Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[N:17]=[CH:16][C:10]2[N:11]=[CH:12][NH:13][C:14](=O)[C:9]=2[CH:8]=1.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[Cl:20][C:14]1[C:9]2[CH:8]=[C:7]([Cl:6])[N:17]=[CH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Clc1cc2c(Cl)ncnc2cn1
Reaction time: 1 h

Procedure:
DMF (0.1 ml) was added to 6chloro-3H-pyrido[3,4-d]pyrimidin-4-one (1.82 g, 10 mmol) followed by dropwise addition of thionyl chloride (10 ml). The flask was fitted with a condenser and a drylng tube and the contents heated to reflux for ˜20 minutes whereupon the solids dissolved. The heating was continued for a further 1 h and then cooled. Toluene was added to wash the sides of the flask and the solvents were evaporated in vacuo. Azeotroping with toluene was repeated twice and the crude so obtained was taken through to the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>O1CCCC1>[C:26]1([CH3:29])[CH:27]=[CH:28][C:23]([NH:22][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])=[CH:24][CH:25]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Nc3ccc(C)cc3)c2nc1OC

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and p-toluidine 180 mg (1.68 mmol). Reaction was carried out in refluxing tetrahydrofuran for 50 hours, and the crude product was eluted through a flash column (7:3 hexanes:ethyl acetate), 200 mg (65%), mp 214-215° C.; 1H NMR (CDCl3): δ 8.33 (s, 1H), 7.69 (d, 2H, J=8.3 Hz), 7.65 (s, 1H), 7.15 (d, 2H, J=8.3 Hz), 4.17 (s, 3H), 4.03 (s, 3H), 2.58 (s, 3H), 2.32 (s, 3H); MS (APCI): m/z 383 (M+H). Anal Calcd. for C19H18N4O5: C, 59.68; H, 4.74; N, 14.65. Found: C, 59.97; H, 4.68; N, 14.71.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)CCC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CCC(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 47.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with 3-(morpholin-3-yl)propanoic acid hydrochloride (0.39 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.55 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH:8](O)[C:9]([OH:11])=[O:10])=[O:6])[CH:2]=[CH2:3].[S:13]1[CH:17]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]1=2>FC(F)(F)C(O)=O>[CH2:1]([O:4][C:5]([N:7]([C:16]1[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13][CH:17]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH:2]=[CH2:3]
Reactant: c1ccc2sccc2c1
Reactant: C=CCOC(=O)NC(O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)N(CC(=O)O)c1csc2ccccc12
Yield: 88 %

Procedure:
A solution of 5.15 g (29.4 mM) of DL N-allyloxycarbonyl-α-hydroxyglycine and 3.95 g (29.4 mM) of benzo[b]thiophene in 40 ml of trifluoroacetic acid was stirred at 22.5° C. for eighteen hours. The reaction mixture was then concentrated by evaporation under reduced pressure to given an oil, and the oil was dissolved in a mixture of 100 ml of ethyl acetate and 100 ml of water. The organic layer was separated, and the aqueous layer was extracted twice more with 50 ml portions of fresh ethyl acetate. The organic extracts were combined, washed with water, and then extracted twice with 100 ml portions of 10% aqueous sodium bicarbonate. The aqueous extracts were combined, added to 100 ml of fresh ethyl acetate, and acidified to pH 2.0 by the addition of conc. hydrochloric acid. The organic layer was separated and the aqueous acid layer was extracted with two 50 ml portions of fresh ethyl acetate. The organic portions were combined, dried, and the solvent was removed by evaporation to provide 7.55 g (88% yield) of N-allyloxycarbonyl-(3-benzothienyl)glycine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10]1([OH:16])C=CC=CC=1>>[OH:9][C:3]1[C:4]([CH:10]=[O:16])=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Oc1ccccc1
Reactant: Cc1ccc(C)c(O)c1
Product: Cc1ccc(C)c(C=O)c1O

