C(=O)CCC1=O>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][C:10]=1[Cl:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccccc2)oc1Cl
Yield: 37.7 %

Procedure:
Mixture of 2-phenyl-oxazole-4-carboxylic acid ethyl ester (217 mg, 1 mmol), 1-chloro-pyrrolidine-2,5-dione (400 mg, 3 mmol) and two drops of sulfuric acid in chloroform (10 mL) was heated at 90 degrees for overnight. After the reaction was complete, solvent was evaporated. To the residue, water was added, and then the mixture was extracted with ethyl acetate twice. The organic layers were collected, combined, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 5-40% ethyl acetate in hexane for 30 min) gave 5-chloro-2-phenyl-oxazole-4-carboxylic acid ethyl ester (95 mg, 37%) as a white solid. LCMS calcd for C12H10ClNO3 (m/e) 251, obsd 252 (M+H).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:23]=[C:22]2[C:11]([CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH2:18][C@@H:19](O)[CH3:20])[C:14]=32)=[CH:10][CH:9]=1.C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:31]([C@H:19]([CH3:20])[CH2:18][N:15]1[CH:16]=[CH:17][C:13]2[CH2:12][C:11]3[C:22]([C:14]1=2)=[CH:23][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)-c1c(ccn1C[C@H](C)O)C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)N=[N+]=[N-])C2
Yield: 60.5 %

Procedure:
0.96 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.5 g of (S)-1-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol1-yl)-propan-2-ol and 3.45 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 200 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of diethyl ether. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 60 ml of anhydrous dimethylformamide, treated with 0.71 g of sodium azide and the reaction mixture was heated to 60° for 15 hours while stirring. After cooling the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.0 g (60%) of (R)-1-(2-azido-propyl)-7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)([O-])=O>COCCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3ccc(N)cc23)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 94.9 %

Procedure:
To a suspension of Pd/C (5% w/w, 800 mg, 0.38 mmol) in 100 mL 2-methoxyethanol (degassed with nitrogen prior to use) was added a solution of 4-(6-nitro-quinazolin-4-yl)-1-Boc-piperazine (4.0 g, 11.1 mmol) in 10 mL 2-methoxyethanol. A balloon of H2 was bubbled through the reaction mixture, and the reaction mixture was stirred at room temperature under an atmosphere of H2 for 13 hours. Celite was then added, and the reaction mixture was filtered through a pad of celite and rinsed with MeOH. The filtrate was concentrated, and the resulting oil was filtered through a short plug of silica gel with EtOAc. The resulting filtrate was concentrated to give 4-(6-amino-quinazolin-4-yl)-1-Boc-piperazine (3.47 g, 95%). LCMS (APCI+) m/z 330 [M+H]+. HPLC Rt 2.31 min.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]3([C:44](O)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)[CH:25]=1.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]3([C:44]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)[CH:25]=1
Reactant: CS(N)(=O)=O
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C3(C(=O)NS(C)(=O)=O)CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (60.4 mg, 0.31 mmol) is added to a stirred ice cold solution of 4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid [150 mg, 0.3 mmol, Example 80(a)], methanesulfonamide (30 mg, 0.31 mmol) and 4-dimethylaminopyridine (38.5 mg, 0.3 mmol) in dry DCM under nitrogen and the reaction mixture is stirred overnight, while warming to room temperature. The mixture is concentrated in vacuo, the residue is dissolved in ethyl acetate, washed with 0.1 N HCl, brine and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2 packed column), eluting with ethyl acetate/heptane to afford N-[4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carbonyl]-methanesulfonamide [65 mg, Example 80(b)] . LCMS: RT=2.54 minutes; MS: 579, 581 (M+H); 1H NMR (300 MHz, CDCl3): □8 (1H, s), 7.85 (1H, d, J=3.5 Hz), 7.45 (3H, m), 7.2 (2H, s), 6.4 (1H, s), 5.38 (1H, b), 4 (3H, s), 3.65-3.9 (6H, m), 3.2 (3H, s), 3.08 (2H, t, J=3.5 Hz), 2.45 (2H, b), 2.18 (2H, m). IC50<1 nM