Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.[CH2:22](I)[CH:23]=[CH2:24]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH2:24]([N:9]1[C:10]2[C@@:11]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:14]([CH2:13][CH2:12]3)[C:15]=2[C:16](=[O:17])[N:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH:23]=[CH2:22]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Reactant: C=CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c2c(c(=O)n1-c1ccccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
A mixture of a (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 12; 150 mg, 0.52 mmol) and allyl iodide (100 μL, 1.1 mmol) in N,N-dimethylformamide (2 mL) in a microwave reaction tube was heated to 100° C. and stirred for 18 h. The reaction mixture was allowed to cool, diluted with saturated sodium bicarbonate, and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO CombiFlash® Sg100c chromatography system with an Isco 12 g column, eluting with 25-100% ethyl acetate/hexanes to give (4S,7R)-1-allyl-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (56 mg, 33%) as an orange solid. ES(+)-MS (M+H) 327.
Reaction SMILES: [NH:1]([CH:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[C:2]#[N:3].[ClH:24]>O1CCOCC1>[ClH:24].[C:18]1([C:4](=[N:1][C:2]#[N:3])[N:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(NC#N)c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CN=C(c1ccccc1)N1CCNCC1
Reaction time: 4 h

Procedure:
tert-Butyl 4-(cyanamido(phenyl)methyl)piperazine-1-carboxylate (1.5 g) was dissolved in 16 ml of 2M HCl in dioxane. After four hours, the solution was diluted with dioxane (20 ml) and the solid, (phenyl(piperazin-1-yl)methylene)cyanamide hydrochloride (1 g), was collected via filtration. It was washed with ether before further use.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:20]([Sn](CC)(CC)CC)[CH3:21]>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([CH2:20][CH3:21])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Sn](CC)(CC)CC
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Product: CCCCOC(=O)c1nc(CC)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 28 from 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and tetraethyltin: MS (m/z) 295.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[O:41]1[CH2:45][CH2:44]OS1=O>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([N:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:44][CH2:45][OH:41])[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(-c3nccc(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Reactant: O=S1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3nccc(N(CCO)c4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
120 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)-pyrimidin-4-amine (5-1-1, 0.262 mmol, 1. eq.) were suspended in 12 ml of dry DMF. 426 mg of cesium carbonate (1.31 mmol, 5 eq.) and 142 mg of 1,3,2-dioxathiolane 2-oxide (1.31 mmol, 5 eq.) were added under nitrogen atmosphere. The reaction mixture was stirred at 60° C. bath temperature for 18 hours. 142 mg of 1,3,2-dioxathiolane 2-oxide (1.31 mmol, 5 eq.) were added and the mixture was stirred at 60° C. bath temperature for further 22 hours. Then the mixture was partitioned between water and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 14.2 mg (0.03 mmol, 10.5%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:25])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH3:22])=[C:16]([CH3:23])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:24]=2)=[C:4]([CH3:26])[CH:3]=1.[O:27]1CCOCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:25])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]=[O:27])=[C:16]([CH3:23])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:24]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C)[nH]c(=O)c3c2n1C
Reactant: C1COCCO1
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=O)[nH]c(=O)c3c2n1C
Temperature: 100 °C
Yield: 82 %

Procedure:
