Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].I[CH3:17]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH3:17])[CH2:9]2)=[N:6][CH:7]=1
Reactant: CI
Reactant: O=C1NCC(c2ccc(Br)cn2)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CC(c2ccc(Br)cn2)OC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Compound 14b (350 mg, 1.44 mmol) was dissolved in dried tetrahydrofuran, cooled to 0° C. NaH (86.4 mg, 2.16 mmol) was added, and iodomethane (0.18 mL, 2.88 mmol) was added dropwise. After the addition was completed, the reaction mixture was raised to room temperature for reacting overnight. The reaction was monitored by TLC (petroleum ether/ethyl acetate=5/1). After the reaction completed, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. Column chromatography (petroleum ether/ethyl acetate=8/1) afforded 315 mg of white solid (compound 14c), yield 85%.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[O:21][CH2:22][C:23]1C=[CH:27][CH:26]=[CH:25][C:24]=1C#N.[CH2:31]([OH:34])[CH2:32]O>>[NH2:3][C:4]1[C:5]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:32]=2[C:31]([OH:34])=[O:1])=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: OCCO
Reactant: [OH-]
Reactant: CS(=O)(=O)Nc1ccc(-c2cnc(N)c(OCc3ccccc3C#N)c2)cc1
Agent: [Na+]
Product: CS(=O)(=O)Nc1ccc(-c2cnc(N)c(OCc3ccccc3C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10% NaOH solution (25 mL) was added to N-{4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-phenyl)methanesulfonamide (Example I-135, 650 mg, 1.65 mmol) in ethylene glycol (55 mL). The mixture was heated to reflux and allowed to stir for 24 hr. The reaction was cooled to room temperature. Most of the solvent was evaporated and the mixture was acidified. The precipitated solid was filtered out to afford 2-[2-Amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzoic acid as light brown solid. The filtrate was neutralized and extracted with EtOAc (5×20 mL). The organic layer was combined, dried over MgSO4, and concentrated to yield 2-[2-Amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzamide as an off-white solid.
Reaction SMILES: C([Li])C[CH2:3][CH3:4].[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([C:20]2(C=O)[CH2:25][CH2:24]OCC2)[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C[O:31][CH2:30][CH2:29]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:20]2[CH2:25][CH:24]([CH:3]=[CH2:4])[CH2:29][CH2:30][O:31]2)[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: O=CC1(c2cccc(OCc3ccccc3)c2)CCOCC1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=CC1CCOC(c2cccc(OCc3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
n-Butyl-lithium (1.6M in hexane, 1.375 ml) was added dropwise to a solution of methyltriphenylphosphonium bromide (0.786 g) in a mixture of THF (15 ml) and diethyl ether (2 ml). The mixture was stirred at ambient temperature for 2 hours. The solution so obtained was added dropwise to a solution of 4-(3-benzyloxyphenyl)-4-formyltetrahydropyran (0.592 g) in diethyl ether (10 ml) and the mixture was stirred at ambient temperature for 4 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using increasingly polar mixtures of petroleum ether (b.p 40°-60° C.) and ethyl acetate as eluent. There was thus obtained 4-(3-benzyloxyphenyl-4-vinyltetrahydropyran (0.407 g, 70%), as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[NH2:18][C:19]1[C:28](I)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[C:28]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([C:12]3[O:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[O:11])[CH:4]=2)[C:19]([NH2:18])=[N:20][CH:21]=1
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
In a 4 mL vial, N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide (0.607 g, 2.70 mmol) and methyl 6-amino-5-iodonicotinate (0.5 g, 1.80 mmol) were dissolved in DMF (6 mL). The solution was degassed by bubbling N2(g) through it for ˜30 min. To the degassed solution was added DIPEA (1.25 mL, 7.19 mmol), followed by Pd(PPh3)2Cl2 (0.126 g, 0.18 mmol) and CuI (0.068 g, 0.360 mmol). The reaction mixture was allowed to stir at 50° C. for 3 h. The reaction mixture then was taken up in EtOAc (10 mL) and was extracted with brine (3×10 mL). The organic layers were combined and concentrated in vacuo. The crude mixture was purified via column chromatography (gradient eluant mixture of EtOAc in Hexanes: 25% to 100% EtOAc) to give the title compound as a white solid (0.554 g, 82%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)[C:4](=[O:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCc1nc(C)c(-c2ccccc2)c(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-methyl-5-phenyl-2-propylpyrimidin-4(3H)-one (0.26 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (0.37 g) in N,N-dimethylformamide (6 mL) was added 60% sodium hydride (0.06 g), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.30 g, 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4](=[O:16])[N:3]=1.C(N(CC)CC)C.[CH3:24][C:25]1([CH3:38])[C:29]([CH3:31])([CH3:30])[O:28][B:27]([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)[O:26]1>C(Cl)(Cl)Cl.O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:5]2[CH:6]=[N:7][C:2]([N:35]3[CH2:34][CH2:33][C:32]([B:27]4[O:28][C:29]([CH3:31])([CH3:30])[C:25]([CH3:38])([CH3:24])[O:26]4)=[CH:37][CH2:36]3)=[N:3][C:4]2=[O:16])=[CH:10][CH:11]=1
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Reactant: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OB(C2=CCN(c3ncn(Cc4ccc(Cl)cc4)c(=O)n3)CC2)OC1(C)C
Yield: 40.1 %

