Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:7]=2)[CH:3]=[N:2]1.Cl[CH2:44][CH2:45][N:46]([CH3:48])[CH3:47].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:47][N:46]([CH3:48])[CH2:45][CH2:44][N:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[CH:7]=2)[CH:3]=[N:2]1
Reactant: CN(C)CCCl
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cn[nH]c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(CCN(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 57 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (43 mg, 0.07 mmol) and 2-chloro-N,N-dimethylethanamine chlorhydrate (43 mg, 0.30 mmol) were dissolved in DMF (3 ml) and cesium carbonate (240 mg, 0.74 mmol) was added. After stirring the mixture at 75° C. for 3.5 h, the solvent was evaporated under reduced pressure and the residue was suspended in water and extracted with dichloromethane (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 3%, dichloromethane-methanol) to obtain 31 mg (57% yield) of the title compound as a brown solid. Purity 90%.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:16]([N:25]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:26][CH3:27])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][C:9]1[N:10]=[N:11][NH:12][N:13]=1.[OH-].[Na+].[CH2:45](Cl)Cl.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:38][C:37]([F:40])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:16]([N:25]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:26][CH3:27])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][C:9]1[N:10]=[N:11][N:12]([CH3:45])[N:13]=1
Reactant: ClCCl
Reactant: CCN(CC1CCCC1)c1nc2ccccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1nn[nH]n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCN(CC1CCCC1)c1nc2ccccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1nnn(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.3 %

Procedure:
To a suspension of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-ylmethyl)-amino]-methyl}-quinolin-2-yl)-cyclopentylmethyl-ethyl-amine (0.25 g, 0.423 mmol) in water (4 mL) was added sodium hydroxide (0.033 g, 0.846 mmol), the resulting mixture was stirred for 15 min at RT, and then DCM (4 mL) was added. Dimethyl sulfate (0.058 g, 0.465 mmol) was then added to this mixture, followed by tetrabutylammonium bromide (0.006 g, 0.021 mmol), and stirring of the resulting mixture was continued for 15 min. The organic layer was then separated from aqueous layer, the aqueous layer was extracted with DCM (3×10 mL), and the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum to afford a residue. This residue was purified by column chromatography over 100-200 mesh silica gel using 4% ethyl acetate in petroleum ether, to give the title compound (0.08 g), yield: 31.3%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[C:11]([CH:15]=[CH:16][CH3:17])=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH3:2].C1C[O:21]CC1>[OH-].[Na+]>[CH2:1]([O:3][C:4]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:16][CH3:17])[C:7]=1[C:8]([OH:21])=[O:10])=[O:9])[CH3:2]
Reactant: C1CCOC1
Reactant: CC=Cc1cccc2nc(OCC)oc(=O)c12
Agent: [Na+]
Agent: [OH-]
Product: CC=Cc1cccc(NC(=O)OCC)c1C(=O)O

