Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH:7]=O)[CH:4]=[C:3]([CH:9]=O)[CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].[BH4-].[Na+].[OH-:35].[Na+]>CO>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH2:7][NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH:4]=[C:3]([CH2:9][NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:35][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCNCCCN
Reactant: [OH-]
Reactant: O=Cc1cc(C=O)cc(-c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCNCCCNCc1cc(CNCCCNCCCNC(=O)OC(C)(C)C)cc(-c2ccccc2)c1
Reaction time: 24 h

Procedure:
[1,1′-Biphenyl]-3,5-dicarbaldehyde (3.62 g, 17.24 mmol) and MeOH (100 mL) were added to a round-bottom flask. To the solution was added tert-butyl (3-((3-aminopropyl)amino)propyl)carbamate (7.96 g, 34.4 mmol), and the reaction mixture was stirred for 24 h. Sodium borohydride (2.62 g, 69.0 mmol) was added, and the mixture was stirred for 1 h. The solvent was removed under reduced pressure to afford a white solid. Aqueous NaOH (10%, 200 mL) was added, and the solution was extracted with EtOAc (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (200 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product as a clear oil that was used without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:24]([CH3:26])[CH3:25])[C:18](=[O:27])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:24]([CH3:25])[CH3:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1
Reactant: COC(=O)Cl
Reactant: CC(C)N1C(=O)Cc2cc(N3CC(CN)OC3=O)cc(F)c21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3C(C)C)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.097 ml, 1.26 mmol) is added dropwise to 5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-7-fluoro-1-isopropyl-1,3-dihydro-indol-2-one (21, 0.355 g, 0.842 mmol) and diisopropylethylamine (0.616 ml, 3.37 mmol) in dichloromethane (4 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried (Na2SO4) and evaporated. The residue is purified to give the title compound as a solid. HPLC r.t. 4.42 min; 1H NMR (300 MHz, CDCl3) δ7.33 (d, J=1.2 Hz, 1H), 7.24 (dd, J=2.1, 14 Hz, 1H), 5.14 (br s, 1H), 4.80-4.92 (m, 1H), 4.75-4.84 (m, 1H), 4.05 (t, J=8.7 Hz, 1H), 3.81 (dd, J=6.6, 9 Hz, 1H), 3.71 (s, 3H), 3.57 (s, 2H), 3.52-3.65 (m, 2H), 1.44 (d, J=6.9 Hz, 6H); MS for C17H20FN3O5 m/z 366 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][OH:12])([O-:3])=[O:2].C(N(CC)CC)C.O=C(Cl)[O:23][C:24](Cl)(Cl)[Cl:25]>O1CCCC1>[Cl:25][C:24]([O:12][CH2:11][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:13])=[O:23]
Reactant: CC(CO)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 130 %

Procedure:
A solution of 2-(2-nitrophenyl)propanol (16.12 g, 89 mmol) and triethylamine (12.4 mL, 89 mmol) in anhydrous tetrahydrofuran (THF) (96 mL) was added to a cold solution (0° C.) of diphosgene (10.7 mL, 89 mmol) in anhydrous THF (40 mL) over a period of 15 min with stirring and under nitrogen. After 30 min the cooling bath was removed and stirring was continued at room temperature for 3 h. The mixture was filtered and washed with THF. The solvent was removed in vacuo to give 28.20 g of 2-(2-nitrophenyl)propyl chloroformate as light brown oil that was directly used for the next reaction step. TLC: 20% ethyl acetate in hexanes, Rf=0.66.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH3:11][O:10][C:9]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: CCCCCBr
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1c(C=O)cccc1OC
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Hydroxy-3-methoxybenzaldehyde (3.00 g, 19.7 mmol) and DMF (25 ml) were mixed, and potassium carbonate (3.00 g, 22.0 mmol) and bromopentane (2.73 ml, 22.0 mmol) were successively added to this solution. The reaction mixture was stirred at 100° C. for 2 hours and the obtained solid was filtered. Water (20 ml) and ethyl acetate (50 ml) were added for separation. The aqueous layer was extracted twice with ethyl acetate (25 ml). The organic layers were combined, washed twice with saturated brine (20 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 3-methoxy-2-pentyloxybenzaldehyde. (2) THF (30 ml) and methyl (triphenylphosphoranilidene)acetate (7.36 g, 22.0 mmol) were added to the above-mentioned compound. The mixture was re iuxed under heating for 5.5 hours and THF was evaporated under reduced pressure. Hexane (100 ml) was added to the obtained residue, and the precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure. To the obtained residue were added ethanol (40 ml) and a 1N aqueous sodium hydroxide solution (40 ml). The mixture was refluxed under heating for 1 hour. After removing ethanol by evaporation under reduced pressure, concentrated hydrochloric acid was added to make the aqueous layer acidic. The aqueous layer was extracted twice with ethyl acetate (70 ml). The organic layers were combined, washed 3 times with saturated brine (40 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate to give 3- (3-methoxy-2-pentyloxyphenyl)cinnamic acid (3.82 g, 73% in 3 steps) as colorless needles.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:8]CC2C=CC(OC)=CC=2)[CH:7]=1.N[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.Br[C:33]1[CH:38]=C(OCC2C=CC(OC)=CC=2)C=C(Br)[CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1>[NH:29]1[C:28]2[C:26](=[C:34]([C:2]3[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH:18][C:19]4[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=4)[CH:3]=3)[CH:33]=[CH:38][CH:27]=2)[CH:31]=[CH:30]1
Reactant: Nc1ccncc1
Reactant: COc1ccc(COc2cc(Br)cc(Br)c2)cc1
Reactant: COc1ccc(COc2cc(Br)cc(Nc3ccncc3)c2)cc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cc(Nc2ccncc2)cc(-c2cccc3[nH]ccc23)c1
Temperature: 110 °C

