Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH3:14]>CCO>[CH3:14][NH:13][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN
Reactant: Oc1cccc2ccc(Cl)nc12
Solvent: CCO
Product: CNc1ccc2cccc(O)c2n1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-8-hydroxyquinoline* (2.0 g, 11.1 mmol) in EtOH (40 mL) was added H2NMe (40% aqueous solution, 40 mL, 464 mmol). The mixture was heated in a sealed Pyrex tube at 100° C. for 24 h. The solvent was evaporated and the resulting crude product was purified by column chromatography [gradient: CH2Cl2/MeOH (99:1) to 1% NH4OH in CH2Cl2/MeOH (80:20)] to give the title compound as a black-green solid. Yield 1.31 g (67%); MS m/z 174 (M)+. Anal. (C10H10N2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH:22]=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[CH:22]=[CH:21][C:13]=2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccc(F)cc3)c2)c1
Reaction time: 1 h

Procedure:
0.056 mL of triethylamine and 0.036 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate at room temperature sequentially and stirred at the same temperature for 1 hour. 0.014 mL of triethylamine and 0.012 mL of 4-fluorobenzoyl chloride were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(4-fluorobenzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate.
Reaction SMILES: [S-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Br[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=2)[CH:15]=1>CN1CCCC1=O>[N+:19]([C:16]1[N:14]2[CH:15]=[C:10]([S:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=[CH:12][C:13]2=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: [S-]c1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cn12
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cnc2ccc(Sc3ccccc3)cn12

Procedure:
A solution of 1.61 g. (0.012 mole) of sodium thiophenoxide and 2.42 g. (0.01 mole) of 6-bromo-3-nitroimidazo [1,2-a] pyridine in 10 ml. N-methylpyrolidinone is heated at 150° C for 0.40 minutes under a nitrogen atmosphere. The cooled solution is poured onto 100 ml. of ice-water and the resultant suspension is extracted with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the solvent to a small volume and dilution with N-hexane yields crystalline material. The solids are purified by chromatography on silica gel. Elution with methylene chloride yields pure 3-nitro 6-phenylthioimidazo [1,2-a] pyridine m.p. 108°-109° C.
Reaction SMILES: [H][H].C([O:10][CH2:11][C@@H:12]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH2:14][C@H:13]1[OH:21])C1C=CC=CC=1.C(OCC)(=O)C>[C].[Pd].C(O)(=O)C>[CH2:17]([C@H:16]1[CH2:15][CH2:14][C@@H:13]([OH:21])[C@@H:12]1[CH2:11][OH:10])[CH2:18][CH2:19][CH3:20]
Reactant: [H][H]
Reactant: CCCC[C@H]1CC[C@@H](O)[C@@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCC[C@H]1CC[C@@H](O)[C@@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
In an atmosphere of hydrogen, a mixture of 4.29 g of (1R,2S,3S)-2-benzyloxymethyl-3-butylcyclopentan-1-ol (prepared in Reference Example 7), 500 ml of 10% palladium-carbon, 20 ml of ethyl acetate and 10 ml of acetic acid was stirred for 16 hrs at room temperature. After stirring the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:3) as eluent to give 2.59 g of the title compound having the following physical characteristics in a 91.8% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([Br:16])[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]O)[N:6]2[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37].O>O1CCCC1>[Br:16][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][Br:37])[N:6]2[C:7]=1[C:2]([NH2:1])=[N:3][CH:4]=[N:5]2
Reactant: Nc1ncnn2c(CCCCO)cc(Br)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCCCBr)cc(Br)c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
To a cooled (0° C.) solution of 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)butan-1-ol (600 mg, 2.10 mmol) and triphenylphosphine (828 mg, 3.16 mmol) in tetrahydrofuran (15 mL) was added carbon tetrabromide (837 mg, 2.53 mmol). The reaction was stirred (0° C.) for 90 min and then was warmed to rt and stirred an additional 1 h. Water (25 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organics were dried (Na2SO4) and evaporated. The crude material was purified via ISCO® chromatography using a gradient of 25 to 50% ethyl acetate in hexanes to afford 597 mg (82%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.82 (s, 1 H), 6.62 (s, 1 H), 3.54 (t, 2 H), 2.84 (t, 2 H), 1.86-1.70 (m, 4 H); ES-MS m/z 347.2 [M+H]+, HPLC RT (min) 2.58.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([I:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.FC1C(F)=CC=CC=1N.ClC1C=C[C:26]([O:29]C)=CC=1N>>[I:11][C:8]1[S:9][C:10]2[CH:2]=[CH:3][C:4]([O:29][CH3:26])=[CH:5][C:6]=2[N:7]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: Fc1cccc2nc(I)sc12
Agent: Nc1cccc(F)c1F
Product: COc1ccc2sc(I)nc2c1