Procedure:
Alternatively, the title compound was prepared by stirring a solution of 2-ethoxy-5-propenyl-4H-3,1-benzoxazin-4-one in THF (5 ml) and 2% sodium hydroxide (5 ml) for 6 hours. The organic solvent was removed by evaporation. The aqueous solution was acidified to pH=2 with dropwise addition of 6 M HCl. The solution was extracted with ethyl acetate and the organic was dried (magnesium sulphate) and evaporated to give an oil.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:12]([CH3:24])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C@@H:8]([CH3:11])[CH:9]=O)([CH3:4])[CH3:3].[CH3:27][NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(O)(=O)C.CCOC(C)=O>[CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:12]([CH3:24])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C@@H:8]([CH3:11])[CH2:9][NH:28][CH3:27])([CH3:4])[CH3:3]
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O)cc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)COCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
A solution of 2,4-dideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-5-O-[(4-methoxyphenyl) methyl]-2,4-dimethyl-L-arabinose (2.8 g, 7.37 mmol) in THF (10 mL) is added slowly to a stirred solution of methylamine (14.7 mL, 29.5 mmol) in THF at room temperature. After being stirred at room temperature for 20 min, sodium triacetoxyborohydride (2.3 g, 11.05 mmol), followed by acetic acid (10 drops) are added at room temperature. After being stirred at room temperature overnight, the reaction mixture is diluted with EtOAc (100 mL), and washed with saturated NaHCO3 (2×30 mL), H2O (50 mL), brine (50 mL) and dried over Na2SO4. After removal of the solvent in vacuo, the residue is chromatographed on silica gel with MeOH/CH2Cl2 (1/99) to give the desired compound (1.54 g, 52.9%) as a pale viscous oil.
Reaction SMILES: CN(C)CN(C)C.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[O:21].[C:22](O)(=O)C.C(OC(=O)C)(=O)C>O1CCCC1>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:19])([CH3:20])[C:13](=[CH2:22])[C:12]2=[O:21]
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2O1
Reactant: CC(=O)O
Agent: CN(C)CN(C)C
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: C=C1C(=O)c2cc(Br)ccc2OC1(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
N,N,N′,N′-tetramethylmethanediamine (4.8 g, 47 mmol) was added to a solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (3.0 g, 12 mmol) and acetic acid (0.67 ml, 12 mmol) in tetrahydrofuran (43 ml), and the mixture was stirred at 70° C. for 24 hours. To the mixture was added acetic anhydride (4.4 ml, 47 mmol), and the mixture was stirred at 70° C. for 4 hours and concentrated in vacuo. The residue was directly purified by silica gel column chromatography (hexane/ethyl acetate=20:1) to afford 6-bromo-2,2-dimethyl-3-methylene-2,3-dihydro-4H-chromen-4-one (2.8 g).
Reaction SMILES: [CH2:1](F)[O:2][CH:3]([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)C(F)(F)F.BrC[C:25]([O:27]CC)=[O:26]>>[F:5][C:4]([F:7])([F:6])[CH:3]([O:2][CH2:1][C:25]([OH:27])=[O:26])[C:8]([F:11])([F:10])[F:9]
Reactant: FCOC(C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)CBr
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: O=C(O)COC(C(F)(F)F)C(F)(F)F
Yield: 66 %

Procedure:
U.S. Pat. No. 6,271,422 describes the synthesis of sevoflurane by fluoromethylation of alcohols via decarboxylative halogenation. In this way, hexafluoroisopropanol is submitted to reaction with ethyl alpha-bromoacetate providing alpha-(hexafluoroisopropoxy) acetic acid in a yield of 66%. This intermediate is subjected to reaction with the highly toxic lead tetra-acetate, using the carcinogenic benzene as the solvent. In the reaction sequence, the homogeneous benzene/sevochlorane solution, which is inseparable by distillation, is reacted with potassium fluoride providing at the end of the process sevoflurane with a low yield of 28%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:35])([F:34])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:34])([F:33])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:28]([F:30])([F:31])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoate (680 mg, 1.27 mmol, 1.00 equiv), water (5 mL), methanol (10 mL), LiOH (153 mg, 6.39 mmol, 5.00 equiv). The resulting solution was stirred for 2 h at 50° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 30 mL of H2O. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 420 mg (65%) of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:12])[CH:9]=[C:10](Br)[C:5]2=[N:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:12])[CH:9]=[C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[CH3:13])[C:5]2=[N:4][CH:3]=1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Reactant: Cc1ccncc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1-c1cc(Cl)nn2c(Br)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
A microwave vial was charged with a mixture of 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (1.0 g, 3.21 mmol), 4-methylpyridin-3-ylboronic acid (0.440 g, 3.21 mmol), tetrakis(triphenylphosphine)palladium(0) (0.371 g, 0.321 mmol), dioxane (16 mL), and K3PO4 (4.82 mL, 9.64 mmol) (2.0 M solution in water) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 4 h in a microwave heater. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE® (20-80% EtOAc/CH2Cl2, 1.5 L, then 20%-65% B/CH2Cl2 (0.9 L); B: 10% MeOH/CH2Cl2) to give 320 mg (15.4%) product. 1H NMR (400 MHz, CD3OD) δ ppm 8.91 (1H, s), 8.82 (1H, d, J=5.79 Hz), 8.04 (1H, d, J=5.79 Hz), 7.88 (1H, s), 7.57 (1H, s), 2.54 (3H, s). LC (Conditions B & C): >95% purity; LC/MS: Rt=1.47 min. LC/MS (Condition A): 322.96/324.96.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:19]=[CH:18][C:12]([CH2:13][S:14][C:15](N)=[NH2+])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[C:22](=O)([O-])[O-].[K+].[K+].CO.[OH-].[K+]>C1(C)C=CC=CC=1.O>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:19]=[CH:18][C:12]([CH2:13][S:14][CH2:15][CH3:22])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: NC(=[NH2+])SCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CCSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
S-(4-(4-chlorobenzoyl)benzyl)thiouronium bromide (3.3 g) and potassium carbonate (1.5 g) were dissolved in dimethylformnamide (20 ml). A methanol solution (10 ml) of potassium hydroxide (1.0 g) was added and stirred at room temperature for 30 minutes. To the reaction mixture, water (100 ml) and toluene (100 ml) were added. The organic layer was separated, and washed with water and an aqueous saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silica gel column chromatography (developing solvent: ethyl acetaten:hexane=1:9) to obtain 4-chloro-4'-ethylmercaptomethylbenzophenone (1.3 g).
Reaction SMILES: [NH2:1][C:2](=[NH:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1CCN2C(=NCCC2)CC1.C(O[CH:24]=[CH:25][C:26](=O)[C:27]([F:30])([F:29])[F:28])C>C(#N)C>[NH2:9][C:2]1[N:1]=[C:26]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:24][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=N)N
Reactant: CCOC=CC(=O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccc(C(F)(F)F)nc1N
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
19.5 g (0.12 mol) of ethyl 3-amino-3-iminopropanoate (described in Chemical and Pharmaceutical Bulletin, vol. 43, No. 5, p. 793 (1995)) was added to 100 mL of acetonitrile, and 18.6 g (0.12 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto at room temperature. The resulting mixture was stirred for 5 minutes. 20.6 g (0.12 mol) of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one was added to the above mixture, and 18.6 g (0.12 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto. The resulting mixture was stirred for 3 hours at 80° C. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was concentrated to half the original volume. Ice water was added thereto. Crystals precipitated therefrom were separated by filtration, and were dissolved in ethyl acetate. The filtrate was extracted with ethyl acetate. The solution having the crystals dissolved therein and the organic phase extracted were combined, and the resultant was washed with brine, and then was dried and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:9 to 1:4), and thus 17.8 g of the title compound was obtained as colorless crystals (yield: 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:15])[CH2:7]1>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:15])[CH2:7]1
Reactant: CC(C)(C)OC(=O)CCCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reaction time: 19.5 h
Yield: 199.8 %