To a 200 mL round-bottom flask equipped with a magnetic stir bar was added 2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (1.3 g, 3.7 mmol) selenium dioxide (1.23 g, 11.0 mmol) and dioxane (100 mL). The flask was fitted with a reflux condenser and heated to 100° C. in an oil bath for 5 h. The flask was then cooled to room temperature and the mixture filtered through a plug of celite, washing with 10% MeOH/DCM. The filtrate was concentrated to dryness and the resulting brown solid further purified by trituration with cold DCM to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (1.11 g, 82%) as a red-yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.80 (br s, 1H), 10.70 (br s, 1H), 10.25 (s, 1H), 8.02 (d, 1H, J=8.8 Hz), 7.80 (d, 1H, J=8.8 Hz), 7.57 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.26 (td, 1H, J1=3.1 Hz, J2=8.6 Hz), 4.14 (s, 3H), 2.69 (s, 3H), 2.31 (s, 3H); ESMS (m/z): found, 365.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C(N(CC)CC)C.[Cl:22][C:23]1[C:28]([C:29](Cl)=[O:30])=[C:27]([Cl:32])[N:26]=[CH:25][N:24]=1>ClCCl>[Cl:22][C:23]1[C:28]([C:29]([NH:1][C:2]2[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[O:30])=[C:27]([Cl:32])[N:26]=[CH:25][N:24]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COc1cc(N)cc(NS(C)(=O)=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)cc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
N-(3-Amino-5-methoxyphenyl)methanesulfonamide (1 g, 87% purity, 4.02 mmol) was dissolved in dichloromethane (36 ml) and triethylamine (1.35 ml, 9.65 mmol) was added. Then a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (1.52 g, 67% purity, 4.82 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was added dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude was purified by flash chromatography (0% to 40%, hexane-ethyl acetate) using an Isolera® Purification System to give 617 mg (28% yield) of the title compound as a reddish oil. Purity 73%.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][N:18]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C(=O)c1ccc2nonc2c1)C1CCN(S(C)(=O)=O)CC1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-Methyl-N-piperidin-4-yl-[2,1,3]-benzoxadiazole -5-carboxamide hydrochloride (0.38 g, 1.3 mmol) was suspended in chloroform (70 ml) and triethylamine (2 ml) was added. A solution of methane sulfonyl chloride (0.14 g, 1.26 mmol) in chloroform (10 ml) was added and the mixture was stirred at 20° C. for 2 h. The mixture was washed with water (50 ml) and H2SO4 (→pH 2) and NaHCO3 solution (50 ml) and the aqueous re-extracted with dichloromethane (2×50 ml). The combined organics were dried (MgSO4), concentrated under vacuum, and the crude product was purified on a silica gel column eluting with dichloromethane/THF (85:15) to give a white crystalline product, after crystallization from MTBE/hexane (204 mg). Mp=177-179° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=9.3 Hz, 1H); 7.85 (s, 1H); 7.42 (d, J=9.3 Hz, 1H); 4.75-4.46 and 4.10-3.90 and 3.10-2.40 (m, 5H); 2.92 (s, 3H), 2.83 (s, 3H) and 2.10-1.70 ppm (m, 4H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH:10]=[O:11].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.O>CN(C)C=O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH:10]=[O:11])=[CH:15][C:14]=1[CH2:20][OH:21]
Reactant: N#Cc1ccc(F)c(C=O)c1
Reactant: OCc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(CO)c2)c(C=O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of 4-fluoro-3-formylbenzonitrile (14.2 g, 96.0 mmol), 4-bromo-3-hydroxymethylphenol (19.4 g, 96 mmol), and potassium carbonate (15.2 g, 110 mmol) in N,N-dimethylformamide (200 mL) was stirred at 70° C. under nitrogen atmosphere for 2 h. The mixture was poured into ethyl acetate/water. The organic layer was washed with water twice and with brine, then dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (3:1 to 7:3 hexane/ethyl acetate) to give 4-[4-bromo-3-(hydroxymethyl)phenoxy]-3-formylbenzonitrile (26.0 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:30])[N:13]([CH2:20][CH2:21][C:22](=[O:29])[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1COCC1.C(Cl)Cl>[C:38]([N:26]1[CH2:25][CH2:24][N:23]([C:22](=[O:29])[CH2:21][CH2:20][N:13]2[C:12](=[O:30])[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[C:14]2=[O:19])[CH2:28][CH2:27]1)(=[O:40])[CH3:39]
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC(=O)N1CCNCC1)C2=O)c1ccc(Cl)s1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)CCN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