Procedure:
The title compound was prepared following the route for 7-fluoro-2-iodo-1,3-benzothiazole from 2,3-difluoroaniline, starting from 2-chloro-5-methoxyaniline and conducting the first step at 150° C. for 16 h.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][O:22]C1C=CC(CCl)=CC=1.O>C1(C)C=CC=CC=1>[CH3:21][O:22][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[N:11]2)=[CH:9][CH:8]=1
Reactant: OCc1nn(Cc2ccccc2)c2ccccc12
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cn2nc(CO)c3ccccc32)cc1
Temperature: 25 °C
Yield: 27.2 %

Procedure:
To a suspension of 60% NaH (2.7 g; 0.07 mol) in toluene (200 ml) was added 1-benzyl-3-hydroxymethylindazole (10 g; 0.07 mol). The mixture was brought to boiling point and left stirring at reflux for 1 hour. 4-Methoxybenzyl chloride (14 g; 0.09 mol) was then added. The mixture was then stirred at reflux for 4 hours. The reaction was completed by cooling the mixture to room temperature and adding water (50 ml). The organic phase was separated out and washed, respectively, with 2N HCl (50 ml) and water (5×50 ml). The solvent was evaporated off under reduced pressure. The crude residue thus obtained was purified by flash chromatography on silica gel, using as eluent a 3/2 hexane/ethyl acetate mixture. The product obtained was crystallized from a 5/1 hexane/ethyl acetate mixture to give 5.1 g of [1-(4-methoxybenzyl)-1H-indazol-3-yl]methanol with a melting point of 95°-97° C.
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(O)C>[OH:1][C@@H:2]([CH2:18][N:32]1[CH2:33][CH2:34][CH:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[CH2:30][CH2:31]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Solvent: CCO
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H](O)CN1CCC(c2ccc3ccccc3c2)CC1
Yield: 53.8 %

Procedure:
(S)-α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (50 g) and 4-(naphthalen-2-yl)piperidine (43 g) were dissolved in ethanol (500 ml) and the mixture was refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the obtained crystals were collected by filtration. The crystals were recrystallized once from acetonitrile and once from a mixed solvent of ethyl acetate and ethanol to give the title compound (50 g), melting point 138-140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:26](=[O:28])[CH3:27])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:30][C:31]1[C:36]([CH2:37][CH2:38][CH3:39])=[C:35]([OH:40])[CH:34]=[CH:33][C:32]=1[C:41](=[O:43])[CH3:42].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:26](=[O:28])[CH3:27])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:40][C:35]3[CH:34]=[CH:33][C:32]([C:41](=[O:43])[CH3:42])=[C:31]([OH:30])[C:36]=3[CH2:37][CH2:38][CH3:39])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)COc1ccc2ccc(OCCOCCOCCBr)c(C(C)=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 72.5 %

