Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)(=O)CO.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[C:10]([C:2]#[N:1])[C:5]([O:4][CH2:3][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Agent: CCOC(=O)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 1.55 g (3.93 mmol) of the product from Step A in toluene (20 mL) was treated with ethyl glycolate (0.41 mL; 4.33 mmol) and cesium carbonate (2.54 g; 7.8 mmol). The reaction mixture was heated in a sealed pressure tube at 80° C. and stirred for 6 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 460.9 (M+1), 462.9 (M+3); Rt=4.50 min.
Reaction SMILES: C1C2C(COC([NH:18][C:19]3[CH:45]=[CH:44][C:22]([C:23]([NH:25][NH:26][C@H:27]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24])=[C:21]([N+:46]([O-:48])=[O:47])[CH:20]=3)=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C)C=O>[C:40]([O:39][C:37](=[O:38])[C@H:27]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:26][NH:25][C:23](=[O:24])[C:22]1[CH:44]=[CH:45][C:19]([NH2:18])=[CH:20][C:21]=1[N+:46]([O-:48])=[O:47])([CH3:42])([CH3:43])[CH3:41]
Reactant: CC(C)(C)OC(=O)CC[C@H](NNC(=O)c1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NNC(=O)c1ccc(N)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a mixture of 10 g of di-tert-butyl N-(4-(((9H-fluorene-9-yl)methoxy)carbonylamino)-2-nitrobenzamido)-L-glutamate in 200 ml of N,N-dimethylformamide 1.34 ml pyrrolidine were added. The mixture was stirred for 30 min. at room temperature and then evaporated to dryness under vacuum. After addition of 200 ml of diisopropylether and stirring for 15 min., the resulting suspension was kept at 0° C. over night. The product was sucked-off, washed with 60 ml of diisopropylether and then dried under vacuum to give 4.3 g of N-(4-amino-2-nitrobenzamido)-L-glutamic acid di-tert.-butylester as yellow needles (HPLC, assay 99.7% area).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[C-:18]#[N:19].[Na+]>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:18]#[N:19])=[CH:12][CH:13]=1
Reactant: Oc1ccc(NCCCCCCCCBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCCCCCCCCNc1ccc(O)cc1
Yield: 73 %

Procedure:
9-[(4-Hydroxyphenyl)amino]nonanenitrile was prepared in 73% yield from 37.5 g (0.11 mol) of 4-[(8-bromooctyl)amino]phenol and 27 g (0.55 mol) of sodium cyanide according to the procedure of Example 4, part c, except that the crude free base was precipitated from ethyl acetate solution with hexane.
Reaction SMILES: FC1C=C(C2CCNCC2)C(C)=CC=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][N:17]=1.BrCC1CC1(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:28][C:26]1[NH:25][N:24]=[C:23]([NH:22][C:20]2[C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][N:17]=[C:16]([NH2:15])[N:21]=2)[CH:27]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2C(F)(F)F)n[nH]1
Agent: FC1(F)CC1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(N)ncc2C(F)(F)F)n[nH]1
Temperature: 60 °C

Procedure:
A mixture of N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (100 mg, 0.22 mmol), 2-(bromomethyl)-1,1-difluorocyclopropane (76.4 mg, 0.45 mmol) and triethylamine (60.6 μL, 0.42 mmol) in 1 mL of DMF was heated at 60° C. in a microwave reactor for 2 h. The crude product was purified by RP-HPLC to afford N2-(4-(1-(2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4— (5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; ESMS m/z 540.2 (M+H+).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:29])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl.C(=O)([O-])O.[Na+]>C(OCC)C.[Cl-].[Zn+2].[Cl-].O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:29])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1cccc(SC(F)(F)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (3.74 g, 27.4 mmol) in diethyl ether (100 ml) was added sodium borohydride (2.08 g, 54.8 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and to the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-{3-[(trifluoromethyl)thio]benzyl}propanoate (5.5 g, 13.7 mmol) in diethyl ether (50 ml) at 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acid was added to the reaction solution to stop the reaction. After neutralization with saturated aqueous sodium hydrogen carbonate, water (200 ml) was further added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective substance (5.40 g, 98%).
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[CH2:15]([CH2:17][NH2:18])[OH:16]>C(O)C>[OH:16][CH2:15][CH2:17][NH:18][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:18][CH2:17][CH2:15][OH:16])=[O:13])=[CH:11][CH:10]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Solvent: CCO
Product: O=C(NCCO)c1ccc(C(=O)NCCO)cc1

