Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([O-:5])(C)C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:18][CH:19]=[CH2:20])[CH2:15][CH:16]=[CH2:17])[CH:11]=[CH:10][C:9]=1[C:21](=O)[CH3:22].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:18][CH:19]=[CH2:20])[CH2:15][CH:16]=[CH2:17])[CH:11]=[CH:10][C:9]=1[CH:21]([CH3:22])[CH:2]=[O:5]
Reactant: CC(C)(C)[O-]
Reactant: C=CCN(CC=C)c1ccc(C(C)=O)c(Cl)c1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: C=CCN(CC=C)c1ccc(C(C)C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Potassium tert-butylate (1.33 g) was added to a solution of 1-(2-chloro-4-diallylamino-phenyl)-ethanone (2.36 g) and (methoxymethyl)triphenylphosphonium chloride ([CAS Reg. No. 4009-98-7], 3.75 g) in THF (55 ml). The mixture was stirred for 1 h at room temperature. Additional (methoxymethyl)triphenylphosphonium chloride (324 mg) and potassium tert-butylate (133 mg) were added and stirring was continued for 1 h. More (methoxymethyl)triphenylphosphonium chloride (324 mg) and potassium tert-butylate (133 mg) was added and stirring was continued for 30 min. HCl (25% aq, 15 ml) was added. The mixture was stirred for 1 h at room temperature and then for 45 min at 50° C. Water (100 ml) was added, neutralized carefully by addition of sodium bicarbonate, and then extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane 0:100-20:80) to give the title compound as a light yellow oil (2.1 g). MS (m/e)=264.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[N:23][N:22]([CH2:28][CH2:27][O:26][CH3:25])[CH:21]=3)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2cn[nH]c2)ccc1OCc1ccc(F)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)OC)c2)cn1
Temperature: 25 °C

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-(1H-pyrazol-4-yl)benzoate (may be prepared as described in Description 115; 200 mg, 0.61 mmol) was added 2-bromoethyl methyl ether (0.10 ml, 1.23 mmol), potassium carbonate (254 mg, 1.84 mmol) and the reaction mixture was stirred at room temperature. The reaction mixture was then warmed to 50° C. for 5 hours. The reaction was filtered to remove the potassium carbonate, and the organics were evaporated on a buchi under reduced pressure. The solid was taken up into ethyl acetate (50 ml) and this was washed with water (1×25 ml). The organics were dried (MgSO4) and evaporated under reduced pressure on a buchi to yield the title compound. The crude product was used directly without further purification. 240 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([NH:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[C:24]([N+:33]([O-])=O)=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[NH2:33][C:24]1[C:25]([NH:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:26][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[CH:15][CH:16]=2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc([N+](=O)[O-])c(NC4CCCC4)n3)cc2)CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(N)c(NC4CCCC4)n3)cc2)CC1

Procedure:
Hydrogenation of 2-[[4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-amino]-4-(cyclopentylamino)-5-nitropyrimidine (from Example 2(9) above) over Pd/C gave the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH:4]([OH:6])[CH3:5])[CH3:3].Cl[P:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:3])[CH:4]([CH3:5])[O:6][P:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7]1
Reactant: CC(O)C(C)(C)O
Reactant: ClP(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1OP(c2ccccc2)OC1(C)C

Procedure:
5 g of (+)2 methyl butane 2,3-diol, ##STR24## are mixed with 8.6 g of dichlorophenylphosphin at 0° C. under stirring in 250 ml of dry toluene, in an atmosphere. Then 10.2 g of triethylamine are added within a few minutes. After 1 hour of reaction triethylamine hydrochloride is formed; it is separated by filtration and the toluene solvent is vaporized.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[C:6]2[C:29](=[CH:30][CH:31]=1)[C:10]1=[N:11][O:12][C:13]([C:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:16][N:15]=3)=[C:9]1[CH2:8][CH2:7]2.[NH:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:33]1>CC(O)C>[OH:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:29](=[CH:30][CH:31]=1)[C:10]1=[N:11][O:12][C:13]([C:14]3[C:18]([C:19]([F:22])([F:20])[F:21])=[C:17]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:16][N:15]=3)=[C:9]1[CH2:8][CH2:7]2)[CH2:3][N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:33]1
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(C4CO4)ccc2-3)noc1-c1ccccc1
Reactant: CCOC(=O)C[C@H]1CCCNC1
Solvent: CC(C)O
Product: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 85 °C
Reaction time: 5 h
Yield: 59.5 %

