Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[Na+].Br[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]>CC(C)=O>[I:1][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: [I-]
Reactant: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CI)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2.25 h
Yield: 89.6 %

Procedure:
Sodium iodide (3.5 g) was slowly added to a stirred solution of 4-nitrobenzyl bromoacetate (5.0 g) in acetone (50 ml) at room temperature over 5 minutes, and the solution was stirred at the same temperature for 2.25 hours. The resultant mixture was evaporated in vacuo, and the residue was dissolved in a mixture of ethyl acetate (40 ml) and water (15 ml). The organic layer was separated, washed with a saturated aqueous solution of sodium chloride and an aqueous solution of sodium thiosulfate in turn, and then dried over anhydrous magnesium sulfate. After the solution was evaporated in vacuo, the residue was allowed to stand in a refrigerator overnight, and triturated with methanol (10 ml) to give crystals (5.25 g) of 4-nitrobenzyl iodoacetate, mp 62.5° to 63.5° C.
Reaction SMILES: C(Cl)Cl.[N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N+:5]=[N-:6].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH:25]=O)=[CH:23][N:22]=[CH:21]2)=[CH:16][CH:15]=1.[O-]CC.[K+]>C(O)C>[N:4]([C:7](=[CH:25][C:24]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=2)[CH:21]=[N:22][CH:23]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N+:5]=[N-:6]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cncn1-c1ccc(Br)cc1
Agent: CC[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(=Cc1cncn1-c1ccc(Br)cc1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A commercially available 34% methylene chloride solution of ethyl azidoacetate (6.6 mL, 21.6 mmol) was concentrated in vacuo, the residue reconstituted in anhydrous ethanol (100 mL) and the resulting solution treated with 3-(4-bromophenyl)-3H-imidazole-4-carbaldehyde (6) (2.7 g, 10.8 mmol). The mixture was cooled to 0° C., treated dropwise with potassium ethoxide solution (5.1 mL, 13.0 mmol, 24% (w/w) EtOH solution) and the mixture stirred at 0° C. for 5 h. The resulting white solid was collected by filtration and dried in air to yield ethyl 2-azido-3-[3-(4-bromophenyl)-3H-imidazol-4-yl]acrylate (7). LC-MS (ES+): m/z 362/364 (1/1) [MH+]. 1H NMR (CDCl3, 400 MHz): δ=1.31 (t, J=7.1 Hz, 3H), 4.30 (q, J=7.1 Hz, 2H), 6.52 (d, J=0.7 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 7.67 (s, 1H), 7.68 (d, J=8.7 Hz, 2H), 8.03 (d, J=0.7 Hz, 1H).
Reaction SMILES: [C:1]([NH:4][CH:5]([O:16]CC)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(F)(F)F.CCOCC.O.C([O-])(O)=O.[Na+]>>[C:1]([NH:4][CH:5]([OH:16])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)NC(O)C(=O)NCc1ccccc1

Procedure:
Reacting 2-acetamido-N-benzyl-2-ethoxyacetamide (1.00 g, 4.0 mmol), BF3.Et2O (0.91 g, 6.4 mmol) and H2O (0.12 g, 6.7 mmol) followed by aqueous NaHCO3 workup gave an aqueous reaction mixture. The solution was then extracted with EtOAc (3×50 mL), and the combined EtOAc extracts were dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 gel (3% MeOH/CHCl3) to give the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:21]([O:23][CH2:24][C:25](Cl)=O)[CH3:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:13]([CH2:14][CH:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]4)[C:22]([CH2:21][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2cc(Br)ccc2c1NCC1CCCCC1
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC1CCCCC1
Temperature: 90 °C

Procedure:
A modification of the method described in Part A of Example 9 was used to treat 7-bromo-N4-(cyclohexylmethyl)quinoline-3,4-diamine (7.3 g, 22 mmol) with ethoxyacetyl chloride (2.75 mL, 24.0 mmol). The reaction was heated overnight at 90° C. and then concentrated under reduced pressure to provide 7-bromo-1-cylcohexylmethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as a dark brown semi-solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[Cl:15]
Reactant: Oc1ncnc2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccc(Br)cc12
Temperature: 110 °C

