Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[O:7][C@@H:6](N2C=CC(=O)NC2=O)[CH2:5]1)=[N+:2]=[N-:3].[NH2:26][C:27]1[N:35]=[C:34]2[C:30]([NH:31][CH:32]=[N:33]2)=[C:29]([Cl:36])[N:28]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[O:7][CH:6]([N:33]2[CH:32]=[N:31][C:30]3[C:34]2=[N:35][C:27]([NH2:26])=[N:28][C:29]=3[Cl:36])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC(n2cnc3c(Cl)nc(N)nc32)C[C@@H]1N=[N+]=[N-]
Temperature: 85 °C

Procedure:
A suspension of 1-((2R,4S,5S)-4-azido-5-((tert-butyldimethylsilyloxy)methyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H, 3H)-dione, 75 (TBS protected AZU)1 (0.2 g, 0.544 mmol) and 2-amino-6-chloropurine (0.25 g, 1.51 mmol) in acetonitrile (6 mL) was added BSA (2 ml, 1.51 mmol). The reaction mixture was heated to 85° C. for 30 min, then cooled to 0° C. TMSOTf (0.51 mL) was added. The reaction mixture was heated to 85° C. overnight, cooled to room temperature, poured into saturated sodium bicarbonate, extracted with ethyl acetate (20 mL×2), dried, conc., and purified by flash column chromatography with ethyl acetate:hexane=1:1 to get the desired compound 0.1 g. 43%. It contained two isomers (alpha:beta=1.1:1)
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4]([C:5](Cl)=[O:6])[C@@H:3]1[CH:8]=[C:9]1[CH2:12][CH2:11][CH2:10]1.[CH3:14][C:15]1[CH:20]([OH:21])[CH2:19][C:17](=[O:18])[C:16]=1[CH2:22][CH:23]=[CH2:24]>N1C=CC=CC=1.C1C=CC=CC=1.C(O)=O.O>[CH3:1][C:2]1([CH3:13])[C@@H:4]([C:5]([O-:18])=[O:6])[C@@H:3]1[CH:8]=[C:9]1[CH2:12][CH2:11][CH2:10]1.[CH3:14][C:15]1[CH:20]([OH:21])[CH2:19][C:17](=[O:18])[C:16]=1[CH2:22][CH:23]=[CH2:24]
Reactant: CC1(C)[C@@H](C=C2CCC2)[C@@H]1C(=O)Cl
Agent: C=CCC1=C(C)C(O)CC1=O
Solvent: O
Solvent: O=CO
Solvent: c1ccncc1
Product: CC1(C)[C@@H](C=C2CCC2)[C@@H]1C(=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.885 gm of dl-trans 3,3-dimethyl-2-cyclobutylidenemethyl-1-cyclopropanecarboxylic acid chloride were introduced into 5 cc of benzene and then a solution of 1.46 gm of dl-allethrolone in a mixture of 2 cc of pyridine and 10 cc of benzene was added dropwise. Next, the reaction mixture was agitated for 15 hours at room temperature and a few drops of formic acid were added thereto and the reaction mixture was then diluted with water. The organic phase was separated by decanting and the aqueous phase was extracted with ether. The ether extracts were combined with the principal organic phase and the organic solution obtained was washed successively with a dilute aqueous solution of hydrochloric acid, with water with an aqueous solution of sodium bicarbonate and again with water. The solution was dried and concentrated to dryness and the residue was dissolved in benzene. Then the solution was passed through an alumina column and the eluate was concentrated to dryness to obtain 2.74 gm of dl-trans 3,3-dimethyl-2-cyclobutylidenemethyl-1-cyclopropanecarboxylate of dl-allethrolone having a refractive index nD23 = 1.5192.
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7])=O.Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[O:13][C:4]3[C:5]([C:6]([OH:8])=[O:7])=[CH:10][CH:11]=[CH:12][C:3]=3[CH:1]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc2cc(-c3ccc(Cl)cc3)oc12
Temperature: 100 °C
Yield: 60.8 %