90 mg (0.2 mmol) of 5-chloro-N-{1,3-dioxo-2-[3-oxo-3-(1-piperazinyl)propyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide and 41 mg (0.4 mmol) of triethylamine are dissolved in 10 ml of THF, and 20.6 mg (0.2 mmol) of acetic anhydride are added. The reaction mixture is stirred at room temperature for 5 h, diluted with methylene chloride, washed with water, dried over magnesium sulfate, filtered and concentrated. This gives 81 mg (82% of theory) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([NH:34][C:33]3[CH:35]=[CH:36][C:30]([F:29])=[C:31]([C:37]([F:40])([F:38])[F:39])[CH:32]=3)=[O:24])=[CH:21][C:11]=2[N:10]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c3c(c21)CC(C)(C)O3
Yield: 52 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.237 mmol), 4-fluoro-3-(trifluoromethyl) aniline (0.063 g, 0.356 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.070 g of the desired product. 1HNMR (DMSO-d6): δ 1.60 (s, 6H), 3.48 (s, 2H), 3.59 (s, 3H), 7.22 (s, 1H), 7.51 (t, J=9.9 Hz, 1H), 7.85-7.88 (m, 1H), 8.30 (m, 1H), 8.47 (s, 2H), 9.87 (s, 1H), 10.90 (s, 1H); MS [M]+: 568.03.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[OH:36])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(N(CC)CC)C.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl>[CH:45]1([C:51]([O:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:28]2[O:27][N:26]=[C:25]([C:23]3[N:24]=[C:20]([CH:17]4[CH2:16][CH2:15][N:14]([C:12](=[O:13])[CH2:11][N:5]5[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:1])[F:37])=[N:4]5)[CH2:19][CH2:18]4)[S:21][CH:22]=3)[CH2:29]2)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1)C1CCCCC1
Reaction time: 3 h

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (150 mg) and triethylamine (33 mg) in methylene chloride (10 ml) is added, at 0° C., a solution of cyclohexanecarbonyl chloride in methylene chloride (2 ml). The ice bath is removed and the reaction mixture is stirred at 0° C.-RT for 3 h. Then the mixture is admixed with dilute sodium hydrogencarbonate solution and extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl cyclohexanecarboxylate (150 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[N+:30]([C:33]1[O:37][C:36]([CH:38]=O)=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:38][C:36]3[O:37][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=3)=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccc([N+](=O)[O-])o2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccc([N+](=O)[O-])o2)c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with 5-nitro-2-furaldehyde (65) (0.282 g, 2 mmol) afforded, after workup, a purple oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/hexane as the eluant to obtain 0.85 g (1.61 mmol, 81%) of 76 as a brown gum; IR (CH2Cl2) 3440, 1698, 1622, 1528, 1470, 1350, 1215, 1100, 1012, 810 cm-1 ; 1H NMR (CDCl3) δ 1.09 (d, J=6.2 Hz, 3H), 1.23 (d, J=6.2 Hz, 3H), 2.33 (s, 6H), 3.35 (s, 3H), 3.55-3.59 (m, 2H), 4.17-4.21 (m, 2H), 4.94 (septet, J=6.2 Hz, 1H), 5.09 (s, 1H), 6.20 (s, 1H), 7.34-8.29 (m, 7H); 13C NMR (CDCl3) δ 19.49, 19.59, 21.92, 22.18, 40.22, 58.85, 62.91, 67.36, 70.73, 103.11, 103.88, 113.84, 116.76, 118.98, 120.73, 122.43, 128.83, 131.37, 144.54, 145.28, 147.09, 149.47, 150.02, 151.63, 166.83, 167.31. Anal. Calcd for C26H29N3O9 : C, 59.20; H, 5.50. Found: C, 59.47; H, 5.74.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:34](OC(N1CCC2(CCNC2)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:34][C:10]2([CH2:14][CH2:13][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)C2)C1

Procedure:
Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester hydrochloride in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a pale yellow oil (96 mg, 67%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:8]([O:35][CH3:36])=[C:9]([NH:11][C:12](=[O:34])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31](O)=[O:32])[CH:26]=3)=[CH:16][CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:43][N:44](C)[CH2:45]CCN=C=NCC.C(N(CC)CC)C.CNC>CN(C=O)C.O>[CH3:43][N:44]([CH3:45])[C:31]([C:27]1[CH:26]=[C:25]([O:24][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([NH:13][C:12]([NH:11][C:9]3[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=[C:7]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:8]=3[O:35][CH3:36])=[O:34])=[CH:15][CH:16]=2)[CH:30]=[CH:29][N:28]=1)=[O:32]