Procedure:
To a chloroform solution (3.0 mL) of 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one (128 mg, 0.500 mmol) synthesized in Reference Synthesis Example 11, triethylamine (70.0 μL, 0.500 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (156 mg, 0.750 mmol) were added and the resultant mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0→4/1) to obtain the title compound (86.0 mg, yield 40%).
Reaction SMILES: C(=O)=O.[S:4]([F:8])(F)([F:6])[F:5].[CH2:9]([N:11]([Si](C)(C)C)[CH2:12][CH3:13])[CH3:10]>ClC(Cl)(Cl)F>[CH2:9]([N:11]([S:4]([F:8])([F:6])[F:5])[CH2:12][CH3:13])[CH3:10]
Reactant: CCN(CC)[Si](C)(C)C
Reactant: FS(F)(F)F
Agent: O=C=O
Solvent: FC(Cl)(Cl)Cl
Product: CCN(CC)S(F)(F)F
Temperature: 25 °C
Yield: 80 %

Procedure:
a dry 1-l. four-necked round-bottomed flask is equipped with a thermometer (-100° to 50°), a solid carbon dioxide-cooled reflux condenser (protected from the atmosphere through a drying tube), a gas inlet tube above the liquid level, and a magnetic stirrer. The apparatus is flushed with dry nitrogen, and 300 ml of trichlorofluoromethane is added to the flask. As the nitrogen atmosphere is maintained, the trichlorofluoromethane is cooled to -70° by means of a solid carbon dioxide-acetone bath and 119 g (1.1 mole) of sulfur tetrafluoride is added from a cylinder through the gas inlet tube. The gas inlet tube is then replaced with a 250-ml pressure-equalized dropping funnel charged with a solution of 145 g (1 mole) of N,N-diethylaminotrimethylsilane in 90 ml trichlorofluoromethane. This solution is added dropwise, with stirring, to the sulfur tetrafluoride solution at a rate slow enough to keep the temperature of the reaction mixture below -60° (about 40 minutes). The cooling bath is removed, and the reaction mixture is allowed to warm spontaneously to room temperature. The condenser is replaced with a simple distillation head, and the solvent (bp 24°) and by-product fluorotrimethylsilane (bp 17°) are distilled off into a well cooled receiver by warming the reaction mixture gently to 45° by means of a heating mantle. The yellow to dark brown residual liquid is transferred and distilled at reduced pressure through a spinning band column to give 129-145 g (80-90%) of diethylaminosulfur trifluoride as a light yellow liquid, bp 46-47 (10 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[C:10]=1[CH3:11].ClC1C(C)=CC2[O:20][CH:19]=[CH:18]C=2C=1.BrN1[C:28](=[O:29])[CH2:27]CC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:8][CH:7]([O:20][CH2:19][CH3:18])[O:29][CH2:28][CH3:27])=[CH:6][C:10]=1[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)ccc2occc12
Reactant: Cc1cc2occc2cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(COc1ccc(Cl)c(C)c1)OCC

Procedure:
A mixture of 5-chloro-4-methyl-benzofuran with 5-chloro-6-methyl-benzofuran (19.6 g), N-bromosuccinimide (23 g) and benzoyl peroxide (160 mg) in carbon tetrachloride (350 ml) was heated under reflux under a 200 W lamp for 36 h. The cooled mixture was filtered through hyflo and the filtrate evaporated to give the title compound as a dark oil (28.8 g)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(C1C=CC=CC=1)CCCCCC>N1C=CC=CC=1>[CH2:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:27])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCc1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2cccnc12
Agent: CCCCCCCc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 97.35 %

