Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[F-].[CH:11]1[CH:16]=CC=C[CH:12]=1>C(OCC)C.C1(C=CC[Ti])C=CC=C1>[C:2]1([C@H:1]([OH:8])[CH2:16][CH:11]=[CH2:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccccc1
Agent: [Ti]CC=CC1C=CC=C1
Agent: [F-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CC[C@@H](O)c1ccccc1
Temperature: -74 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A solution in 100 ml of diethyl ether of 9.8 mmol of cyclopentadienylallyltitanium bis-(1,2:5,6-di-O-isopropylidene-α-glucofuranose) complex according to Example 1 is cooled to -74° C. by means of a CO2 /acetone bath, and 0.89 ml (8.8 mmol) of freshly distilled benzaldehyde is added. The clear yellow solution is stirred for a further 2 hours at -74° C., and 50 ml of NH4F solution (45% in water) are added. The beige emulsion is warmed to RT and separated in a separating funnel. The ether phase is extracted once with 50 ml and then with twice 30 ml of 2N HCl and is diluted with 300 ml of ether and is then washed with twice 300 ml of water and once with 300 ml of saturated NaCl solution, dried by means of MgSO4, filtered and evaporated to dryness on a rotary evaporator. The crude product is flash chromatographed (45 g of silica gel, 25 cm length, diameter 2 cm, 10 ml/fraction, 0.3 bar, 1:5 ether/n-hexane) and distilled (boiling point 150° C./14 mbar); 1.02 g (79% yield) of a clear, colourless oil are obtained: [α]D =+44.1° (c 6.5, benzene), 91% ee (methods A and B).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:13][C:14]1[N:15]=[C:16]([CH:19]2[CH2:24][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[CH2:22][N:21]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:20]2)[S:17][CH:18]=1>CN1CCCC1=O>[CH:1]1([NH:4][CH2:13][C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH:23]([C:25]4[CH:26]=[CH:27][C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=4)[CH2:22][N:21]([C:33]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[O:34])[CH2:20]3)[S:17][CH:18]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCc1ccc(C2CC(c3nc(CCl)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCc1ccc(C2CC(c3nc(CNC4CC4)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
24 mg (0.411 mmol) of cyclopropylamine and 70 mg (0.685 mmol) of triethylamine were added to a solution of 119 mg (0.274 mmol) of the compound from Example 141A in 2 ml of N-methylpyrrolidone. The reaction mixture was stirred at 80° C. overnight. Diastereomer separation of 13 mg of the cis/trans isomer mixture according to Method 15C gave 5 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:20][N:21]=[C:22]=[O:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH:12][C:22]([NH:21][CH3:20])=[O:23])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN=C=O
Reactant: NC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Yield: 21.3 %

Procedure:
A solution of rac-2-(3,4-dichloro-phenyl)-2-(tetrahydro-pyran-4-yloxy)-acetamide (278 mg, 0.91 mmol) in toluene (10 mL) was treated with methyl isocyanate (0.08 mL, 1.37 mmol). The resulting solution was heated at reflux for 24 h and then the cooled reaction was concentrated in vacuo. The resulting oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/80 hexanes/ethyl acetate) to afford [1[(3,4-dichloro-phenyl)-(tetrahydro-pyran-4-yloxy)-acetyl]-3-methyl-urea (70 mg, 21% yield) as a colorless oil: EI-HRMS m/e calcd for C15H18N2Cl2O4 (M+) 360.0643, found 360.0865.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:15](O)[C:16]3[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][C:17]=3[CH3:31])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>CO.[Pd].[C]>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:18][C:17]=2[CH3:31])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COc1ccc(C(O)c2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(Cc2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Yield: 78.8 %

Procedure:
590 mg of tert-butyl 4-[[3-(4-fluorobenzyl)-4-methoxyphenyl](hydroxy)methyl]-3,5-dimethylphenylcarbamate (Example VIII), 24 mg of Pd/carbon (10%) and a drop of acetic acid are hydrogenated in 10 ml of methanol with hydrogen at atmospheric pressure for 4 h. The suspension is filtered through kieselguhr. The filtrate is concentrated in a rotary evaporator. Chromatography (cyclohexane/ethyl acetate=6:1) affords 449 mg (77%) of tert-butyl 4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:28]CC3C=CC=CC=3)=[CH:5][C:4]=2[N:3]=1.C(OC1C=CC2C3N(CC(C)C)C(CCC)=NC=3C(N)=NC=2C=1)C1C=CC=CC=1>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:28])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Agent: CCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Yield: 40.3 %