Procedure:
6-Hydroxy-2,5-dimethylbenzaldehyde was prepared by the method of Example 104 Step 1 except that 2,5-dimethylphenol was used as the starting phenol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1.[CH3:50][N:51]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:54]3[CH2:55][CH2:56][CH2:57][N:51]([CH3:50])[CH2:52][CH2:53]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CN1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(CN4CCCN(C)CC4)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.034 g, 0.05 mmol), 1-methylhexahydro-1H-1,4-diazepine (0.0069 g, 0.06 mmol), and acetic acid (0.0036 g, 0.06 mmol) were combined in 1,2-dichloroethane (2 mL). The reaction mixture was stirred for 30 min. Sodium triacetoxyborohydride (0.0148 g, 0.07 mmol) was added and the mixture stirred overnight at room temperature. Solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 2.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a white solid. LC-MS m/z 777.1 (M+H)+, 1.39 min (ret time); mp 105-107° C. Analytical HPLC shows 95.3% purity, (ret time 10.044 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Mg]Br.O.[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([OH:14])([CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.05 mmol) in diethyl ether (20 mL) at −25 to −30° C. was added methyl magnesium bromide (3M in diethyl ether, 3.35 mL, 10.05 mmol) dropwise under argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water (20 mL) was then added dropwise, followed by saturated ammonium chloride (20 mL) and the ether layer was separated. The aqueous phase was further extracted with ether (50 mL) and the combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (2.09 g, 97%). 1H NMR (CDCl3, 300 MHz): 3.76-3.62 (m, 2H), 3.30-3.13 (m, 2H), 2.48-2.39 (m, 1H), 1.57-1.51 (m, 4H), 1.46 (s, 9H), 1.27 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:11])[CH2:10][O:9]2)=[CH:4][CH:3]=1.Br[C:13]1[NH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=1>C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:11])[O:9][C:13]3=[N:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]3[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(Br)cc2)CO1
Reactant: O=[N+]([O-])c1cnc(Br)[nH]1
Solvent: CCN(CC)CC
Product: CC1(c2ccc(Br)cc2)Cn2cc([N+](=O)[O-])nc2O1

Procedure:
2-(4-Bromo-phenyl)-2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazole was synthesized according to the scheme shown in FIG. 6. 2-(4-Bromo-phenyl)-2-methyl-oxirane (213 mg, 1 mmol), 2-bromo-5-nitroimidazole (191 mg, 1 mmol) and triethylamine (0.4 mL) were stirred in a sealed tube at 80° C. for 6 hours Column chromatography (EtOAc/Hexanes, v/v, 1/1 to 3/1) gave 330 mg yellow solid. The solid was dissolved in 5 mL DMF with Cs2CO3 (780 mg, 2.4 mmol). The resulting mixture was stirred at 50° C. for 24 hours and then partitioned in EtOAc/water (200 mL, 1/1, v/v). The organic layer was washed with brine and dried over Na2SO4 Column chromatography (EtOAc/Hexanes, v/v, 1/1 to 3/1) gave the titled compound (178 mg, 55% yield in two steps) as yellow solid. ESI MS m/z 324, 326 (M+H). 1H NMR (400 MHz, Acetone-d6) δ 7.66 (s, 1H), 7.76 (s, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.58 (d, J=10.8 Hz, 1H), 4.47 (d, J=10.8 Hz, 1H), 1.89 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:32])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([O:28]CC)=[O:27])[C:15]3=[O:31])=[CH:8][CH:7]=1)[CH3:2].[OH-].[Na+].C(O)C>O1CCCC1>[CH2:1]([NH:3][C:4](=[O:32])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[C:15]3=[O:31])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCOC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CCOC)cn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of ethyl 6-(6-(3-ethylureido)pyridin-3-yl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 42, 59 mg, 0.13 mmol) and sodium hydroxide (0.202 mL, 0.40 mmol) in tetrahydrofuran (1 mL) was heated to 60° C. After 2 h, the reaction was not yet complete. Ethanol (2 mL) was added and the reaction was heated for another 1 h, then cooled to room temperature and concentrated under reduced pressure. The resulting solid was dissolved in water and acidified to pH 4 with 10% HCl. The solid that formed was collected by filtration and placed under high vacuum to remove residual water. MS (ESP): 411 (M+H+) for C21H22N4O5; NMR: 1.11 (t, J=6 Hz, 3H), 3.20 (m, 2H), 3.23 (s, 3H), 3.74 (m, 2H), 4.83 (m, 2H), 7.50 (m, 1H), 8.01 (br s, 1H), 8.21 (m, 1H), 8.31 (m, 1H), 8.58 (m, 1H), 8.69 (m, 1H), 8.94 (s, 1H), 9.38 (s, 1H), 15.20 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[C:17]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH2:21][CH2:20]1)=[O:18]
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=C(c1ccccc1F)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1F)C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 9.1 g of 3-(2-bromoethyl)indole in 100 ml of dimethylformamide is added to a stirring solution of 11.2 g of 4-(2-fluorobenzoyl)piperidine hydrochloride and 13 g of potassium carbonate in 400 ml of dimethylformamide. The reaction mixture is stirred at ambient temperature for 24 hours, and then 800 ml of water are added dropwise, yielding a dark precipitate. This mixture is again stirred at ambient temperature for 24 hours and filtered to give a yellow crystalline material which is recrystallized thrice from an ethanol-water mixture to give an off-white crystalline material, mp 106°-108° C., 3-{2-[4-(2-fluorobenzoyl)piperidyl]ethyl}indole.
Reaction SMILES: [C:1]([Si:5]([CH3:34])([CH3:33])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20](Cl)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]2=[O:32])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH2:35][C:36]1[CH:37]=[C:38]([O:44][CH3:45])[C:39]([O:42][CH3:43])=[CH:40][CH:41]=1>CC(O)C>[C:1]([Si:5]([CH3:34])([CH3:33])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]2=[O:32])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Reactant: COc1ccc(N)cc1OC
Solvent: CC(C)O
Product: COc1ccc(N2Cc3cnc(Nc4ccc(OC)c(OC)c4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Temperature: 160 °C