Procedure:
Example II was essentially repeated using 46.4 g. (0.32 mole) 8-aminoquinoline, 180 ml. pyridine and 82.35 g. (0.3 mole) heptylbenzenesulfonyl chloride. The latter reactant was as prepared in Table 2 from the heptylbenzene of Table 1. There was obtained 112.6 g. (97.35% yield) of 8-(heptylbenzenesulfonamido)quinoline of the structure ##STR23## where a + b equals 4.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CC(C)=O.[I-].[Na+]>[N:19]([CH2:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)n1cnc2c(CN=[N+]=[N-])cccc21
Yield: 83.6 %

Procedure:
A mixture of 4-(bromomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (1.08 g, 3.5 mmol), sodium azide (240 mg, 3.7 mmol), and sodium iodide (5 mg) in acetone (10 mL) was heated at reflux for 66 h. The solvent was evaporated and dichloromethane was added. The solution was washed with dilute aqueous sodium hydrogen carbonate, dried (Na2SO4), filtered and evaporated to give 4-(azidomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (800 mg, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.Cl.[F:10][C:11]([F:22])([F:21])[C:12]1[N:16]2[CH2:17][CH2:18][NH:19][CH2:20][C:15]2=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:19]2[CH2:18][CH2:17][N:16]3[C:12]([C:11]([F:22])([F:10])[F:21])=[N:13][N:14]=[C:15]3[CH2:20]2)[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nnc2n1CCN(c1cc(Br)ccn1)C2
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-fluoropyridine (0.216 mL, 2.1 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.399 g, 1.75 mmol) and potassium carbonate (0.482 g, 3.49 mmol) in anhydrous DMF (7.0 mL) was heated at 100° C. for 16 h. Reaction mixture was cooled, diluted with ethyl acetate, washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 50% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C11H10BrF3N5: 348.0. (M+H+); Found: 348.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:4]=2[O:3]1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[N:23]=[C:11]([C:8]3[CH:9]=[CH:10][C:4]4[O:3][C:2](=[O:1])[NH:6][C:5]=4[CH:7]=3)[O:13][N:15]=2)[CH:18]=1
Reactant: O=C(O)c1ccc2oc(=O)[nH]c2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: O=c1[nH]c2cc(-c3nc(-c4cccnc4)no3)ccc2o1

Procedure:
The title compound was prepared according to Method C using 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxylic acid (Matrix) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, CD3OD) δ 7.40 (d, J=8.5 Hz, 1H), 7.64 (ddd, J=8.0, 5.0, 0.9 Hz, 1H), 7.90 (d, J=1.7 Hz, 1H), 8.01 (dd, J=8.3, 1.9 Hz, 1H), 8.55 (dt, J=7.8, 1.9 Hz, 1H), 8.74 (dd, J=4.8, 1.7 Hz, 1H), 9.29 (dd, J=2.2, 0.9 Hz, 1H). ppm; MS (DCI/NH3) m/z 281 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl.O.[NH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.C(N(CC)CC)C.Cl>C(#N)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(=O)CC1
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
2-Chloro-5-nitrobenzonitrile (15 g), 4-piperidone monohydrate hydrochloride (13.9 g) and triethylamine (25 ml) were added to acetonitrile (100 ml), and the mixture was stirred at a refluxing temperature for 1.5 h. 0.5 N Aqueous hydrochloric acid solution (200 ml) was added to the reaction mixture to allow crystallization to give the title compound (16.1 g), melting point: 109° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:10]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:10][NH:4][CH2:3][CH2:2][OH:1])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrCC1CCCC1
Reactant: NCCO
Product: OCCNCC1CCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][C@@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:19]([O:24][C@@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH:18]=1
Reactant: Nc1ccc(F)cc1O[C@@H]1CCOC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCOC3)c2c1C
Temperature: 110 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (100 mg) and (R)-4-fluoro-2-(tetrahydrofuran-3-yloxy)aniline (Intermediate VI) (81 mg) was dissolved in Dioxan (2 ml) and p-Toluenesulfonic acid (15 mg) was added. The reaction heated at 110° C. under microwave radiation. The resultant precipitate was filtered and dissolved in dichloromethane/Methanol. The solution was dried and concentrated to give the desired product.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([O:17][C:18](=[O:50])[CH2:19][CH:20]([C:33](=[O:49])[N:34]([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH:38]=1)[CH2:35][CH3:36])[CH:21]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22](O)=[O:23])([CH3:16])([CH3:15])[CH3:14].[C:51]([O:70][NH2:71])([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>O.C1COCC1>[C:13]([O:17][C:18](=[O:50])[CH2:19][CH:20]([C:33](=[O:49])[N:34]([C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:41][CH:42]=1)[CH2:35][CH3:36])[CH:21]([C:22](=[O:23])[NH:71][O:70][C:51]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CCN(C(=O)C(CC(=O)OC(C)(C)C)C(CCc1ccccc1)C(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCN(C(=O)C(CC(=O)OC(C)(C)C)C(CCc1ccccc1)C(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(-c2ccccc2)cc1
Reaction time: 24 h