Reactant: COc1c(NC(=O)Nc2ccc(Oc3ccnc(C(=O)O)c3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(NC(=O)Nc2ccc(Oc3ccnc(C(=O)N(C)C)c3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a cold solution (0° C.) of 4-{4-[3-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-ureido]-naphthalen-1-yloxy}-pyridine-2-carboxylic acid (Example 12) (58 mg, 0.1 mmol) in DMF (1 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol) and triethyl amine (0.070 mL, 0.5 mmol). The solution was allowed to stir at 0° C. for 30 min, then dimethylamine (2M solution in THF, 0.25 mL, 0.5 mmol) was added in one portion. The resulting solution was allowed to stir at room temperature for 12 h. Water (4 mL) was added and the product was extracted with EtOAc, dried over magnesium sulfate and concentrated via rotary evaporation. The resulting crude solid was purified by column chromatography (CH2Cl2:MeOH, 93:7) to give the title compound as a light tan solid (42 mg, 70% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:17]([NH2:19])[CH3:18])([OH:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20](=O)[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([OH:16])([CH:17]([N:19]=[CH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[OH:23])[CH3:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)C1(O)CCN(C(=O)OCc2ccccc2)C1
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: CC(N=Cc1ccccc1O)C1(O)CCN(C(=O)OCc2ccccc2)C1
Yield: 35 %

Procedure:
A solution of 3-(1-aminoethyl)-3-hydroxypyrrolidine-1-carboxylic acid benzyl ester (Example A10, 0.34 g, 0.93 mmol) and salicylaldehyde (0.147 g, 1.2 mmol) in dry ethanol (5 mL) is refluxed for 3 hours. After evaporation of the solvent, the residue is purified by column chromatography (30:70:0.01 ethyl acetate/hexanes/ammonium hydroxide) to afford the title compound (0.12 g). 1H NMR (200 MHz, CDCl3): δ 8.39 (s, 1H), 7.41-7.25 (m, 7H), 6.97-6.85 (m, 2H), 5.09 (s, 2H), 3.65-3.34 (m, 5H), 2.01-1.87 (m, 2H), 1.37-1.32 (m, 3H).
Reaction SMILES: COC(=O)CC1CCN(C(OC(C)(C)C)=O)CC1.C(C1C=NC=CC=1[CH2:27][C:28]([CH3:33])([CH3:32])[C:29]([NH2:31])=[O:30])=O.[OH:34][CH:35]([C:54]1[C:55](NC(=O)C(C)(C)C)=[N:56][CH:57]=[CH:58][CH:59]=1)[CH:36]([CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1)[C:37]([O:39][CH3:40])=[O:38]>>[OH:34][CH:35]([C:54]1[CH:55]=[N:56][CH:57]=[CH:58][C:59]=1[NH:31][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH:36]([CH:41]1[CH2:42][CH2:43][N:44]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:45][CH2:46]1)[C:37]([O:39][CH3:40])=[O:38]
Reactant: CC(C)(Cc1ccncc1C=O)C(N)=O
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccnc1NC(=O)C(C)(C)C
Agent: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cnccc1NC(=O)C(C)(C)C
Yield: 54 %

Procedure:
tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (1.33 g, 5.2 mmol) and N-(3-formyl-4-pyridinyl-2,2-dimethylpropanamide (1.0 g, 4.7 mmol) were reacted in a manner analogous to the preparation of tert-butyl 4-(1-hydroxy-3-methoxy-3-oxo-1-(2-pivalamidopyridin-3-yl)propan-2-yl)piperidine-1-carboxylate. Title compound was obtained as white foam in 54% yield. (M+H)+=464.2.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH2:9][CH:10]([O:19][C:20](=[O:22])C)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3]C(OCC)=O.[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[OH:1][C:2]1([CH3:3])[CH2:9][CH:10]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:19][C:20](=[O:22])[CH2:23]1
Reactant: CCOC(=O)CC(C)(O)CC(CCc1ccccc1)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(O)CC(=O)OC(CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
Using 1.48 g of 4-acetoxy-6-phenylhexan-2-one, 1 ml of ethyl bromoacetate and 0.62 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 1.03 g of ethyl 3-hydroxy-3-methyl-5-acetoxy-7-phenylheptanoate. The ester (0.90 g) thus obtained was dissolved in 5 ml of methanol and 2 ml of 4 N sodium hydroxide was added thereto. The mixture was stirred for 4 hours at room temperature, acidified by the addition of 4 N hydrochloric acid, 5 ml of ethyl acetate was added and the mixture was stirred for 3 days. The usual treatment of the organic solvent layer afforded 400 mg of the desired compound.