Procedure:
A mixture of 194 g (1.0 mole) of dimethyl terephthalate, 150 ml (2.46 mole) ethanolamine and 300 ml ethanol was refluxed for 7 hours. On cooling the title product separated. It was filtered and then washed with ethanol. After drying, it melted at 227°-229° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(O)(c2ccc(F)c(F)c2)C1

Procedure:
Preparation according to Example 24: Enantiomer E2 of 3-(3,4-difluorophenyl)-pyrrolidin-3-ol (0.27 g, 1.35 mmol), acetonitrile (3 mL), potassium carbonate (0.279 g, 2.02 mmol) and iodoethane (0.21 g, 1.35 mmol). Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 35:65 to 50:50). Yield 0.14 g. [α]D=−18.8° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 136-137° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 11), 141, (20), 113 (17), 72 (43), 71 (bp).
Reaction SMILES: [K].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:14])=[C:7]([C:9]([CH:11]2[CH2:13][CH2:12]2)=O)[CH:8]=1.[C:15]1(C)C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([F:14])=[C:7]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[CH2:15])[CH:8]=1
Reactant: O=C(c1cc(Br)ccc1F)C1CC1
Reactant: Cc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K]
Product: C=C(c1cc(Br)ccc1F)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (7.142 g, 20 mmol) in toluene (50 ml) was treated with potassium amylate (1.7 M in toluene, 11.76 ml, 20 mmol), and the mixture was stirred at 0° C. for 30 minutes. A solution of (5-bromo-2-fluoro-phenyl)-cyclopropyl-methanone (4.05 g, 17 mmol) in toluene (17 ml) was added and the mixture stirred at room temperature for 2 hours. For the workup, the mixture was extracted with water and ethyl acetate, the organic layer separated, dried and evaporated at reduced pressure. After chromatography on silica gel using a mixture of hexane and ethyl acetate as the eluent, the 4-bromo-2-(1-cyclopropyl-vinyl)-1-fluoro-benzene was obtained as yellow oil (3.816 g, 95% of theory). Mass (calculated) C11H10BrF [241.102]; (found) [M+H]+=241, [M+2-H]+=243.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1.[Br:15]Br.S([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([Br:15])[C:10]=2[CH3:12])[S:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(C)c2c1SCCC2(C)C
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)c(C)c2c1SCCC2(C)C
Yield: 87.1 %

Procedure:
100 ml of methylene chloride was added to 13.2 g (0.064 mol) of 4,4,5,8-tetramethylthiochroman, 10.2 g (0.064 mol) of bromine was dropwise added at room temperature, and then the mixture was allowed to react for 2 hours. After the completion of the reaction, 70 ml of a 2% sodium hydrogensulfite aqueous solution was added, excessive bromine was removed, and the reaction mixture was liquid-separated. An organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The methylene chloride was distilled off under reduced pressure, and the resultant oily substance was purified by silica gel column chromatography to give 15.9 g (yield 87%) of 4,4,5,8-tetramethyl-6-bromothiochroman.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:27][CH2:28][CH:29]([CH2:31]O)[OH:30].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:31][CH:29]([OH:30])[CH2:28][OH:27])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CO
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g of 4-(n-hexadecylamino)benzoic acid, 1.00 g of glycerol, and 5.35 ml of boron trifluoride etherate in 200 ml of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[O:7]2.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH:16]2[O:18][CH2:17]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[O:7]2
Reactant: BrCC1CO1
Reactant: Cc1ccc(O)c2oc(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(OCC2CO2)c2oc(=O)ccc12