Procedure:
A solution of 6-bromoquinazolin-4-ol (1.0 g, 4.44 mmol) in POCl3 (10 mL) was stirred and heated at 110° C. in a sealed tube overnight. The solution was cooled to room temperature and poured onto ice (200 g.) The solution was extracted with DCM (300 mL), washed with water (200 mL), dried over Na2SO4 and concentrated in vacuo to give the impure 6-bromo-4-chloroquinazoline as a brown solid that was not purified further (1.5 g.) MS (APCI+) [M+H]+ 243.1.
Reaction SMILES: [NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Cl:13][C:14]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:15]=1[C:16](C1C=CC=CC=1)=[O:17].S(=O)(=O)(O)[OH:31]>C(O)(=O)C>[Cl:13][C:14]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:15]=1[C:16]([OH:17])=[O:31]
Reactant: O=S(=O)(O)O
Reactant: O=C(c1ccccc1)c1cc(F)c(F)cc1Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C(O)c1cc(F)c(F)cc1Cl
Temperature: 90 °C
Yield: 80.8 %

Procedure:
8 g of ammonium peroxodisulfate are introduced into 5 g (19.8 mmol ) of 2-chloro-4,5-difluorobenzophenone and 20 g of glacial acetic acid and the mixture is heated at 90° C. (12 h). 100 g of 70% sulfuric acid are then added and the mixture is heated for 2 h at 150° C. Dilution with 200 g of water and filtration gives 3.1 g (16.0 mmol, 81%) of 2-chloro-4,5-difluorobenzoic acid (purity (GC) ca. 92%). Recrystallization from water gives 2.5 g of product melting at 104° C.-105° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][N:10]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][NH2:10]
Reactant: COc1ccc(F)cc1OCCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1OCCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylazide (3.97 g, 0.019 mol) and triphenylphosphine (5.95 g, 0.023 mol) in tetrahydrofuran (80 ml) and water (1.5 ml) was allowed to stir for 18 hours at room temperature. The solvent was removed under vacuum. Chromatography (ethyl acetate followed by 25-50% methanol-ethyl acetate plus ammonium hydroxide) removed triphenylphosphine and triphenylphosphine oxide and afforded 3.14 g (90%) of product as a clear oil. MS EI m/e 185 (M+)
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1.C(Cl)Cl.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][OH:36])[CH3:32]>C(OCC)C>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:36][CH2:35][CH2:34][N:33]([CH2:37][CH3:38])[CH2:31][CH3:32])=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1
Reactant: O=C(Cl)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Reactant: CCN(CC)CCO
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCN(CC)CCOC(=O)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1

Procedure:
A mixture of 9.45 g. (21 mmole) 4-{2-[1-(2-chlorobenzyl)-piperazin-4-yl]-ethyl}-benzoyl chloride dihydrochloride, 50 ml. methylene chloride and 3.3 g. (28 mmole) 2-diethylaminoethanol is maintained at reflux temperature for 3 hours, then cooled and mixed with diethyl ether until turbidity appears. A thick precipitate is slowly deposited. This is filtered off with suction, washed with sec.-butanol and dissolved in a hot mixture of sec.-butanol and ethanol. Upon cooling and partial concentration, there are obtained 5.0 g. (35% of theory) of the desired compound in the form of its dihydrochloride; m.p. 220°-221° C.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6][SH:7].Cl[C:10]1[C:11]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1>C(O)C>[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6][S:7][C:10]1[C:11]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: CN(C)CCCS
Reactant: Clc1nc(-c2ccccc2)nc2c1Cc1ccccc1O2
Agent: [Na]
Solvent: CCO
Product: CN(C)CCCSc1nc(-c2ccccc2)nc2c1Cc1ccccc1O2
Yield: 52 %

