Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C@@H:6]1[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:28][C@H:29]([CH2:32][CH2:33][CH3:34])[CH2:30][CH3:31]>C1COCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C@@H:9]([CH2:28][C@@H:29]([CH2:30][CH3:31])[CH2:32][CH2:33][CH3:34])[C:8](=[O:11])[N:7]([CH3:12])[C@@H:6]1[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4]
Reactant: CCC[C@H](CC)CI
Reactant: COC(=O)N1CCC(=O)N(C)[C@@H]1C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC[C@H](CC)C[C@@H]1CN(C(=O)OC)[C@@H](C(C)(C)C)N(C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To a −78° C. stirred solution of (S)-2-tert-butyl-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester (1.04 g, 4.57 mmol) in dry THF (15 mL) was added NaHMDS (5.03 mL, 1.0 M in THF) dropwise. The reaction was stirred at −78° C. for 1 hour and then a solution of (S)-3-Iodomethyl-hexane (1.24 g, 5.48 mmol) in dry THF (5 mL) was added dropwise. The reaction was stirred at this temperature for 2 hours and than was placed in a −10° C. refrigerator overnight. The reaction was quenched with sat. NH4Cl (20 mL) and was allowed to warm to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The organic extracts were combined and washed with brine (2×15 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified by chromatography using hexanes/EtOAc (10–>20%) to yield 0.185 g (12%) of pure product: 1H NMR (400 MHz, CD3OD) 8 ppm 0.9 (m, 6 H), 1.3 (m, 5 H), 1.4 (m, 3 H), 1.7 (m, 1 H), 2.5 (m, 1 H), 2.9 (d, J=6.6 Hz, 2 H). MS: M+1 (328).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7](=[N:20][OH:21])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1
Yield: 93.3 %

Procedure:
242 g (1 mole) of 4,4'-dimethoxybenzophenone was suspended in 2,000 ml of ethanol and 210 g (3 mole) of hydroxylamine hydrochloride and 300 ml (3 mole) of a 10 N aqueous solution of NaOH were thereto. Then the obtained mixture was heated under reflux. After two or three hours, the ethanol was distilled off in vacuo and then a saline solution was added thereto followed by extracting with chloroform. The chloroform phase was washed with water and dried over magnesium sulfate. After distilling the chloroform off, the residue was recystallized from ethanol. Thus 240 g of the title compound was obtained in the form of colorless needles.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].C(OC(=O)[NH:14][C@H:15]([C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=1)[C@H:16]([OH:18])[CH3:17])(C)(C)C>C(OCC)(=O)C>[ClH:7].[NH2:14][C@H:15]([C:19]1[CH:20]=[C:21]([F:27])[C:22]([F:26])=[C:23]([F:25])[CH:24]=1)[C@H:16]([OH:18])[CH3:17]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](N)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 4 N hydrochloric acid ethyl acetate solution (20 mL) was added to an ethyl acetate solution (50 mL) of [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]carbamic acid tert-butyl ester (4.49 g). This reaction solution was stirred at room temperature for 5 hr. The reaction solution was concentrated under reduced pressure to give 3.5 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[O:7].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[Cl-].[Na+].C(OCC)(=O)C>O1CCCC1>[OH:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)c2nccs2)C1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(O)c2nccs2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
Under a nitrogen atmosphere, 17.2 g (0.058 mol) of tert-butyl (S)-3-(thiazole-2-carbonyl)-piperidine-1-carboxylate were dissolved in 200 ml of tetrahydrofuran, and 121.8 ml (0.122 mol) of lithium tri-tert-butoxyaluminium hydride (1.0 M solution in tetrahydrofuran) were subsequently added dropwise between −4 and +2° C. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. Ice-water was subsequently added, during which the temperature rose to 1° C. After addition of saturated sodium chloride solution and ethyl acetate, the inorganic residue was filtered off. Water and saturated sodium chloride solution were added to the filtrate, which was then extracted with ethyl acetate, and the organic phase was evaporated, giving 19.0 g of tert-butyl (S)-3-(hydroxythiazol-2-ylmethyl)piperidine-1-carboxylate as diastereomer mixture of the S-piperidine in the ratio 30:70 (polar:nonpolar); HPLC/MS (M+H)+=299; rotation value in methanol [α]20D=+4.80. 1H NMR (400 MHz, DMSO) δ 7.72 (dd, J=14.9, 3.3, 1H), 7.62 (dd, J=3.2, 0.8, 1H), 6.22 (dd, J=11.4, 5.3, 1H), 4.66 (dd, J=9.8, 4.6, 1H), 3.82 (t, J=11.8, 2H), 2.71-2.54 (m, 2H), 1.88-1.72 (m, 1H), 1.73-1.57 (m, 2H), 1.40-1.30 (m, 11H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][CH2:17]O.S(=O)(=O)(O)O>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([O:11][CH2:16][CH3:17])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(N)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To the flask of 2-(4-Amino-3-nitrophenyl)propanoic acid residue was added EtOH (200 mL) and catalytic amounts of sulfuric acid (1 mL) at room temperature. The reaction mixture was refluxed for 6 hrs then cooled to room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[CH3:28][S:29]([O:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH2:8][NH:9][C:10]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:16])=[CH:5][CH:4]=1)(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(COS(C)(=O)=O)cc1
Reaction time: 0.83 h
Yield: 100 %