Procedure:
5-Methyl-8-hydroxycumarin (synthesized from isovanilin in 4 steps) is allowed to react with epibromohydrin in methyl ethyl ketone in the presence of potassium carbonate to give 5-methyl-8-(2,3-epoxypropoxy)-cumarin [cf. Chem. Phar. Bull. 20,205 (1972)].
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCCCCCCCCCC.[NH2:20][C:21]1[N:22]=[N:23][N:24](CC2C=CC=CC=2)[N:25]=1>>[NH2:20][C:21]1[N:25]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:24]=[N:23][N:22]=1
Reactant: Nc1nnn(Cc2ccccc2)n1
Reactant: ClCc1ccccc1
Agent: CCCCCCCCCCBr
Product: Nc1nnnn1Cc1ccccc1

Procedure:
Following the general procedure of Example 2 only substituting an appropriate amount of benzyl chloride for 1-bromodecane, 5-amino-2-benzyltetrazole and 5-amino-1-benzyltetrazole were obtained.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][CH3:19])=[C:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC4C=CC=CC=4)=[CH:22][CH:21]=1)[C:12]3=[C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[CH:35]=2)C1C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH2:18]([C:14]1[C:15]2[N:11]3[C:10](=[CH:35][C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:12]3[C:13]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:9]([OH:8])=[CH:17][CH:16]=2)[CH3:19]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCCCCN3CCCCC3)cc3c(OCc4ccccc4)ccc1n32
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(O)cc2)c2c(COCCCCCCCCN3CCCCC3)cc3c(O)ccc1n32
Yield: 85.4 %

Procedure:
A suspension of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-((8-piperidinooctyloxy)-methyl)pyrrolo[2,1,5-cd ]indolizine (0.30 g, 0.44 mmol) and 30 mg 10% palladium on charcoal in 12 ml of ethanol and 8 ml of tetrahydrofuran was stirred in a hydrogen atmosphere for 6 hours. The reaction mixture was filtered twice and the solvent was evaporated. The resulting oil was purified by column chromatography over netural aluminium oxide activity grade I, using 10% of methanol in dichloromethane as the eluent. The product was crystallised from dichloromethane, diethyl ether and petroleum ether to afford 189 mg (85%) of 1-ethyl-5-hydroxy-2-(4-hydroxyphenyl)-3-((8-piperidinooctyloxy)methyl)pyrrolo[2,1,5-cd ]indolizine as yellow crystals. M.p. 91-95° C. (decomp.). MS(FAB): m/z 503 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ:1.17-1.71 (m, 21H); 2.61-3.09 (m, 8H); 3.38 (t, 2H); 4.68 (s, 2H); 6.92 (d, 2H); 7.12 (d, 1H); 7.22 (s, 1H); 7.48 (d, 2H); 7.83 (d, 1H); 9.58 (s, 1H); 10.59 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:28][CH2:29][CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[O:18][CH:19]=2)=[CH:9][C:8]=1[CH3:27])C.[Li+].[OH-]>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[O:18][CH:19]=[C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:28][CH2:29][CH3:30])[C:4]([OH:31])=[O:3])=[C:8]([CH3:27])[CH:9]=2)[N:16]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2coc(-c3ccccc3Cl)n2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2coc(-c3ccccc3Cl)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], [rac]-3-{4-[2-(2-chloro-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(2-chloro-phenyl)-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless liquid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:22][O:21][N:20]([CH3:19])[C:15]([CH:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:14]1)=[O:17]
Reactant: CNOC
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid (2.30 g, 9.78 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.14 g, 11.73 mmol) in THF (45 mL) was added EDCl (2.06 g, 10.76 mmol), HOBt (1.45 g, 10.76 mmol), N,N-diisopropylethylamine (5.11 mL, 29.33 mmol). The reaction was stirred at rt for 16 h. The mixture was partitioned between ethyl acetate (75 mL) and H2O (75 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude material was filtered through a plug of silica gel, eluting with 3:1 ethyl acetate/hexanes to afford 1.66 g (61%) of the desired product after concentration of the filtrate. ES-MS m/z 279.03 [M+H]+, HPLC RT (min) 3.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:32]C)[C:10](=[O:31])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:16](=[O:30])[C:12]3=2)[C:7]1=[O:34].Br>C(O)(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:32])[C:10](=[O:31])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:16](=[O:30])[C:12]3=2)[C:7]1=[O:34]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCN1CCOCC1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C1c2c(c3n(c(=O)c2O)CCCCN(CCN2CCOCC2)C3=O)CCN1Cc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-morpholin-4-ylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (30 mg, 0.06 mmol) and 33% hydrogen bromide in acetic acid (0.4 mL) in dioxane (2 mL) was stirred at room temperature for 30 minutes. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and Iyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Cl.[CH:29]([N:32]([CH:36](C)C)[CH2:33]CCl)(C)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:33][N:32]([CH3:36])[CH2:29][CH2:30][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[C:5]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2CCN(C)C
Temperature: 0 °C
Yield: 34.5 %