Procedure:
Intermediate 25 (0.345 g) was dissolved in 4M hydrogen chloride in dioxane (5 ml), and the mixture was allowed to stand at 22° C. for 19.5 h. The solvent was evaporated in vacuo to give the title compound as a white solid (0.330 g).
Reaction SMILES: C(O[C:4]([C:6]1(C)[C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=O)C.Cl>>[CH2:13]([N:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH:6]([CH3:4])[CH2:7]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1(C)CN(Cc2ccccc2)CCC1=O
Agent: Cl
Product: CC1CN(Cc2ccccc2)CCC1=O
Temperature: 100 °C
Yield: 76.2 %

Procedure:
Ethyl-1-benzyl-3-methyl-4-oxo-piperidine-3-carboxylate (85 g, 0.31 mol) was dissolved in conc HCl (82 ml, 0.77 mol) and the reaction mixture was heated to 100° C. for 32 hrs. Solvent was removed under reduced pressure and the resulting solid was dissolved in the 300 ml CHCl3 and 400 ml pet ether was added to this under stirring to provide a solid. The solid was filter and was dissolved in 400 ml ethyl acetate and organic layer was washed with 10% NaOH aqueous solution. Layers were separated and concentration of organic layer afforded 48 g (75%) oil as a titled product.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]([CH3:28])[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[N:8]=[C:7](SC)[N:6]=1>C(O)C.O.O.[Ni]>[CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]([CH3:28])[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[N:8]=[CH:7][N:6]=1
Reactant: CSc1nc(Nc2cc(-c3nnc[nH]3)ccc2C)c(C#N)c(N(C)CC(C)(C)C)n1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nnc[nH]2)cc1Nc1ncnc(N(C)CC(C)(C)C)c1C#N
Yield: 10.5 %

Procedure:
To a solution of 4-[(2,2-dimethyl-propyl)-methyl-amino]-2-methylsulfanyl-6-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenylamino]-pyrimidine-5-carbonitrile (60 mg, 0.142 mmol) in 3 mL of 50% ethanol/water (v/v) was added 0.4 mL of 50% Raney-Ni in water solution. The solution was refluxed under argon for 18 hours. The solution was evaporated under vacuum. The resulting residue was purified by flash chromatography to afford 5.6 mg of the final product (Yield: 10%). MS (m/z) calcd for C20H24N8 (MH+), 377.2, found, 377.4.
Reaction SMILES: [CH2:1]([N:4]([CH2:15]/[CH:16]=[N:17]/[OH:18])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].Cl[O-].[Na+]>ClCCl>[N:17]1[O:18][CH2:3][CH:2]2[CH2:1][N:4]([C:5]([O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:14])[CH2:15][C:16]=12
Reactant: C=CCN(C/C=N/O)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2=NOCC2C1
Yield: 75.7 %