Procedure:
The general method described in Example 5 was followed using N-[2-(4-amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (1.00 g, 2.01 mmol) in lieu of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine. The crude product was recrystallized from methanol (20 mL). The crystals were collected in three crops and washed with methanol and ethyl acetate. The crops were combined and purified by column chromatography on silica gel (eluting with 89.1:9.9:1 chloroform:methanol:ammonium hydroxide) to provide 330 mg of N-[2-(4-amino-2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white powder, mp 255-256° C. 1H NMR (300 MHz, DMSO-d6 350K) δ 9.18 (br s, 1H), 8.09 (d, J=8.9 Hz, 1H), 7.00 (br s, 1H), 6.96 (d, J=2.5 Hz, 1H), 6.77 (dd, J=8.9, 2.5 Hz, 1H), 6.11 (s, 2H), 4.84 (s, 2H), 4.81 (s, 2H), 3.56 (q, J=7.0 Hz, 2H), 2.97 (s, 3H), 1.29 (s, 6H), 1.15 (t, J=7.0 Hz, 3H);
Reaction SMILES: [OH-].[Na+:2].CO.[CH2:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH3:6]>O>[CH2:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:11][CH2:12]1)[CH3:6].[Na+:2]
Reactant: CCN1CCN(c2ccc(C(=O)OC)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN1CCN(c2ccc(C(=O)[O-])cn2)CC1
Yield: 111.1 %

Procedure:
A solution of 3.1 g of sodium hydroxide in 15 ml of water was added to 75 ml of methanol. 15 g of methyl 6-(4-ethyl-1-piperazinyl)pyridine-3-carboxylate was added and the mixture was heated under reflux for 1.5 hours. The solvent was distilled off under reduced pressure, to the resulting residue was added hot acetone and the crystal thus precipitated out was recovered by filtration. It was again washed with hot acetone to afford 17.2 g of the title compound as a crystal.
Reaction SMILES: [CH2:1]([NH2:7])[CH:2]1O[CH2:5][CH2:4][CH2:3]1.[ClH:8].S(Cl)([Cl:11])=O>>[ClH:11].[Cl:8][CH:2]([CH2:3][CH2:4][CH2:5][Cl:11])[CH2:1][NH2:7]
Reactant: NCC1CCCO1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: NCC(Cl)CCCCl

Procedure:
An N-alkenyl-2-aminomethyl-pyrrolidine is prepared by firstly reacting tetrahydrofurfurylamine with gaseous hydrochloric acid and thionyl chloride to produce 2,5 dichloropentylamine hydrochloride. This is acetylized, possibly by acetyl chloride in dichloroethane in the presence of triethylamine, into N-acetyl-2,5-dichloropentylamine which is condensed with an alkenylamine into an N-alkenyl-2-acetylaminomethyl pyrrolidine from which the acetyl group is separated, for example by boiling with concentrated hydrochloric acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([OH:35])=O)[C:30]([O:36][CH3:37])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][NH2:46])=[N:43][CH:44]=1.CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[N:32]=[C:31]([C:33]([NH:46][CH2:45][C:42]5[CH:41]=[CH:40][C:39]([F:38])=[CH:44][N:43]=5)=[O:35])[C:30]([O:36][CH3:37])=[CH:29][CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cn1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(C(=O)O)n3)cc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OC)c(C(=O)NCc4ccc(F)cn4)n3)cc12
Reaction time: 3 h
Yield: 35 %

Procedure:
To a solution of 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-methoxypicolinic acid (50 mg, 0.09 mmol), (5-fluoropyridin-2-yl)methanamine (200 mg, 1.58 mmol) and Et3N (0.2 mL) in THF (50 mL) was added T3P (0.05 mL) dropwise at 0° C. and the mixture was stirred for 3 h. After being diluted with water and extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by prep-TLC (PE:EtOAc=1:2) to give the pure product of 6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-((5-fluoropyridin-2-yl)methyl)-3-methoxypicolinamide (20 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 8.60 (t, J=4.8 Hz, 1H), 8.36 (d, J=2.4 Hz, 1H), 7.99 (s, 1H), 7.92˜7.95 (m, 2H), 7.73 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.24˜7.42 (m, 2H), 7.17˜7.22 (m, 2H), 5.91 (d, J=3.6 Hz, 1H), 4.73 (d, J=5.6 Hz, 2H), 4.01 (s, 3H), 3.18 (s, 3H), 2.97 (d, J=4.8 Hz, 3H), 2.78 (s, 3H). MS (M+H)+: 636.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:10]=1[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)[CH2:13][CH3:14])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CCCCCC>ClCCl>[Br:29][C:26]1[CH:27]=[CH:28][C:9]([OH:8])=[C:10]([CH:25]=1)[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)[CH2:13][CH3:14]
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.1 %