Procedure:
Eight and one tenth (8.1) gram 4-hydroxy-2-phenyl[1]benzopyrano[2,3-d]pyrimidine, 9.0 g phosphoruspentachloride and 36 ml phosphorusoxychloride are heated for two hours under reflux. Excess phosphorusoxychloride is then distilled off under a vacuum and the residue is partitioned to chloroform and water, a pH 6 value being adjusted by the addition of 10% sodium hydroxide. The organic phase is separated and the chloroform removed by distillation in a rotary evaporator. The residue obtained is separated by chromatography using cyclohexane/chloroform 1:1 as an eluting agent. There are obtained 4.0 g 4-chloro-2-phenyl[1]benzopyrano[2,3-d]pyrimidine, mp 168°-170° C. as colorless crystals. Thereafter 0.05 g sodium are dissolved in 10 ml anhydrous ethanol and 0.25 g 3-dimethylamino-1-propane-thiol added to the solution. The mixture obtained is added dropwise to a solution of 0.6 g 4-chloro-2-phenyl[1]benzopyrano[2,3-d]pyrimidine at reflux temperature. The reaction mixture is then kept under reflux for another two hours. After cooling the reaction mixture is filtered and the filtrate is evaporated to dryness and the residue partitioned to chloroform and water. The organic phase is separated off, the chloroform is evaporated and the residue recrystallized from ethanol. There are obtained 0.4 g colorless crystals, mp 93° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH2:69]([O:71][C:72](=[O:76])[CH2:73][CH2:74][NH2:75])[CH3:70].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:75][CH2:74][CH2:73][C:72]([O:71][CH2:69][CH3:70])=[O:76])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (200 mg, 0.43 mmol) in 10 ml of anhydrous DMF were added HATU (179 mg, 0.47 mmol) and N,N-diisopropylethylamine (166 mg, 1.29 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine ethyl ester hydrochloride (100 mg, 0.65 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added slowly until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give ethyl 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoate as white solid. Yield: 200 mg, 82%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[CH2:23][N:24]1[C@@H:28]([CH3:29])[C@@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:26][C:25]1=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[CH2:43]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]2[C@@H:28]([CH3:29])[C@@H:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][C:25]2=[O:36])[CH:4]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To {4-hydroxy-3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid (0.07 g, 0.14 mmol) and cesium carbonate (0.09 g, 0.28 mmol) in DMF was added benzyl bromide (0.03 mL, 0.28 mmol), and the reaction was stirred at room temperature for 3 days. The mixture was partitioned between H2O and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)c1nccc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1nccc(N(CC(=O)N(C)C)S(=O)(=O)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3,4-Dichloro-N-(2-isopropyl-pyrimidin-4-yl)-benzenesulfonamide (80 mg, example 14) was dissolved in DMF (1 mL) and treated with cesium carbonate (113 mg). To the mixture was added 2-chloro-N,N-dimethylacetamide (37 mg) and the resulting suspension was allowed to stir at room temperature for 48 hours and then at 80° C. for 24 hours. The mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using DCM/MeOH/NH4OH 9:1:0.1 as an eluant. The desired product was obtained as a colorless glass (28 mg). MS (ESI): 431.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([CH:27]([CH:29]4[CH2:31][CH2:30]4)[OH:28])=[N:25][N:26]=[C:18]1[C:17](=[O:32])[NH:16]3)=[O:12])[CH2:6][CH2:5]2.ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])=[N:25][N:26]=[C:18]1[C:17](=[O:32])[NH:16]3)=[O:12])[CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1nnc(C(O)C3CC3)n12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1nnc(C(=O)C3CC3)n12
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a mixed solution of 100 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-[cyclopropyl(hydroxy)methyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and 5 mL of dichloromethane was added 113 mg of Dess-Martin periodinane under ice-cooling. The mixed reaction liquid was returned to room temperature, followed by stirring for 4 hours. To the mixed reaction liquid were added a saturated aqueous sodium thiosulfate solution and chloroform, followed by stirring for a while, and then extracting with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3). To the obtained solid was added 4 mL of methanol to give a mixed solvent, followed by warming and washing. The precipitate was collected by filtration and dried under reduced pressure to obtain 36 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-(cyclopropylcarbonyl)-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one as a skin-colored solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH2:13][C:14]([O:18][CH3:19])([CH3:17])[CH2:15]I)[CH:11]=[C:6]1[C:5]2=[O:24].[CH3:25][Mg]Cl.[Li+].[B-](CC)(CC)CC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH2:13][C:14]([O:18][CH3:19])([CH3:17])[CH3:15])[CH:11]=[C:6]1[C:5]2([CH3:25])[OH:24]
Reactant: C[Mg]Cl
Reactant: COC(C)(CI)COc1cnc2oc3ccc(Br)cc3c(=O)c2c1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(C)COc1cnc2c(c1)C(C)(O)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-bromo-3-(3-iodo-2-methoxy-2-methylpropoxy)-5H-chromeno[2,3-b]pyridin-5-one (4.10 g, 8.13 mmol) in 100 mL THF was cooled to −40° C. and was treated with methylmagnesium chloride (5.42 mL, 16.27 mmol). After stirring for two hours, the reaction mixture was allowed to warm to room temperature and superhydride (40.7 mL, 40.7 mmol) was added. After stirring for an additional 2 hours the reaction mixture was cooled to 0° C. and was quenched with MeOH. The reaction mixture was poured into saturated NH4Cl solution and was extracted with EtOAc. The organics were washed with waer, brine, dried over MgSO4 and concentrated yielding 7-bromo-3-(2-methoxy-2-methylpropoxy)-5-methyl-5H-chromeno[2,3-b]pyridin-5-ol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=2)[C:16]=1[C:26](=O)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[BH4-].[Na+].C([BH3-])#N.[Na+]>ClCCl>[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:15]3[CH:24]=[CH:23][C:22]4[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18][C:17]=4[C:16]=3[CH:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]4)=[CH:29][CH:28]=3)[NH:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1-c1ccc2cc(O)ccc2c1C(=O)c1ccc(OCCN2CCCCC2)cc1
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Oc1ccc2c3c(ccc2c1)-c1ccc(F)cc1NC3c1ccc(OCCN2CCCCC2)cc1
Yield: 35.2 %