Procedure:
WSC.HCl (683 mg, 3.49 mmol) was dissolved in water (1 mL) and the pH was adjusted to 4.8. The compound of Example 55 (300 mg, 0.582 mmol) was dissolved in the same amount of THF and added to the former solution. O-Trityl hydroxylamine (505 mg, 1.746 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was partitioned between HCl (0.5N, excess) and ethyl acetate. The water phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, a saturated sodium hydrogen carbonate solution, and brine. The solvent was evaporated, following drying over sodium sulfate, and the crude was flashed with 30% ethyl acetate in hexanes. 1H NMR(CDCl3, 400 MH: 1.32(s, 9H); 1.50(m, 1H); 1.74(m, 1H); 2.32(m, 6H); 2.53(m, 2H); 3.46(m, 2H); 7.00(m, 1H); 7.16–7.57(m, 30H); FAB: 774(MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.S1C=CC=C1.[CH3:22][NH2:23].[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:23][CH3:22])[CH2:8][CH2:7]1
Reactant: CN
Reactant: [H][H]
Reactant: O=C1CCN(Cc2ccc(F)c(F)c2)CC1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CNC1CCN(Cc2ccc(F)c(F)c2)CC1
Yield: 81 %

Procedure:
A suspension of D4 (5.4 g, 24 mmol), thiophene solution (4% in diisopropylether; 2 ml), methylamine solution (40% in water, 10 ml) and 10% palladium on carbon (2 g) in methanol (150 ml) were hydrogenated at atmospheric pressure and temperature until 1 eq. (˜600 ml) of hydrogen had been taken up. After this period, the reaction mixture was filtered and the filtrate evaporated in vacuo. The crude product was purified by column chromatography (silica; 5%-10% ammonia in methanol/dichloromethane) to give D5 (4.7 g, 81%). C13H18F2N2 requires 240; Found 241 (MH+)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[N:18]=3)[S:14][C:13]=2[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>ClCCl>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)[N:18]=3)[S:14][C:13]=2[CH:34]=1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccc(CNC(=O)OC(C)(C)C)cc4s3)n2)CC1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCCNc2nccc(-c3cc4ccc(CN)cc4s3)n2)CC1
Reaction time: 20 h

Procedure:
(2-{2-[3-(4-Methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophen-6-ylmethyl)-carbamic acid tert-butyl ester (1.36 g, 2.74 mmol) is dissolved in dichloromethane (20 mL) and TFA (3.2 mL) is added. After stirring for 20 hours, methanol is added and the mixture is passed through an SCX column. After eluting with methanol to remove the salts, 20% 2.0 M NH3/MeOH)/EtOAC is used to elute the product which is then passed through a 15 g silica gel column using the same solvent system. The title compound is obtained as a yellow solid (0.73 g, 68% yield). ES+(m/z) 397 [M+H].
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)(O)[CH:16]([CH3:18])[CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN(C=O)C.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:16]([CH3:18])[CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccncc2)C(C)C)CCN(C)C1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-3-methyl-2-(pyridin-4-yl)butan-2-ol (0.2 g, 0.55 mmol) was dissolved in dry DCM and a drop of DMF was added. The solution was cooled to 0° C. and thionyl chloride (0.194 g, 1.65 mmoL) dissolved in dry DCM (1 mL) was added. Stirring was continued for 1 h at 0° C. and for 2 h at RT. Volatiles were removed under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate, and the product was extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.42 (d, 2H), 7.50 (d, 2H), 7.12 (s, 1H), 7.10 (d, 1H), 6.90 (d, 1H), 5.22 (d, 2H), 4.60 (d, 1H), 4.22 (d, 1H), 3.82 (m, 1H), 3.50 (m, 1H), 3.16 (m, 2H), 3.05 (s, 3H), 2.38 (s, 3H), 2.20 (s, 3H), 1.65 (s, 3H).