Procedure:
A solution of methyl 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]-5-pyridylcarboxylate (10.0 g, 22 mM) in dichloromethane (150 ml) was treated with boron trichloride dimethyl sulfide complex (40 ml, 2M, 80 mM). The reaction was stirred at ambient temperature for 48 hours. Saturated sodium bicarbonate solution was added and the layers were separated. The aqueous layer was washed with dichloromethane. The organic layers were combined, dried (MgSO4) and evaporated to give an off-white solid. The off-white solid was subjected to chromatography (diluted with ethyl acetate/hexane) to give the title compound (6.02 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH3:20][C:21]1[C:22](=[O:27])[O:23][C:24](=O)[CH:25]=1.C(O)(=O)C>O>[CH3:20][C:21]1[C:22](=[O:27])[N:1]([C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[NH:8][N:7]=3)[CH:3]=2)[C:24](=[O:23])[CH:25]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Solvent: CC(=O)O
Solvent: O
Product: CC1=CC(=O)N(c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)C1=O
Reaction time: 65 h

Procedure:
A stirred mixture of 4-(3-aminobenzyl)-2H-phthalazin-1-one (0.1 g, 0.4 mmol; prepared in a manner similar to that described in Example 1), 3-methylfuran-2,5-dione (0.045 g, 0.4 mmol) and acetic acid (4 ml) was heated under reflux for 8.25 hours and allowed to stand at ambient temperature for 65 hours, then it was diluted with water (10 ml). The resulting solid was collected by filtration, washed with water (10 ml) and dried in vacuo to give 3-methyl-1-[3-(4oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]pyrrole-2,5-dione (0.068 g) as an off-white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.95 (s, 3H) (CH3), 4.3 (s, 2H) (ArCH2—), 6.7 (s, 1H) (—COCH═CMeCO—), 7.15 (d, 1H) (ArH), 7.2 (s, 1H) (ArH), 7.25–7.35 (m, 2H) (2×ArH), 7.7–7.9 (m, 3H) (3×ArH), 8.2 (d, 1H) (ArH), 12.55 (s, 1H) (CONH); m/z (M+H)+. 346, 100% purity.
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([Cl:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][C:18]=1[O:37][CH3:38]>O1CCOCC1.CCOC(C)=O>[ClH:34].[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23](=[O:24])[C:25]2[CH:26]=[CH:27][C:28]([S:31]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8]3)(=[O:33])=[O:32])=[CH:29][CH:30]=2)=[CH:19][C:18]=1[O:37][CH3:38]
Reactant: c1ccc2c(N3CCCCC3)c[nH]c2c1
Reactant: COc1cc(CNC(=O)c2ccc(S(=O)(=O)Cl)cc2)ccc1F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(CNC(=O)c2ccc(S(=O)(=O)n3cc(N4CCCCC4)c4ccccc43)cc2)ccc1F
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
Add KotBu (211 mg, 1.88 mmol) to a solution of 3-piperidin-1-yl-1H-indole (299 mg, 1.49 mmol) in dioxane (15 mL). Stir the yellow solution at RT for 30 min then treat with 4-(4-fluoro-3-methoxy-benzylcarbamoyl)-benzenesulfonyl chloride (560 mg, 1.56 mmol). Stir the solution at RT for an additional 2 h, then dilute with EtOAc (50 mL) and wash with satd NaHCO3 (25 mL). Remove the organic phase and extract the aqueous layer with additional EtOAc (50 mL). Combine the organic solutions, dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography (3×) using an oversized silica column and a gradient of 100% hexanes to 40% EtOAc/hexanes. Concentrate fractions containing pure material then redissolve in CH2Cl2 (10 mL) and treat with 4M HCl/dioxane (0.5 mL). Filter the off-white precipitate and dry under vacuum to give the title compound as a white powder (417 mg). MS (ES+) 522.1 (M+1)+, (ES−) 520.2 (M−1)−. 1H NMR (400 MHz, DMSO-d6): δ 9.19 (m, 1H), 8.03 (d, 2H, J=8.4), 7.97 (m, 1H), 7.95 (d, 2H, J=8.4), 7.61 (d, 1H, J=7.5), 7.37 (t, 1H, J=7.6), 7.26 (t, 2H, J=7.5), 7.06-7.13 (m, 2H), 6.81 (m, 1H), 6.12 (br s, 1H), 4.39 (d, 2H, J=5.7), 3.78 (s, 3H), 3.06 (s, 4H), 1.72 (s, 4H), 1.56 (s, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.ClCC1N=C(NC2C=CC(OC)=CC=2F)C2C(=CC=CC=2)[N:28]=1.[H-].[Na+].CI>C1COCC1.CO>[NH2:28][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)c(F)c1
Reactant: COc1ccc(Nc2nc(CCl)nc3ccccc23)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N(C)c2nc(CN)nc3ccccc23)c(F)c1
Reaction time: 2 h