Procedure:
A solution of tert-butyl 4-(hydroxymethyl)phenethylcarbamate (2.51 g, 9.99 mmol) and N,N-diisopropylethylamine (1.9 mL, 11 mmol) in tetrahydrofuran (50 mL) was stirred and cooled in an ice bath. Methanesulfonyl chloride (0.85 mL, 11 mmol) was added in several portions, and stirring was continued in the bath for 50 minutes. The reaction mixture was transferred to a separatory funnel containing ethyl acetate (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate and concentrated to afford 4-(2-(tert-butoxycarbonylamino)ethyl)benzyl methanesulfonate as a soft white solid. (3.29 g, 100% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>O1CCCC1>[CH3:35][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:34])[O:18][C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:28][CH:27]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: Cc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)Oc2ccc3c(c2)N(Cc2ccccc2)CCC3)cc1
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (824 mg, 3.44 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, p-tolyl isocyanate (651 mg/ml, 5.16 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was quenched with distilled water followed by the extraction with chloroform (3×15 mL). The combined fractions of chloroform was again washed with water and dried over sodium sulphate. Further concentration of chloroform fraction under vacuum afforded the crude product, which was finally crystallized with methanol-ether (1:5) to give 8b as solid. Yield: 1.023 g, 79.77%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10]C=CC)=[C:6]([N:14]([S:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])(=[O:20])=[O:19])[CH:15]=[CH:16]C)[CH:5]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH:16]=[CH:15][N:14]([S:18]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:6]=2[CH:5]=1)=[O:30]
Reactant: CC=COc1ccc(C(=O)OC)cc1N(C=CC)S(=O)(=O)c1cc(Cl)ccc1OC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)C=CO2
Yield: 50.1 %

Procedure:
A solution of 3-[(5-chloro-2-methoxy-benzenesulfonyl)-propenyl-amino]-4-[(propenyl)oxy]-benzoic acid methyl ester (170 mg, 0.378 mmol) and dichloro(1,3-dimesityl-4,5-dihydroimidazol-2-ylidene)(phenylmethylene)(tricyclohexylphosphine)ruthenium (32 mg, 38 μmol) in toluene (1.7 mL) was stirred at 45° C. for 24 h, then the solvent was evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded 4-(5-chloro-2-methoxy-benzenesulfonyl)-4H-benzo[1,4]oxazine-6-carboxylic acid methyl ester (75 mg, 50%). Light red solid, MS (ISP)=395.7 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1I)[C:6]#[N:7])[CH3:2].[C:12]1(B(O)O)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1.C[O-].[Na+]>CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:12]1([C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:1][CH3:2])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CCc1cc(C#N)ccc1I
Agent: Cl[Pd]Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1cc(C#N)ccc1C1=CCCCC1
Temperature: 80 °C
Yield: 81.5 %

Procedure:
A mixture of 3-ethyl-4-iodobenzonitrile (D10) (1.23 g, 4.80 mmol), 1-cyclohexen-1-ylboronic acid (907 mg, 7.20 mmol), sodium methoxide (778 mg, 14.4 mmol) and bis(triphenylphosphine)palladium (II) chloride (337 mg, 0.48 mmol) in anhydrous methanol (12 mL) was heated at 80° C. for 10 minutes in the microwave. The reaction mixture was partitioned between ethyl acetate (40 mL) and water (40 mL) before the organic layer was further washed with water (40 mL), dried (phase separator) and concentrated in vacuo. The crude material was purified by silica chromatography, eluting 0-5% EtOAc in hexane over 30 minutes to give the title compound as a yellow oil (824 mg, 3.91 mmol). δH (methanol-d4, 400 MHz) 7.56 (1H, d), 7.46 (1H, dd), 7.19 (1H, d), 5.61-5.56 (1H, m), 2.68 (2H, quart), 2.23-2.16 (4H, m), 1.85-1.68 (4H, m), 1.20 (3H, t).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11][N:12]2[CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=3)[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCCC2
Reactant: Fc1ccc(CBr)cc1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CCC2