Procedure:
A mixture of 7-(oxiran-2-yl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 13A, 150 mg, 0.353 mmol) and (R)-ethyl 2-(piperidin-3-yl)acetate (90 mg, 0.526 mmol) in 2-propanol (5 mL) was stirred at 85° C. under a nitrogen atmosphere for 5 hr. The reaction mixture was concentrated and purified by silica gel column chromatography using ethyl acetate/heptane followed by 10% methanol in ethyl acetate to afford ethyl 2-((3R)-1-(2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethyl)piperidin-3-yl)acetate (125 mg, 0.210 mmol, 59.4% yield) as a yellow solid. LC/MS M+1=596.3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]([CH3:30])[C@@H:15]1[CH2:20][CH2:19][C@H:18]([O:21]C(=O)C2C=CC=CC=2)[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>CO.CCOC(C)=O>[C:7]([O:11][C:12](=[O:13])[N:14]([C@H:15]1[CH2:16][CH2:17][C@@H:18]([OH:21])[CH2:19][CH2:20]1)[CH3:30])([CH3:10])([CH3:8])[CH3:9]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](OC(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.807 g potassium carbonate were added to a solution of 1.3 g cis-benzoic acid 4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl ester in 10 ml methanol. The reaction mixture was stirred at rt overnight. 2 ml sodium hydroxide solution (2M) were added and the mixture was stirred for 4 hours. After that time the mixture was diluted with EtOAc and washed with water and brine. The organic phase was passed through a hydrophobic frit and the solvent was evaporated. Purification was achieved by silica gel column chromatography (gradient: 100% i-hex.→100% methylene chloride→20:1 methylene chloride/methanol).
Reaction SMILES: CN(OC)[C:3](=[O:15])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CO>O1CCCC1>[CH3:7][CH:6]([CH3:8])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH:3]=[O:15]
Reactant: CON(C)C(=O)CC(c1ccccc1)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)C(CC=O)c1ccccc1
Reaction time: 1 h
Yield: 124.2 %

Procedure:
Under a nitrogen atmosphere, N-methyl-N-methoxy-4-methyl-3-phenyl-pentaneamide (215 mg) was dissolved in tetrahydrofuran (9.1 mL) at −78° C., and a diisobutylaluminum hydride/toluene solution (1.5 M, 1.2 mL) was added. After one hour, methanol (3 mL) was added to the reaction system, the temperature of the mixture was returned to room temperature after termination of foaming, and the mixture was continuously stirred. The organic layer was separated by adding diethyl ether, water and a 1N aqueous hydrochloric acid thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated, to give the title compound as a colorless oil (200 mg). The resulting compound was used for the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:13][C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Yield: 92.7 %

Procedure:
Prepared according to the procedure described for Example 121 using 3,4-dichlorobenzenesulfonyl chloride (2.45 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol) and pyridine (25 mL) to afford the product (4.183 g); m.p. 191-193° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]([CH3:8])[CH3:7])=[O:4].[NH:9]1[CH2:12][CH:11]([C:13]2[CH:35]=[CH:34][C:16]3[C:17]4[N:18]=[C:19]([C:25]5[N:26]([CH:31]([CH3:33])[CH3:32])[N:27]=[C:28]([CH3:30])[N:29]=5)[S:20][C:21]=4[CH2:22][CH2:23][O:24][C:15]=3[CH:14]=2)[CH2:10]1.C(N(CC)CC)C.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH:6]([NH:5][C:3](=[O:4])[CH2:2][N:9]1[CH2:12][CH:11]([C:13]2[CH:35]=[CH:34][C:16]3[C:17]4[N:18]=[C:19]([C:25]5[N:26]([CH:31]([CH3:33])[CH3:32])[N:27]=[C:28]([CH3:30])[N:29]=5)[S:20][C:21]=4[CH2:22][CH2:23][O:24][C:15]=3[CH:14]=2)[CH2:10]1)([CH3:8])[CH3:7]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Reactant: CC(C)NC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(CC(=O)NC(C)C)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.6 %