Procedure:
[3-Bromo-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-4-yl-amine. A solution of 4-aminopyridine (71 mg, 0.75 mmol), 1,3-dibromo-5-(4-methoxybenzyloxy)benzene (372.0 mg, 1.0 mmol), XantPhos (56 mg, 0.1 mmol), (dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), and sodium tert-butoxide (192 mg, 2.0 mmol) in dioxane (3 mL) was flushed with nitrogen and the reaction tube was sealed. The reaction mixture was heated to 110° C. for 16 h. After cooling, the reaction mixture was filtered through a short pad of Celite®, and the filtrate was concentrated. The residue was purified by silica gel column chromatography using 5% MeOH in methylene chloride to give a major fraction as a desired product which crystallized from a mixed solution of MeOH/methylene chloride. The crystals were filtered and washed with methanol to give 115 mg of pure 3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-4-yl-amine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][C:9]=2[NH2:10])[CH2:3][CH2:2]1.[CH:24](=O)[CH3:25].OOS([O-])=O.[K+].[C:33](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:24][C:25]1[N:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[C:8]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][C:17]4[CH:23]=[CH:22][CH:21]=[C:20]([CH3:33])[C:18]=4[N:19]=3)=[CH:11][C:9]=2[N:10]=1
Reactant: CC=O
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2oc(-c3ccc4c(c3)nc(C)n4C3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
To a solution of 2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 46-2) (0.56 g, 1.7 mmol) in dimethylformamide (5 mL) containing water (0.18 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 90 mg, 1.8 mmol) and oxone (0.69 mg, 1.1 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (123 mg, 20.4% yield) as light brown crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.N1C=CC=CC=1.O>O1CCOCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]2=[O:1])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccnc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=c1c([N+](=O)[O-])cccn1-c1ccc(F)cc1
Temperature: 80 °C
Yield: 86.8 %

Procedure:
(1a-1) To a solution of 2-hydroxy-3-nitropyridine (Aldrich, 3.0 mmol, 420 mg) in 1,4-dioxane (20 mL), were added 4-fluorophenyl boronic acid (Combi-block, 6.0 mmol, 840 mg), copper(II) acetate (Aldrich, 4.5 mmol, 815 mg) and pyridine (2 mL). The reaction was heated at 80° C. for 20 h. After cooling to room temperature, 30 mL of cold water was added. The solid formed was collected by filtration, washed with ammonium hydroxide and water, and dried under vacuum to give 1-(4-fluorophenyl)-3-nitropyridin-2(1H)-one (610 mg, 87% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[C:18](OC(Cl)(Cl)Cl)=[O:19]>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1)=[C:18]=[O:19]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)CSc1cccc(N)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CSc1cccc(N=C=O)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
tert-Butyl (3-isocyanatophenylthio)acetate can be obtained in the following manner: a solution of 2.9 g of tert-butyl (3-aminophenylthio)acetate in 25 cm3 of toluene is added dropwise, at a temperature near to -30° C., to a suspension of 0.24 g of carbon in 1.46 cm3 of trichloromethyl chloroformate and 15 cm3 of toluene. The reaction mixture is stirred for 2 hours at a temperature near to 20° C. and then for 2 hours and 30 minutes at a temperature near to 110° C. The reaction mixture is then cooled to a temperature near to 20° C., degassed by bubbling nitrogen in, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 50° C. 2.6 g of tert-butyl (3-isocyanatophenylthio)acetate are thus obtained in the form of an oil which is used as such in the subsequent syntheses.
Reaction SMILES: [Li+].CCC[CH2-].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.CCCCCC>CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([B:18]([OH:19])[OH:17])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc(Br)c1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-Butyllithium (2.5M; 44 mL; 0.11M) was added dropwise over 15 mins. to a vigorously stirred solution of m-dibromobenzene (25 g; 0.106M) in 500 mL of anhydrous ether at -78° under nitrogen. After stirring 10 mins. more, a solution of triisopropylborate (25.3 mL; 0.11M) in anhydrous ether (200 mL) was added over 20 mins. The cooling bath was then removed, and the stirring solution was allowed to warm to R.T. over ~2 hrs. A small amount of solid separated. After stirring 15 mins. more at R.T., 150 mL of ice cold 8% aqueous hydrochloric acid was cautiously added, and the stirring was continued for 15 mins. The organic phase was separated, washed with 2×100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Solvent removal gave -30G of crude product as a semi-solid, which was shaken well with 150 mL of hexane. The solid was filtered and washed with 2×25 mL of hexane. The resulting silky solid (mp 178°-9° C. after softening at ~160° C.) (6.5 g) was used as 3-bromophenylboronic acid with a small amount of contamination. The hexane filtrate was concentrated and the residue was stirred well with 150 mL of petroleum ether (30°-60°). The resulting solid was filtered and washed with 2×25 mL of petroleum ether. This resulting solid (4.4 g) melting at 178.3°-179° C. was the desired 3-bromophenylboronic acid.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:13])=[CH:6][C:7]=2[N:12]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 8 h