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-methyl-amine: A solution of (2-chloromethyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-amine hydrochloride (291 mg, 0.82 mmol) in THF (4 mL) was treated with NaH (130 mg, 3.12 mmol), followed by MeI (0.26 mL, 4.2 mmol). The reaction was stirred for 2 h, diluted with MeOH and concentrated. Purification by MPLC (SiO2, EtOAc/hexanes, 0-100%) gave the desired compound. 1H NMR (CDCl3) δ 7.84 (d, 1H), 7.55-7.65 (m, 1H), 7.02-7.17 (m, 3H), 6.68-6.79 (m, 2H), 4.74 (s, 2H), 3.85 (s, 3H), 3.58 (s, 3H); LC-MS (ESI+; 332 ([M+H]+)).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccccn3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[O:33][C:34]([CH2:37]Cl)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(#N)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:23])=[O:24])=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5CCOCC5)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Temperature: 80 °C
Yield: 96.1 %

Procedure:
N-(2-Chloro-5-{4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (50 mg, 0.084 mmol) and morpholine (0.015 ml, 0.169 mmol) were placed in acetonitrile (5 ml) and the mixture heated at 80° C. for 4 h. Further morpholine (15 μl) was added and the reaction was continued to heat overnight. The mixture was cooled to room temperature and the mixture loaded onto an SCX (5 g) cartridge. The cartridge was washed with methanol and then eluted with 2M ammonia in methanol. The mixture was purified by chromatography on silica (20 g) cartridge eluting with 0-100% ethyl acetate in cyclohexane followed by 0-20% methanol to give the title compound (52 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[OH:4][CH:5]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([CH2:24]Cl)=[N:22][C:21]([C:26]([NH2:28])=[O:27])=[N:20]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-].[Na+]>CO>[OH:4][CH:5]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([CH2:24][N:2]([CH3:3])[CH3:1])=[N:22][C:21]([C:26]([NH2:28])=[O:27])=[N:20]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNC
Reactant: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(O)c2ccccc2)n1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(O)c1ccccc1

Procedure:
6.8 ml of 33% ethanolic dimethylamine solution is added to a solution of 5.6 g (about 0.015 mole) of 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide and 0.225 g of sodium iodide in 80 ml of methanol, and the whole is refluxed for 5 hours with stirring. The reaction mixtute is thereupon concentrated in vacuo. Water and saturated sodium carbonate solution are added to the residue until the pH-value has reached 10, and extraction is performed twice with ethyl acetate. The organic phase is washed with water, and is then extracted three times with 1N hydrochloric acid solution. Sodium carbonate is added to the aqueous acidified extracts until the pH-value of 10 is obtained. The base that has precipitated is taken up in ether; the ether solution is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo to yield amorphous 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]- 1H-1,2,4-triazole-3-carboxamide. This is converted as follows into the crystalline hydrochloride: the crude base is dissolved in ethyl acetate, and ethereal hydrogen chloride solution is added until the pH-value is 4. The precipitated hydrochloride is filtered off with suction and washed with ethyl acetate and ether. After drying in vacuum, there is obtained 1-[2-(α-hydroxybenzyl) 4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide-hydrochloride, m.p. 155°-157° (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:5][CH2:6][Br:7].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Br-:7].[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][P+:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1ccc(CCBr)cc1F
Solvent: Cc1ccccc1
Product: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Product: [Br-]

Procedure:
A mixture of 19.67 g (89 mmol) of 3,4-difluoro-phenethyl bromide, 28.07 g (107 mmol) of triphenyl phosphine and 134 ml of toluene was heated under reflux for 36 hrs. After cooling, the crystal was washed by decantation with toluene and dried in vacuo, while ice-cooling.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH2:24]([O:31][C:32]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])=[O:20])=[CH:22][CH:23]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCCNC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (413 mg) obtained in Example 2-2 and N-benzyloxycarbonyl-1,4-diaminobutane (247 mg) were dissolved in anhydrous DMF (8.0 ml) and added with WSCI hydrochloride (234 mg) and HOBt (165 mg), followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform, washed with 1 mol/l hydrochloric acid, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution, and dried with anhydrous magnesium sulfate, followed by distilling the solvent off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water) and treated with hydrochloric acid, thereby obtaining hydrochloride (23.0 mg) of the subject compound as a white solid.