Procedure:
A mixture of 2.0 g of methyl 3-formyl-2-hydroxybenzoate, 3.51 g of methyl α-bromo-p-chlorophenylacetate, 5.55 g of potassium carbonate and 60 ml of dimethylformamide is heated at 70°-80° C. for 15 minutes and further heated at 100° C. for 10 minutes. The reaction mixture is filtered and washed with ethyl acetate. The washings and the filtrate are combined and water is added to the mixture. The mixture is acidified with 10% hydrochloric acid. The organic layer is collected and the aqueous layer is extracted with ethyl acetate. The organic layer and the extract are combined, washed with water, dried and evaporated to remove solvent. The residue is dissolved in 30 ml of ethanol and 3.25 g of potassium hydroxide are added to the solution. The mixture is refluxed for 1 hour. The reaction mixture is evaporated to remove solvent, and water is added to the residue. The aqueous mixture is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. 100 ml of xylene and 150 mg of p-toluenesulfonic acid are added to the residue and the mixture is refluxed for 1 hour. After cooling, ethyl acetate is added to the reaction mixture. The mixture is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate to give 1.84 g of 2-(4-chlorophenyl)benzofuran-7-carboxylic acid as colorless needles.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[C:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:23].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[CH:27][CH:26]=1)#[N:23]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#CCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (60 mg, 0.162 mmol), [4-(cyanomethyl)phenyl]boronic acid (52.0 mg, 0.323 mmol) and K2CO3 (67.0 mg, 0.485 mmol) in 1,4-dioxane (0.18 mL) and water (0.08 mL) was degassed in a Biotage microwave vial for 10 min. PdCl2(dppf) (11.83 mg, 0.016 mmol) was added, the vial sealed, and the reaction heated at 100° C. for 5 min (microwave reaction). EtOAc (3 mL) and water (1 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (4×2 mL). The combined organic layers were washed with saturated NaCl (1×2 mL), dried (Na2SO4), and concentrated under a stream of nitrogen at 50° C. Recovered 27 mg (42%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][C:59](C)(C)C)=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:65]OC(NC(C1C=CC=CC=1C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=6[CH3:65])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)c1ccccc1C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1C
Yield: 31.4 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-o-tolyl-acetic acid (0.072 g, 0.332 mmol) to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-o-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.047 g, 31.4%) as a white solid. LCMS-ESI+: calc'd for C48H52N8O6: 836.40 (M+); Found: 837.86 (M+H+).
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6][OH:7].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>ClCCl>[C:10]([O:7][CH2:6][CH2:5][C:4]#[C:3][C:2]([OH:9])([CH3:8])[CH3:1])(=[O:12])[CH3:11]
Reactant: CC(C)(O)C#CCCO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCC#CC(C)(C)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
100 g (0.78 mol) of 5-methylhex-3-yne-1,5-diol were dissolved in 800 ml of dichloromethane and cooled to 0° C. 113 ml (1.11 mol) of acetic anhydride were added in one portion. 127 ml (1.25 mol) of triethylamine were cooled to 0-2° C. and added within 20 min. The reaction mixture was stirred at 0° C. for 2 h. The cooling was removed and the reaction mixture was stirred a 20° C. for 16 h. The mixture was cooled to 0° C. and 1200 ml of a 5% hydrochloric acid solution were added, in the course of which the temperature of the reaction mixture was kept below 5° C. The mixture was extracted three times with 150 ml each time of tert-butyl methyl ether (MTBE), and the combined organic phases were stirred four times with 400 ml each time of 5% aqueous sodium hydrogen carbonate solution for 1 h each time, until no further evolution of gas was observable in each case. The organic phase was washed with 1 l of demineralized water and dried over sodium sulfate, and the solvent was removed. This gave 122.21 g (yield 92%) of a clear, dark yellow liquid. The purity was determined by gas chromatography to be 99.5%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[C:24]([C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1)(=[O:26])[CH3:25]>>[C:24]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[O:35])[CH:30]=[CH:31][CH:32]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Product: CC(=O)c1cccc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3-acetylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:7].O[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>>[Cl:7][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccccc12
Reaction time: 0.33 h
Yield: 93.3 %