Procedure:
A solution of benzyl N-allyl-N-[(2E)-2-hydroxyiminoethyl]carbamate (24 g, 96.6 mmol) in dichloromethane (338 mL) is treated drop wise over 10 minutes with a 5% w/w aqueous solution of sodium hypochlorite (106.08 mmol, 143.06 mL). The resultant mixture is stirred at room temperature overnight. The reaction is quenched with a 40% aqueous solution of sodium bisulfite (7 g). The organic layer is separated, dried over magnesium sulfate, and concentrated under vacuum. The crude product is purified over silica gel eluting with 5% ethyl acetate in hexanes to give the title compound (18 g, 75%). ES/MS (m/e): 247 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:36][CH2:37][CH3:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH3:34])=[C:27]([F:35])[CH:26]=2.[Li+].[OH-]>C1COCC1.CO>[CH2:33]([O:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[F:35])[N:24]=[C:23]([NH:36][CH2:37][CH3:38])[C:22]([CH2:21][C:6]1[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=1[OH:18])=[CH:31]2)[CH3:34]
Reactant: CCNc1nc2cc(F)c(OCC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc(O)c(Cc2cc3cc(OCC)c(F)cc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 155 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (55 mg, 222 μmol) in THF (5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a solution of 3-(chloromethyl)-6-ethoxy-N-ethyl-7-fluoroquinolin-2-amine hydrochloride SMA 44106 (76 mg, 238 μmol) in MeOH (0.5 mL) at RT followed by a 2 N aq. LiOH solution (240 μL, 480 μmol) and the mixture was stirred at 155° C. for 1.5 h under microwave irradiation. After cooling to RT, THF and MeOH were removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave 4-((6-ethoxy-2-(ethylamino)-7-fluoroquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)-7-fluoroquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol 86 as a brown solid (15 mg, 12% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[OH:10])[C:5]#[N:6].B.C1COCC1.B.Cl>C1COCC1>[NH2:11][C:8]1[CH:7]=[C:4]([CH2:5][NH2:6])[CH:3]=[C:2]([Br:1])[C:9]=1[OH:10]
Reactant: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCc1cc(N)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.1 %

Procedure:
A solution of 3-bromo-4-hydroxy-5-nitrobenzonitrile (1.0 g, 4.11 mmol) in 20.0 mL of dry THF was added dropwise to a solution of BH3/THF 1.0 M in THF (12.3 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature for 24 hours. Excess borane was decomposed by the cautious dropwise addition of 1 N HCl at 0° C. It was extracted with EtOAc, washed with NaHCO3, NaCl saturated solution and dried (Na2SO4 anh.) to give a crude. After purification by column chromatography (CH2Cl2/MeOH 8:2+1% NH4OH), 170 mg (19%) of 2-amino-4-(aminomethyl)-6-bromophenol were obtained. 1H NMR (DMSO-d6) δ 6.67 (s, 1H, H-5); 6.53 (s, 1H, H-3); 3.52 (s, 2H, CH2). 13C NMR (DMSO-d6) δ 139.7, 139.4 (C-1, C-4), 136.0 (C-2), 118.5 (C-5), 113.0 (C-3), 111.5 (C-6), 44.9 (CH2).
Reaction SMILES: C([O:4][C:5]1[C:10]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:9][C:8]([OH:26])=[C:7]([CH3:27])[C:6]=1[CH3:28])C=C.[CH:29]1[CH:34]=CC=C[CH:30]=1>>[CH3:28][C:6]1[C:7]([CH3:27])=[C:8]([OH:26])[C:9]([CH2:34][CH:29]=[CH2:30])=[C:10]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]=1[OH:4]
Reactant: c1ccccc1
Reactant: C=CCOc1c(C(=O)CCCCCCCCCCCCC)cc(O)c(C)c1C
Product: C=CCc1c(O)c(C)c(C)c(O)c1C(=O)CCCCCCCCCCCCC

Procedure:
90 g of the allyl ether of step 2 were heated to 210° C. under nitrogen atmosphere within 2 h. After cooling the melt was dissolved in 300 ml of benzine (boiling range: 50°-75° C.) and placed in a cool place. The precipitate formed was filtered with suction the next day.