Procedure:
To a round bottom flask add (5-fluoro-2-{6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-phenyl)-carbamic acid tert-butyl ester (0.060 g, 0.103 mmol), dichloromethane (1.25 mL), anisole (0.15 mL, 1.39 mmol) and trifluoroacetic acid (0.25 mL). Stir the reaction for 1.5 hour at ambient temperature. Add trifluoroacetic acid (2.0 mL) and sodium borohydride (0.024 g, 0.62 mmol) and stir the reaction at ambient temperature for 1.5 hours. Add more sodium borohydride (0.024 g, 0.62 mmol) and stir the reaction at ambient temperature an additional 2 hours. After aqueous work-up and purification LC/MS showed significant amounts of the (M-2) intermediate, so take this material up in acetic acid (3.0 mL) and to it add sodium cyanoborohydride (0.032 g, 0.51 mmol). Stir this mixture for 1.5 hours at ambient temperature. Add more sodium cyanoborohydride (0.032 g, 0.51 mmol) and stir an additional 1.5 hours at ambient temperature. Quench the reaction with saturated aqueous sodium bicarbonate. Extract the resulting aqueous mixture into ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, H2O and brine; then dry (sodium sulfate) and evaporate the filtrate in vacuo. Purify the resulting residue by radial chromatography over silica (5%-10% methanol gradient in dichloromethane) to provide 17 mg (35%) of the title compound: mass spectrum (ion spray) m/z=469 (M+H).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[N:9]=[C:8]([C:10]([NH:13]C(=O)[O-])([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1.CO.O>C(#N)C>[F:17][CH:2]([F:1])[O:3][C:4]1[N:9]=[C:8]([C:10]([NH2:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(NC(=O)[O-])c1cccc(OC(F)F)n1
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CC(C)(N)c1cccc(OC(F)F)n1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 2-(6-(difluoromethoxy)pyridin-2-yl)propan-2-ylcarbamate (12.4 g, 48 mmol) in acetonitrile (50 mL) was added TMST (10 mL). The reaction was stirred 30 min and then poured into methanol (100 mL) and water (5 mL). The mixture was concentrated, dissolved in ethyl acetate (200 mL), and then washed with 1N NaOH (2×30 mL). The organic layer was separated, dried over Na2SO4, concentrated, and chromatographed with silica gel (50% EtOAc/hex, then 5-20% MeOH/CH2Cl2) to afford 2-(6-(difluoromethoxy)pyridin-2-yl)propan-2-amine (8.8 g, 92%) as a yellow oil.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C(Cl)(=O)C.[CH3:8][N:9]([C:13]([NH2:15])=[NH:14])[CH2:10][CH2:11][OH:12].[C:16](O)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[C:16]([O:12][CH2:11][CH2:10][N:9]([CH3:8])[C:13]([NH2:15])=[NH:14])(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CN(CCO)C(=N)N
Reactant: CCCCCCCC(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCC(=O)OCCN(C)C(=N)N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 10.66 mL (150 mmol) of acetyl chloride and 25 mL of dry DCM. The flask is charged with 35.14 g (300 mmol) of Creatinol and 150 mL of dry DCM, and cooled with an ice-water bath to about 0° C., under a nitrogen atmosphere. The acetyl chloride solution is then added slowly with stirring, over a period of 15 minutes, to the Creatinol solution. The solution is stirred for another 10 minutes, after which 13.36 mL (50 mmol) of Octanoic acid is added in one portion and the reaction is slowly heated to about 60° C. for about 4 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 1/3) to yield pure 2-(1-methylguanidino)ethyl octanoate.