Procedure:
A mixture of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g, 0.40 mmol) (from Example 19a supra) and 4-amino-veratrole (80.0 mg, 0.52 mmol) (Aldrich) in 2-propanol (4 mL) was placed in a microwave reactor (SmithSynthesizer™). The reaction mixture was heated at 160° C. for 10 minutes. After cooling, it was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexanes (3:7 then 2:3) to give 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(4-methoxy-phenyl)-7-(3,4-dimethoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.09 g, 36%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:12])[C:7]([CH2:10][OH:11])=[N:8][CH:9]=1)=[O:4].[H-].[Na+].S(OC)(O[CH3:19])(=O)=O.ClCCl>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:12])[C:7]([CH2:10][O:11][CH3:19])=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnc(CO)n1C
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCc1ncc(C(=O)OC)n1C
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of 2-hydroxymethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (250 mg, 1.5 mmol) in dimethylformamide (10 ml) is subsequently treated with sodium hydride (71 mg 60% dispersion in mineral oil, 1.8 mmol) and after 0.5 h with dimethyl sulfate (0.17 ml, 1.8 mmol). After 1 h at ambient temperature, the volatile componantes are removed in vacuo, the residue taken up in ethyl accetate (20 ml) and water (20 ml) and the phases separated. The aqueous phase is extracted twice with ethyl acetate (20 ml each) and the combined organic layers are dryed with magnesium sulfate and evaporated to dryness. Flash chromatography (silica, eluent dichloromethane containing 4% methanol) afforded the title compound as white crystals (42% yield). MS: m/e=185(M+H+), mp 74-77° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24]>O1CCCC1>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([CH:23]=[O:24])[CH:10]=3)[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Brc1ccc2cnn(C3CCCC3)c2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2cnn(C3CCCC3)c2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound 6-bromo-1-cyclopentyl-1H-indazole (1.19 g, 4.15 mmol) in dry tetrahydrofuran (10 ml) was stirred at −78° C. for 15 minutes followed by the addition of butyl lithium (0.532 g, 8.3 mmol). The reaction mixture was again stirred for 30 minutes at −78° C. followed by the dropwise addition of dimethylformamide (1.212 g, 16.6 mmol). The reaction mixture was stirred for 30 minutes at the same temperature followed by stirring it at room temperature for 1 hour. The reaction mixture was quenched with hydrochloric acid (1N) and extracted the compound with ethyl acetate and water. The organic layer was collected, washed with brine and dried over anhydrous sodium sulphate. The mixture was filtered and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield: 465 mg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])([CH3:4])([CH3:3])[CH3:2].O=C1CCC(=O)N1[O:29][C:30](=O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:50]([O:49][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30](=[O:29])[N:9]([CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)CCNCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Reaction time: 42 h
Yield: 85 %

Procedure:
3-(Benzyloxycarbonylmethylamino)propionic acid tert-butyl ester (0,030 g, 0.1 mmol) and octadecanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0,050 mg, 0.1 mmol) was suspended in dry DMF (1 ml). HOAt (0.014 g, 0.1 mmol) and DIPEA (0.21 ml, 1.2 mmol) was added. The yellow reaction mixture was stirred under nitrogen for 42 h. The reaction mixture was concentrated. The residue was redissolved in EtOAc and washed with 0.1 N HCl (2×), water (1×), dried (Na2SO4) and concentrated to give 17-[Benzyloxycarbonylmethyl-(2-tert-butoxycarbonyl-ethyl)-carbamoyl]-heptadecanoic acid tert-butyl ester in 85% yield (55 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([O:20][C:21](=[O:26])[CH2:22][N:23]=[N+:24]=[N-:25])[CH3:19].C1CCN2C(=NCCC2)CC1>C(O)C>[CH2:18]([O:20][C:21](=[O:26])[C:22]([N:23]=[N+:24]=[N-:25])=[CH:14][C:12]1[O:13][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:17][CH:16]=2)=[CH:10][CH:11]=1)[CH3:19]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)o1)N=[N+]=[N-]
Temperature: 70 °C
Yield: 36.6 %