Procedure:
Phosphorus oxychloride (64 mL, 687 mmol) and phosphorus pentachloride (14.89 g, 71.50 mmol) were added to 4-hydroxyquinazoline (7.94 g, 52.3 mmol), and the solution was stirred for 20 minutes under reflux. The reaction mixture was evaporated in vacuo, and the residue was dissolved in chloroform. The chloroform solution was poured on an ice bath, concentrated aqueous ammonia was added to adjust the pH to 10, then, the solution was partitioned. The aqueous layer was extracted with chloroform, and the combined chloroform layers were washed with water. The organic layer was dried over anhydrous magnesium sulfate, then, evaporated in vacuo, and the title compound (8.03 g,48.8 mmol, 93%) was obtained. This was used in the next reaction without purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([Br:14])[S:13][C:8]=2[CH:7]=1)=[O:5])C.Cl>>[Br:14][C:12]1[S:13][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2sc(Br)cc2[nH]1
Agent: Cl
Product: O=C(O)c1cc2sc(Br)cc2[nH]1
Temperature: 25 °C

Procedure:
2-Bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (Eras, J.; Galvez, C.; Garcia, F., J. Heterocycl. Chem., 21: 215-217 (1984)) was hydrolyzed according to Procedure D (after cooling to room temperature, acidification with 2 N HCl; resultant precipitate filtered, suspended in toluene, concentrated; no purification).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].Cl.C(NCC)C>C1(C)C=CC=CC=1>[C:2]1([C:1]2[NH:11][N:10]=[N:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCNCC
Solvent: Cc1ccccc1
Product: c1ccc(-c2nnn[nH]2)cc1
Yield: 96 %

Procedure:
Into the same device as used in Example 1 were placed 5.16 g (0.050 mole) of benzonitrile, 4.23 g (0.065 mole) of sodium azide, 7.13 g (0.065 mole) of diethylamine hydrochloride and 52 ml of toluene. The mixture was reacted for 8 hours in the same manner as in Example 1, giving 7.02 g (0.048 mole) of 5-phenyl-1H-tetrazole (yield 96.0% based on benzonitrile).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:20](O)[CH2:21][OH:22].O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:3][C:4]2([CH2:5][CH2:6][CH:7]=1)[O:22][CH2:21][CH2:20][O:8]2
Reactant: OCCO
Reactant: CC1=CC(=O)CCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=CCCC2(C1)OCCO2
Yield: 62 %

Procedure:
A mixture of 3-methyl-2-cyclohexenone (4 g, 36.36 mmol), toluenesulfonic acid (100 mg) and ethylene glycol (7 mL) in 100 mL of toluene is refluxed overnight and water formed is removed by Dean- Stark trap. The residue after concentration is chromatographed on silica gel (10% ethyl acetate/hexane) to give 3.36 g (62%) of 7-methyl-1,4-dioxa-spiro[4.5]dec-7-ene.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].Cl[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24]>>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(O)CCCCCl
Reactant: CCCCn1cnc2c1c(=O)[nH]c(=O)n2CC
Product: CCCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2CC

Procedure:
According to Example 1 7-butyl-3-ethylxanthine was reacted with 1-chloro-5-hydroxy-5-methylhexane; after isolation the final product was recrystallized from a mixture of ethyl acetate and petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14](=[O:16])[CH3:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C(C1C2C(=CC=C(OC(F)(F)F)C=2)N([CH2:34][C:35]([OH:37])=[O:36])C=1)(=O)C>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14](=[O:16])[CH3:15])=[CH:10][N:11]2[CH2:34][C:35]([OH:37])=[O:36])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: COC(=O)c1ccc2c(C(C)=O)cn(CC(=O)O)c2c1

Procedure:
was prepared from 3-acetyl-1H-indole-6-carboxylic acid methyl ester [106896-61-1] in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Colored solid. MS: 276 [M+H]+; tR (HPLC conditions k): 2.80 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[C:5]([CH3:16])[N:4]([C:17]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:20]=[CH:19][N:18]=2)[N:3]=1.[CH2:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)Cl>[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:7][C:6]3[C:2]([CH3:1])=[N:3][N:4]([C:17]4[N:22]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)[CH:20]=[CH:19][N:18]=4)[C:5]=3[CH3:16])=[CH:9][CH:10]=2)[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1Oc1ccc(C=O)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1Oc1ccc(CN2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.4 %