Procedure:
The title compound was prepared from methyl 3-benzyloxy-4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate using a procedure similar to that found in Example 13, Step 1, except that 4-fluorobenzyl bromide was used in place of iodomethane and purification was not necessary. 1H NMR (400 MHz, CDCl3) δ 7.42-7.32 (m, 5H), 7.08-7.00 (m, 4H), 5.33 (s, 2H), 4.64 (s, 2H), 4.26-4.22 (t, 2H), 3.95 (s, 3H), 1.88-1.81 (m, 2H), 1.62 (br s, 2H); ES MS (M+1)=424.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[C:10]([CH3:11])=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:26])[CH3:25]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:24]([CH3:26])[CH3:25])[C:6]=2[N:7]=1
Reactant: CC(C)Br
Reactant: CCOC(=O)c1cc(Br)nc2[nH]nc(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C(C)C
Yield: 53.1 %

Procedure:
Ethyl 6-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 g, 3.52 mmol) was suspended in acetonitrile (10 mL) and K2CO3 (0.728 g, 5.28 mmol) and 2-bromopropane (0.866 g, 7.04 mmol) was added to it. The reaction mixture was refluxed for overnight. On completion of reaction, acetonitrile was removed under reduced pressure and water added to it. Extraction was carried out using ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (0.61 g, 53.5%). Structure was confirmed by NOE.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([NH:28][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][NH:12]3)=[CH:8][CH:7]=2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3cn[nH]c3c2)cc1Cl
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3cn[nH]c3c2)cc1NCc1ccccc1
Temperature: 100 °C

Procedure:
A stirred solution of the nitro compound (2 mmol) in DMF (4 mL) was added with benzylamine (4 mmol) and contents were heated at 100° C. for 6 h. The reaction mixture was cooled to RT and the contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo. The residue obtained was purified on silica gel column chromatography using hexane/EtOAC as eluent to provide the product, benzyl-[5-(1H-indazol-6-yloxy)-2-nitrophenyl]-amine as a yellow solid.
Reaction SMILES: BrC1C2N(N=C(Cl)N=2)C=CC=1.COC1C=CC=CC=1CN.[Cl:22][C:23]1[N:41]=[C:26]2[C:27]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[CH:28][CH:29]=[CH:30][N:25]2[N:24]=1.[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH2:45][CH2:44]1>>[Cl:22][C:23]1[N:41]=[C:26]2[C:27]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[CH:28][CH:29]=[CH:30][N:25]2[N:24]=1.[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][NH:31][C:27]1[C:26]2[N:25]([N:24]=[C:23]([NH:55][C:52]3[CH:51]=[CH:50][C:49]([N:46]4[CH2:45][CH2:44][N:43]([CH3:42])[CH2:48][CH2:47]4)=[CH:54][CH:53]=3)[N:41]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: COc1ccccc1CN
Agent: COc1ccccc1CNc1cccn2nc(Cl)nc12
Agent: Clc1nc2c(Br)cccn2n1
Product: COc1ccccc1CNc1cccn2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc12