Procedure:
2-Chloro-N-isopropylacetamide (0.124 g, 0.917 mmol) and tetra-n-butylammonium iodide (0.678 g, 0.00183 mol) were premixed in methylene chloride (3 mL). This solution was added dropwise to a solution of 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 519 (0.350 g, 0.917 mmol) and triethylamine (0.256 mL, 0.00183 mol) in methylene chloride (7 mL). The reaction was stirred at room temperature for 24 hours. Water was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by reverse-phase HPLC to obtain 527 as a white solid (51 mg). MS(ESI+) 481.2. 1H NMR (400 MHz, DMSO) δ 8.29 (d, J=8.2 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.20 (dd, J=8.3, 1.6 Hz, 1H), 7.03 (d, J=1.5 Hz, 1H), 5.87-5.65 (m, 1H), 4.36 (t, J=5.0 Hz, 2H), 3.87 (dq, J=13.2, 6.6 Hz, 1H), 3.76-3.59 (m, 3H), 3.42 (t, J=5.0 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 3.04 (s, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H), 1.07 (d, J=6.6 Hz, 6H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:14][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)CN
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Product: CC(C)CNc1cc(Cl)nc(N)n1
Reaction time: 1 h
Yield: 82 %

Procedure:
50 g of 2-amino-4,6-dichloropyrimidine are suspended in 250 ml of ethanol. 45.65 g of isobutylamine are added. The reaction mixture is heated under reflux for 3 hours. It is evaporated to dryness. The oily residue is taken up in 250 ml of water. The mixture is stirred vigorously for 1 hour. The precipitate formed is filtered on sintered glass, washed with 100 ml of water and then dried under vacuum over phosphorus pentoxide. It is recrystallized from 500 ml of isopropyl ether. 50.15 g of 2-amino-4-isobutylamino-6-chloropyrimidine are obtained.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:20]=[C:19]1[CH:40]1[CH2:42][CH2:41]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>C1COCC1>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[CH:40]1[CH2:41][CH2:42]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-4-cyclopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 265, 3.62 g, 5.80 mmol) in THF (30 mL) following the procedure described for Intermediate 18. The desired product was obtained as an off-white foam (2.64 g, 89%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24](=[O:27])[CH2:25][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][OH:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: OCCNCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1