Procedure:
Absolute ethanol (20 ml) was added to 5-(4-nitro-phenoxy)-furan-2-carbaldehyde (275 mg, 1.18 mmol) and the mixture was heated to 70° C. until a limpid solution was obtained. Azido-acetic acid ethyl ester (1.827 grams, 14.2 mmol) and DBU (286.9 mg, 1.89 mmol) were then added and the mixture was heated at 70° C. for one and a half hours. The solvent was thereafter removed under reduced pressure and a solution of HCl 0.1 M (50 ml) and ethyl acetate (20 ml) were added. After separation of the phases the aqueous phase was extracted with ethyl acetate (2×20 ml), the combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 148.5 mg of pure 2-azido-3-(5-(4-nitrophenoxy)-furan-2-yl)-acrylic acid ethyl ester (36.5% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C(O)C.[OH-].[Na+]>ClCCl>[C:2]([C:3](=[O:5])[CH:4]=[CH:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: O=Cc1ccncc1
Reactant: CC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccncc1
Reaction time: 12 h

Procedure:
A mixture of 3,3-dimethyl-2-butanone (2.5 ml, 20.0 mmol), 4-pyridinecarboxaldehyde (2.15 ml, 22.3 mmol), ethanol (7.6 ml), and 4.5% aqueous sodium hydroxide (4.6 ml) was kept at room temperature for 12 h. It was diluted with dichloromethane, washed with aqueous hydrochloric acid and water, dried and evaporated. Subsequent column chromatography (hexane-ethyl acetate=3:1) provided the title compound. MS (m/z): 190.4 (M+H)+ ; C12H15NO requir.189.3.
Reaction SMILES: CS([C:4]1[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N+:21]3([O-])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[N:5]=1)=O.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.S([O-])(O)=O.[Na+].N>C(Cl)(Cl)Cl>[CH:28]1([NH:31][C:4]2[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)[N:5]=2)[CH2:30][CH2:29]1
Reactant: CS(=O)c1nc(Nc2ccc(C[N+]3([O-])CCOCC3)cc2)ncc1C(N)=O
Reactant: NC1CC1
Agent: N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Nc2ccc(CN3CCOCC3)cc2)nc1NC1CC1
Temperature: 90 °C
Reaction time: 15 h
Yield: 23.6 %

Procedure:
A 1 ml portion of chloroform solution containing 11.7 mg of 4-methylsulfinyl-2-({4-[(N-oxidomorpholin-4-yl)methyl]phenyl}amino)pyrimidine-5-carboxamide was mixed with 5.1 mg of cyclopropylamine and 5.8 mg of diisopropylethylamine, followed by stirring at 90° C. for 15 hours. A 1 ml portion of aqueous solution containing 50 mg of sodium hydrogen sulfite was added to the reaction mixture, followed by stirring at room temperature for 4 hours. This was mixed with 0.1 ml of aqueous ammonia and extracted with 2 ml of chloroform. By evaporating the solvent under a reduced pressure and fractionating the residue by an HPLC (Wakosil-II 5C18AR, 0.1% HCOOH—H2O/MeOH=7/3−0/10), 2.6 mg of 4-cyclopropylamino-2-(4-morpholin -4-ylmethylphenylamino)-pyrimidine-5-carboxamide was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH2:20][CH2:21][C:22]#[N:23].O1CCOCC1>C(O)(C)(C)C>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:22]([NH2:23])[C:21]([CH2:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])=[CH:4]2
Reactant: COc1cccc(F)c1CCC#N
Reactant: Nc1ccc(Cl)cc1C=O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COc1cccc(F)c1Cc1cc2cc(Cl)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-chlorobenzaldehyde and 3-(2-fluoro-6-methoxyphenyl)propionitrile. Instead of dioxane, tert-butanol was used from [sic; as] the solvent. Reaction time: 5 minutes at 120° C.