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (2.00 g, 8.60 mmol) and 2-methoxy-benzylamine in a manner analogous to Example 2d. Product isolated as a tan oil that solidified upon standing (1.56 g. 63%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.09 (d, J=6.7 Hz, 1H), 7.21 (m, 2H), 7.04-6.93 (m, 3H), 6.86 (t, J=14.5, 7.2 Hz, 1H), 6.35 (d, J=7.9 Hz, 1H), 4.43 (d, J=6.30 Hz, 2H), 3.86 (s, 3H). 387b) N(8)-(2-Methoxy-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (100.00 mg, 0.34634 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (74.2 mg, 0.388 mmol) in a manner analogous to Example 2d. Product isolated as a brown foam (23.79 mg, 15.5%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.07 (s, 1H), 7.93 (d, J=6.2 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.24 (m, 2H), 7.02 (d, J=8.4 Hz, 1H), 6.88 (m, 3H), 6.70 (t, J=13.70, 6.9 Hz, 1H), 6.29 (d, J=7.9 Hz, 1H), 6.09 (m, 1H), 4.46 (d, J=6.0 Hz, 2H), 3.87 (s, 3H), 3.02 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H). MS=444 (MH)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH3:19])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:18]([CH:15]1[CH2:14][CH2:13][N:12]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:17][CH2:16]1)[C:1](=[O:3])[CH3:2]
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
0.2 mole of acetyl chloride is slowly added to a solution containing 0.2 mole of N-[1-(benzyl)-4-piperidyl]-N-methylamine, 0.2 mole of triethylamine and 500 cm3 of methylene chloride. The mixture is left in contact for 2 hours, evaporated, taken up in ether and then washed with water. After evaporation, an oil which corresponds to the expected compound is obtained:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.C(O)(=O)C>[Fe].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[NH2:10]
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Br)cc1N
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A mixture of 4-bromo-1-methoxy-2-nitrobenzene (3.0 g, 12.9 mmol) and glacial acetic acid (25 ml) was heated at 100° C. under an atmosphere of nitrogen. Iron powder (2.2 g, 38.8 mmol) was added and the mixture was stirred for one hour at a temperature of 100° C. The mixture was cooled to ambient temperature then water (100 ml) was added and the mixture was extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3×25 ml) and then brine. The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (6:4) as an eluent yielded 5-bromo-2-methoxyaniline (2.0 g): 1H NMR (DMSO-d6, 400 MHz) 6.76 (s, 1H), 6.71 (d, 1H), 6.61 (d, 1H), 4.99 (bs, 2H), 3.74 (s, 3H); (TLC (heptane/ethyl acetate 1:1) Rf 0.5; RP-HPLC (Hypersil HyPurity Elite C18, 5 m, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=13.33 min.; MS: MH+443.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4]C1C=CC(Cl)=C2C=1C=C([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)N=C2.[F:34][C:35]1[CH:44]=[CH:43][C:42]([F:45])=[C:41]2[C:36]=1[CH:37]=[C:38](OS(C(F)(F)F)(=O)=O)[N:39]=[CH:40]2>>[ClH:4].[ClH:1].[ClH:4].[F:34][C:35]1[CH:44]=[CH:43][C:42]([F:45])=[C:41]2[C:36]=1[CH:37]=[C:38]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH:26]=3)[CH:21]=1)[N:39]=[CH:40]2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Reactant: O=S(=O)(Oc1cc2c(F)ccc(F)c2cn1)C(F)(F)F
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(F)ccc(F)c2cn1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 5,8-difluoroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester, affording the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.09-2.30 (m, 4H), 3.04-3.17 (m, 2H), 3.41 (d, J=12.1 Hz, 2H), 4.48-4.59 (m, 1H), 7.57-7.68 (m, 1H), 7.79 (td, J=8.8, 3.6 Hz, 1H), 8.15 (s, 1H), 8.47 (s, 1H), 8.68 (s, 1H), 8.83 (br. s., 1H), 9.01 (br. s., 1H), 9.65 (s, 1H). MS (ES+): m/z=407.16 [MH+]. HPLC: tR=1.76 min (ZQ2, polar—5 min).
Reaction SMILES: O=[C:2]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20](=O)[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].O.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:2]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCC)ccc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCc1ccc2c(c1)Cc1cc(CCCCC)ccc1-2
Temperature: 130 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A Dean-Stark trap with reflux condenser was fitted to a 1 liter conical flask, and 2,7-di(1-oxopentyl)fluorene (30.4129 g, 91.0566 mmol), hydrazine monohydrate (44.2 ml) and diethylene glycol (400 ml) were introduced and heated at 130° C. After 2 hours, KOH (20.5628 g) was added and heated at 200° C. After 3 hours, the reaction liquid was returned to room temperature, water was added, and the organic layer was extracted twice with ether. The organic layer was washed with 1N-HCl, saturated sodium bicarbonate solution, water (twice) and a saturated salt solution, and dried using MgSO4. The solution obtained was filtered, and concentrated under reduced pressure to obtain a crude product (27.6591 g, yellow solid). The crude product was purified by silica gel chromatography (hexane) to obtain 2,7-di-n-pentylfluorene (26.2137 g, yellow solid).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2ccccn2)sc2ccc(OCCCO)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.3 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.40 g, 1.5 mmol), 3-bromo-1-propanol (0.66 g, 4.7 mmol) and potassium carbonate (0.43 g, 3.1 mmol) and DMF (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water and extracted with a mixture solvent of ethyl acetate and ethanol. The extract was washed with water and dried. The solvent was evaporated. The obtained crystals were recrystallized from ethanol-hexane to give the titled compound (0.27 g, 54%).