Procedure:
15.1 g (100 mmol) of N-benzylethanolamine is dissolved in 50 ml of tetrahydrofuran and mixed with 15 ml of water and 13.8 g (100 mmol) of potassium carbonate. After instillation of 20.5 g (105 mmol) of bromoacetic acid-tert-butyl ester, it is stirred for 6 hours at 65° C. After cooling, it is filtered, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel with diethyl ether/hexane/triethylamine. The product fractions are concentrated by evaporation in a vacuum and dried.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[ClH:21].O1CCOCC1>C(Cl)Cl>[ClH:21].[ClH:21].[F:20][C:2]([F:1])([F:19])[CH2:3][NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNCC(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)(F)CNCC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of tert-butyl 4-((2,2,2-trifluoroethylamino)methyl)piperidine-1-carboxylate (1.49 g, 5.03 mmol) in DCM (25 mL) was added 4 N HCl in dioxane (5.03 mL, 20.11 mmol). The reaction was stirred at RT. After 16 hours, the white precipitate was collected by vacuum filtration, washed with diethyl ether, and dried in vacuo, to generate 2,2,2-trifluoro-N-(piperidin-4-ylmethyl)ethanamine dihydrochloride as a white powder (1.07 g, 3.98 mmol, 79% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([Br:14])[CH:13]=1)[NH:10][CH:9]=[CH:8]2.[CH3:15]I>CN(C=O)C>[CH3:15][N:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][CH3:3])=[CH:13][C:12]=2[Br:14])[CH:8]=[CH:9]1
Reactant: CI
Reactant: COc1cc(Br)c2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.32 g, 7.96 mmol) in DMF (18 mL) was added a solution of 5-methoxy-7-bromoindole (1.5 g, 6.63 mmol) in DMF (25 mL). The mixture was stirred at room temperature for 1 h, and then methyl iodide (0.62 mL, 9.95 mmol) was added with cooling in an ice-water-bath. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The extract was washed with water and brine, dried (sodium sulfate) and concentrated to give a crude product (1.6 g, 100%), which was used without further purification. 1HNMR (400 MHz, CDCl3) 3.82 (s, 3H), 4.10 (s, 3H), 6.36 (d, J=3.13 Hz, 1H), 6.96 (d, J=2.74 Hz, 1H), 7.0 (d, J=2.35 Hz, 1H), 7.03 (d, J=2.35 Hz, 1H); MS (ES, m/z): C10H10BrNO: 240.08 (M+(79Br)+1), 242.1 (M+(81Br)+1).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:28]N1C(=O)CCC1=O>ClCCl>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[C:17]([CH2:20][CH3:21])=[CH:18][C:19]=1[Br:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCc1ccc(OCc2ccccc2)cc1OCCCC#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cc(Br)c(OCc2ccccc2)cc1OCCCC#N
Reaction time: 5.5 h

Procedure:
Carbon tetrachloride (30 mL) was used to dissolve 4-(Benzyloxy)-2-[(3-cyanopropyl)oxy]-1-ethylbenzene (2.5 g). N-bromosuccinimide (1.66 g) was added to the solution and it was stirred for 5.5 hours. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was crystallized from hexane/ethyl acetate at −20° C. to afford 1-(benzyloxy)-2-bromo-4-ethyl-5-[(3-cyanopropyl)oxy]-benzene as a white crystalline solid solution and it was stirred for 5.5 hours. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil was crystallized from hexane/ethyl acetate at −20° C. to afford 1-(benzyloxy)-2-bromo-4-ethyl-5-[(3-cyanopropyl)oxy]-benzene as a white crystalline solid (1.5 g). NMR (CDCl3) 1.14, t (3H); 2.14, m (2H); 2.55, m (4H); 3.98, t (2H); 5.12, s (2H); 6.45, s (1H); 7.37, m (6H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12]C)=[CH:6][C:3]=1[CH:4]=[O:5].[OH-].[Na+].CCCCCC.CCOC(C)=O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(Cl)c(C=O)cc1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(C=O)cc1O
Temperature: 65 °C

Procedure:
2-Chloro-4,5-dimethoxybenzaldehyde (5.00 g, 24.9 mmol; commercially available from Akos Consulting) is dissolved at room temperature in conc. H2SO4 (23 mL; Riedel) at room temperature. The deeply colored mixture is heated at 65° C. overnight with stirring, and after cooling is poured with caution into ice-water containing 38 g of solid NaOH (pH 14). The water phase is washed twice with AcOEt, and then is adjusted to pH 1 by addition of HCl 37% with ice-cooling to form a white suspension. Extraction with AcOEt, drying of the organics over MgSO4 and evaporation gives the crude product in a mixture with unreacted starting material. The title compound is obtained after silica gel chromatography (hexane/AcOEt gradient from 3:1 to 1:1) as white solid. TLC, Rf (hexane/AcOEt 1:1)=0.35. MS: 187.0 [M+H]+. ]+. 1H-NMR (DMSO-d6): δ 3.41 (s, 3H), 7.14 (s, 1H), 7.45 (s, 1H), 9.83 (s, 1H), 10.2 (s, 1H) ppm.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH:10]([N:12]([CH3:21])[C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[CH3:11])C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH:10]([N:12]([CH3:21])[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:11]
Reactant: Cc1cccc(C)c1N(C)C(C)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(C)c1N(C)C(C)CN
Reaction time: 1 h
Yield: 74.4 %