Procedure:
A mixture of 2 g of [[8-acetyl-7-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 1.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 0.9 g of anhydrous potassium carbonate in 40 ml of anhydrous acetone and 14 ml of anhydrous dimethylformamide was stirred at reflux for 16 hours. The solvent was removed in vacuo and residue was dissolved in ethyl acetate, washed with water, dried (magnesium sulfate) and concentrated in vacuo to give an oil which was purified by high pressure liquid chromatography (60% ethyl acetate-hexane) to yield 1.8 g (73%) of [[8-acetyl-7-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[N:9]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3)cc1)nn2[C@@H]1CCCNC1
Yield: 85.6 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (260 mg, 0.52 mmol, 1.00 equiv) in dichloromethane (50 mL). Trifluoroacetic acid (10 mL) was added dropwise with stirring. The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The residue was diluted with 20 mL of water. The pH value of the solution was adjusted to >7 with sodium carbonate. The resulting solution was extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 180 mg (86%) of 3-[4-(3-fluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>>[C:17]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: CC(C)C(=O)Cl
Product: Cc1c2c(nc3ccccc13)CCN(C(=O)C(C)C)CC2
Yield: 50 %

Procedure:
3-Isobutyryl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline with isobutyryl chloride in pryidine.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:8][CH2:9][CH:10]([NH:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][O:12][C:13](=[O:15])[CH3:14])(=[O:7])[CH3:6].C(N(CC)CC)C>>[C:5]([O:8][CH2:9][CH:10]([N:16]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:1](=[O:3])[CH3:2])[CH2:11][O:12][C:13](=[O:15])[CH3:14])(=[O:7])[CH3:6]
Reactant: CC(=O)OCC(COC(C)=O)NCC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(COC(C)=O)N(CC(=O)OC(C)(C)C)C(C)=O
Yield: 50.3 %

Procedure:
Acetyl chloride (0.357 ml, 5.0 mmol) was added dropwise to a stirred solution of tert-butyl 2-{[1,3-bis(acetyloxy)propan-2-yl]amino}acetate (1.22 g, 4.2 mmol) and triethylamine (0.696 ml, 5.0 mmol). After 2 hours the reaction was quenched by the addition of water. The organic phase was separated and washed with further aliquots of water before being dried over MgSO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with 25% EtOAc:Hept to yield the title compound (0.7 g, 50%). 1H NMR (250 MHz, CHLOROFORM-d) δ 4.04-4.44 (5H, m), 3.98 (1H, s), 3.88 (1H, s), 2.08 (3H, s), 2.05 (6H, s), 1.47 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH: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.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1F
Reaction time: 38 h
Yield: 64 %

Procedure:
1,4-Difluoro-2-methyl-5-nitrobenzene (1.5 mol, 260 mg) in dimethylformamide (10 mL) was treated under argon at room temperature with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 260 μL, 1 eq) then stirred at 70 (→80) ° C. for 38 h. The mixture was concentrated under vacuum, treated with water and extracted twice with ether. Organics were combined, dried on MgSO4 and concentrated under vacuum to give a red-brown residue which was chromatographed (0-25% ethyl acetate/petrol ether 6 CV) to give the title compound as a red solid (0.96 mmol, 340 mg, 64% yield). M+H=298.07, main fragment (molecule has lost its tert-butyl group).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=O.Cl.Cl.[NH2:21][O:22][CH2:23][CH2:24][NH2:25].N1C=CC=CC=1.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36].[NH2:25][CH2:24][CH2:23][O:22][N:21]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: NCCON
Reactant: COCCCCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: COCCCCC(=NOCCN)c1ccc(C(F)(F)F)cc1