Procedure:
To a solution of 4-[3,5-dimethyl-1-(4-pyridin-2-yl-pyrimidin-2-yl)-1H-pyrazol-4-yloxy]-benzaldehyde (0.545 g, 1.47 mmol) and 1-benzylpiperazine (0.310 g, 1.76 mmol) in dichloroethane (10 mL) was added sodium triacetoxyborohydride (0.436 g, 2.06 mmol). The reaction mixture was stirred at room temperature for 17 hours. The solution was diluted with methylene chloride (50 mL) and washed with saturated sodium hydrogencarbonate (2×30 mL) and brine (50 mL). The organic phase was dried (magnesium sulfate), filtered, and concentrated to afford a yellow oil. Flash chromatography over silica (2 M ammonia in methanol/methylene chloride) provided 0.183 g (23%) of the product as a white foam: 1H NMR (CDCl3) δ 8.94-8.93 (m, 1H), 8.75 (d, J=3.9 Hz, 1H), 8.46 (d, J=7.9 Hz, 1H), 8.25 (d, J=3.9 Hz, 1H), 7.90-7.87 (m, 1H), 7.46-7.43 (m, 1H), 7.31-7.21 (m, 7H), 6.89 (d, J=8.5 Hz, 2H), 3.52 (s, 2H), 3.47 (s, 2H), 2.68 (s, 3H), 2.48 (br s, 8H), 2.21 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:15][CH:14]=2)=[N:5][C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=1)[CH3:2].O.NN>C(O)C.O.[Fe](Cl)Cl>[NH2:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[O:27][C:4]1[N:5]=[C:6]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[CH:17][CH:18]=2)[C:7]([C:9]([NH2:11])=[O:10])=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Agent: Cl[Fe]Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CCc1nc(C(N)=O)c(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a mixture of 6-ethyl-3-({4-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)-5-(3-nitrophenoxy)pyrazine-2-carboxamide (112 mg) in ethanol (3 mL) and water (1 mL) were added iron chloride (III) hexahydrate (31 mg), activated carbon (60 mg), and hydrazine monohydrate (221 μL), followed by stirring at 80° C. for 2 hours. The reaction mixture was left to be cooled, and then water was added thereto. The insoluble matter was collected by filtration. To the obtained solid was added a solution in chloroform-methanol (10:1), and the insoluble matter was separated by filtration. The obtained filtrate was concentrated under reduced pressure to obtain 5-(3-aminophenoxy)-6-ethyl-3-({4-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)pyrazine-2-carboxamide (46 mg) as a pale yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([OH:12])=[N:3][CH:2]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][N:3]=[C:4]2[OH:12])(=[O:15])[CH3:14]
Reactant: Oc1ccc2ncnc(O)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2ncnc(O)c2c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of quinazoline-4,6-diol (20 g, 123 mmol) and acetic anhydride (186 mL, 1.97 mol) was heated to 100° C. in pyridine (30 mL) for 2 hours. After cooling to room temperature, ice (200 g) was slowly added to the reaction mixture. The precipitate was filtered, washed with cold water, and dried under high vacuum to provide the product (16.25 g, 65%) as pale yellow solid.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:17]([C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[CH:1]1[C:6]2[CH2:7][N:8]([C:29]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[CH:33][CH:32]=3)=[O:30])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 131.1 %

Procedure:
To a mixture of 0.197 g of 10,11-dihydrodibenz[b,f][1,4]oxazepine and 0.402 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride in 5 ml of dichloromethane (cooled in ice bath) is added dropwise 0.154 g of N,N-diisopropylethylamine in 2 ml of dichloromethane. The mixture is stirred at room temperature under argon for 2 hours. The mixture is poured into water and the organic layer separated. The organic extract is washed with 2N Na2CO3, water, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated to dryness to give 0.65 g of solid. The solid is purified by thick layer chromatography on silica gel with hexane-ethyl acetate (2:1) as solvent to give 0.110 g of a glass, m.p. 107° C.-122° C. Anal. Found: C, 80.8; H, 4.9; N,6.0.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:16][O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COCCCc1ccccc1B(O)O
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Product: COCCCc1ccccc1-c1cc(C(F)(F)F)c(C(=O)OC)cn1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 1 using commercially available methyl 6-chloro-4-(trifluoromethyl)nicotinate and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3, step 1 as starting materials. Purification by column chromatography on silica gel, eluting with Hex/EtOAc 10% afforded the desired compound as a colorless oil.