Procedure:
2.5 ml of a 90% hydrazine hydrate are added to a solution of 3.0 g (9.3 mmoles) of 1-phthalimido-2-[N-methyl-N-(2,6-dimethylphenyl)-amino]-propane in 30 ml of ethanol, and the mixture is boiled for one hour. Next day the mixture is processed as described in Example 11, and the crude product is distilled under reduced pressure. 1.33 g (74.5%) of 1-amino-2-[N-methyl-N-(2,6-dimethylphenyl)-amino]-propane are obtained; b.p.: 97°-99° C./53.3 Pa. The monohydrochloride of the product, prepared as described in Example 1, melts at 158°-160° C.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:14](=[O:15])[CH:13]=[C:12]([CH3:17])[CH3:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)=CC(=O)Cl
Reactant: CC(C)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-isopropylaniline (5.0 g, 37.0 mmol) in 100 ml of anhydrous CH2Cl2 under argon at 0° C. was added 3,3-dimethylacryloyl chloride (4.12 ml, 37.0 mmol). Pyridine (3.0 ml, 40.6 mmol) was added, and the mixture was stirred at 25° C. for 12 hours. The reaction was quenched with water and extracted with ethyl ether. The organic layer was washed with water, and brine, dried over Na2SO4 and were in vacuo to give the title compound as a light brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)=O)(C)(C)C.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:36]2[N:44]3[C:39]([CH:40]=[N:41][C:42](OS(C(F)(F)F)(=O)=O)=[N:43]3)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.C(O)(C(F)(F)F)=O>>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:36]2[N:44]3[C:39]([CH:40]=[N:41][C:42]([NH:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([CH:9]5[CH2:10][NH:11][CH2:12][CH2:13][NH:8]5)[CH:22]=4)=[N:43]3)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2cccc(N)c2)C1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc3cnc(Nc4cccc(C5CNCCN5)c4)nn23)cn1
Yield: 43.2 %

Procedure:
Analogous to Example 1528d, 2-(3-Amino-phenyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (204 mg, 0.540 mmol) and Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (162 mg, 0.432 mmol) were reacted to afford [7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3-piperazin-2-yl-phenyl)-amine (75 mg, 33%) as the TFA salt. LCMS: 402 (M+H); 1H-NMR (DMSO-d6): 9.74 (s, 1H), 9.5 (br s, 3H), 9.03 (s, 1H), 9.00 (s, 1H), 8.50 (m, 1H), 7.93 (d, 1H, J=8.1 Hz), 7.65 (s, 1H), 7.48 (m, 1H), 7.26 (d, 1H, J=4.8 Hz), 7.19 (d, 1H, J=7.9 Hz), 7.03 (m, 2H), 1.41 (m, 1H), 3.94 (s, 3H), 3.71 (m, 1H), 3.60 (m, 2H), 3.2-3.4 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(O)c2cc(Br)c(OCc3ccccc3)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2cc(Br)c(OCc3ccccc3)cc2n1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
7-Benzyloxy-6-bromo-2-methyl-quinolin-4-ol (25.0 g, 72.6 mmol) and phosphorous oxychloride (70 mL, 0.764 mol) were heated 40 min at 130° C. and then cooled down to room temperature. Phosphorous oxychloride was evaporated under high vacuum. Ice water was added and the pH of this solution was adjusted to 9 with ammonium hydroxide. The suspension was extracted with dichloromethane. The combined organic layers were dried under vacuum. 22.8 g of the title compound were obtained. Brown solid, ISP-MS: m/e=364.0 ([M+H]+).