Procedure:
A solution of Compound 107 (1 g, 2.64 mmol), 2-(diisopropylamino)ethyl chloride hydrochloride (2.64 g, 13.2 mmol), and potassium carbonate (3.64 g, 26.4 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0-10% methanol in ethylacetate gradient to yield 409 mg (30%) of pale yellow solids. M.P. 110-117° C. 1H NMR (DMSO-d6): δ 0.93 (s, 12H), 2.40 (s, 3H), 2.59 (m, 2H), 3.01 (m, 2H), 3.61 (m, 4H), 3.91 (m, 4H), 4.15 (m, 2H), 7.16 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 506 (M+1). Anal. (C28H35N5O2S) C,H, N.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]=C)=[CH:14][N:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:21].[Na+].C1COCC1.O>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]=[O:21])=[CH:14][N:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1ccc(OC2CCN(C3CCC3)CC2)nc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OC2CCN(C3CCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.9 %

Procedure:
2-[(1-cyclobutylpiperidin-4-yl)oxy]-5-vinylpyridine (2.59 g, 10 mmol) and sodium periodate (10.7 g, 50 mmol) were stirred in a mixed solvent of THF (10 mL) and water (10 mL) at room temperature. Osmium tetroxide (0.2 M in t-BuOH, 1 mL) was dropwise added to the reaction solution, and stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate, washed with aqueous 1 N sodium hydroxide solution, aqueous saturated sodium thiosulfate solution and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (chloroform/methanol=9/1) to obtain the intended compound (1.04 g, 40%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:22])[C:19]([OH:21])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:23])[NH:6]2.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:22])[C:19]([O:21][CH2:24][CH:26]4[CH2:27][O:28]4)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:23])[NH:6]2
Reactant: ClCC1CO1
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(O)c(C)c34)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCC5CO5)c(C)c34)ccc2[nH]1
Temperature: 50 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
A mixture of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (Example 1), (200 mg, 0.64 mmol), epichlorohydrin (297 mg, 3.21 mmol) and potassium carbonate (445 mg, 3.21 mmol) in DMF (1 ml) was stirred at 50° C. for 6 h. After cooling to RT and concentration in vacuo the crude material was purified by chromatography on silica gel eluting with 50% ethyl acetate in hexanes to afford the title compound (190 mg, 81%) as a yellowish solid. MS: (M+H)+=369.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6][C@@H:5]1[CH3:17])(=[O:3])[CH3:2]>[OH-].[Pd+2].[OH-]>[C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C@@H:5]1[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(Cc2ccccc2)C[C@@H]1C
Agent: [Pd+2]
Agent: [OH-]
Product: CC(=O)N1CCNC[C@@H]1C
Yield: 38.4 %

Procedure:
(S)-1-Acetyl-2-methyl-4-benzylpiperazine (1.87 g) was hydrogenated over palladium hydroxide (600 mg) at ambient temperature for 3 hours. The catalyst was filtered off and the solvent was evaporated off. The residue was purified by column chromatography eluting with a mixture of methanol and chloroform (1:5) to give 440 mg of (S)-1-acetyl-2-methylpiperazine (440 mg).