Procedure:
20.4 Mmol (5.3 g) of 5-methoxy-4'-trifluoromethylvalerophenone (melting point 43°-44° C), 20.5 mmol (3.1 g) of 2-aminooxyethylaminedihydrochloride and 10 ml of pyridine were refluxed for 15 hours in 20 ml of absolute ethanol. After evaporating the pyridine and the ethanol in vacuo, the residue was dissolved in water. This solution was washed with petroleum ether and 10 ml of 50% sodium hydroxide solution were then added. Then three extractions with 40 ml of ether were carried out. The ether extract was washed successively with 20 ml of 5% sodium bicarbonate solution and 20 ml of water. After drying on sodium sulphate, the ether layer was evaporated in vacuo. Toluene was then evaporated another three times (to remove the pyridine) and the oil thus obtained was dissolved in 15 ml of absolute ethanol. An equimolar quantity of maleic acid was added to said solution and the solution was then heated until a clear solution was obtained. The ethanol was then removed in vacuo and the residue was crystallized from 10 ml of acetonitrile at +5° C. After sucking off and washing with cold acetonitrile, it was dried in air. The melting point of the resulting title compound was 120°-121.5° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:32]([N:35]1[CH:39]([C:40]2[CH:41]=[CH:42][C:43]([O:51][CH3:52])=[C:44]([CH:50]=2)[O:45][CH2:46][C:47](O)=[O:48])[CH2:38][C:37]([C:53]2[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=2)=[N:36]1)(=[O:34])[CH3:33]>ClCCl.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:47](=[O:48])[CH2:46][O:45][C:44]1[CH:50]=[C:40]([CH:39]2[N:35]([C:32](=[O:34])[CH3:33])[N:36]=[C:37]([C:53]3[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=3)[CH2:38]2)[CH:41]=[CH:42][C:43]=1[O:51][CH3:52]
Reactant: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)O
Reactant: Nc1nc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)Nc1nc2ccccc2s1
Yield: 799.1 %

Procedure:
To a solution of 2-aminobenzothiazole (359.37 ma, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 ma, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10a) (472 mg, 80% yield)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O>[CH3:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution of 1.90 g (10.0 mmol) of 6,7-dimethyl-1,4-dihydroquinoxaline-2,3-dione in 25 mL of H2SO4 (97%) kept in an ice bath was added dropwise 1.2 mL of HNO3 (69-70%) and the solution was stirred at room temperature for 48 h. It was poured into 300 mL of ice-water and stirred for 10 min. The mixture was filtered, washed with water, and dried to leave a yellow solid 1.40 g (60%). The solid was purified by DMSO/H2O precipitation followed by NaOH/HCl precipitation to leave 0.85 g of a yellow solid; mp >250° C.; 1H NMR (DMSO-d6), 2.079 (s,3), 2.246 (s,3), 7.048 (s,1), 11.770 (s,1), 12.030 (s,1). HRMS calcd. for C10H9N3O4 235.0588; found 235.0584.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:21][C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[F:13])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12]
Reactant: Oc1ccc(F)cc1F
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Br)cc(Oc2ccc(F)cc2F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
1-Bromo-5-fluoro-2-methyl-3-nitro-benzene (9.40 g, 41.45 mmol) was dissolved in 90 mL dry DMF, and 2,4-difluorophenol (5.93 g, 45.58 mmol) and potassium carbonate (6.70 g, 45.58 mmol) were added. The reaction mixture was placed under nitronge and heated to 120° C. with stirring for 18 hours. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was partitioned between water and EtOAc. The organic phase was separated, washed with 1N aqueous NaOH and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-6% EtOAc in hexanes) to give 8.484 g of 1-bromo-5-(2,4-difluoro-phenoxy)-2-methyl-3-nitro-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:42])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:41])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][N:30]4C(=O)C5=CC=CC=C5C4=O)=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:43]=1.O.NN.O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:42])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:41])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][NH2:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:43]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Yield: 56.3 %

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-phthalimidoethoxy)benzoyl-amino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g)in ethanol (5 ml) is added hydrazine monohydrate (0.03 ml), and the mixture is refluxed for one hour, and cooled. To the mixture is added water, and the mixture is made acidic with diluted hydrochloric acid, and washed with diethyl ether. The aqueous layer is made basic with aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-aminoethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (110 mg) as white powder.