Procedure:
To 3,4-diamino-benzoic acid ethyl ester (4.0 g, 22.2 mmol) in 100 mL dichloromethane was added 1,3-dichloro-2-isothiocyanato-benzene (4.5 g, 22 mmol) in 50 mL dichloromethane. After stirring overnight and refluxing for another 6 hrs, the solvent was evaporated. After adding 200 mL dichloromethane, triethylamine (7 mL, 50 mmol) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) have been added, methanesulfonyl chloride (1.7 mL, 22 mmol) in 50 mL dichloromethane was added to the reaction mixture. After stirring for 2 h, another portion of methanesulfonyl chloride (1.7 mL, 22 mmol) was added. After stirring at room temperature overnight, the solvent was evaporated. The residue was mixed with 150 mL methanol and 40 mL 4N NaOH (aq), stirred over night, another 20 mL 4N NaOH (aq) added and refluxed for 2 h. The solvent was removed, the residue mixed with water and methanol and the mixture neutralized with 4 N HCl (aq). The mixture was filtered, washed with water and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCC(NC(=O)c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Amino-3-Fluorobenzoic acid (Fluorochem; 1 g, 6.44 mmol), 4-Amino-1-methylpiperidine (Fluorochem; 811 mg, 7.09 mmol), HATU (2.70 g, 7.09 mmol), DIPEA (3.4 mL, 19.32 mmol) and DMF (15 mL) were combined and stirred for 18 hrs at room temperature. The solvent was evaporated and the resultant material dissolved in DCM (with a little MeOH to aid solubility) and chromatographed on silica eluting with a gradient of 0-10% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to give an orange solid which was dissolved in MeOH and added to a 50 g SCX-2 column pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated to yield the title compound as a beige solid. (1.72 g, 100%)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16]Br)[CH:3]=1.C(N(CC)CC)C.Cl.[C:26]([O:30][C:31](=[O:34])[CH2:32][NH2:33])([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[C:26]([O:30][C:31](=[O:34])[CH2:32][NH:33][CH2:16][C:4]1[CH:3]=[C:2]([Br:1])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nc2cc(Br)cc(CNCC(=O)OC(C)(C)C)c2nc1OC

Procedure:
850 mg (2.35 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxy-quinoxaline, 0.982 ml of triethylamine and 719 mg of glycine tert-butyl ester hydrochloride are dissolved in 15 ml of acetonitrile and the solution is stirred at reflux for 18 hours. The mixture is concentrated by evaporation and the residue is dissolved in diethyl ether and washed with aqueous 5% sodium carbonate solution and brine. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate and petroleum ether (1:2). The title compound is obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.[CH3:66][C:67]1([C:85](O)=[O:86])[CH2:72][O:71]C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:69][CH2:68]1.S(=O)(=O)(O)O.O>C1COCC1>[CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([O:55][C:68]([C:67]([CH2:85][OH:86])([CH2:72][OH:71])[CH3:66])=[O:69])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Reactant: CC1(C(=O)O)COC(c2ccccc2)(c2ccccc2)OC1
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Temperature: 2.5 °C
Reaction time: 24 h

Procedure:
(189 mg) of 31-trimethyl silyl-42-ester of rapamycin with 5-methyl-2,2-diphenyl-1,3-dioxane-5-carboxylic acid [IId10] was dissolved in 2.8 ml THF and cooled to 0-5° C. Into the reaction mass 0.52 ml 2N sulphuric acid was added and stirred at 25-30° C. for 24 hrs. Then 2 ml THF and 0.52 ml 2 N sulphuric acid was added and stirred at 25-30° C. for 76 hrs. It was then concentrated on rotavapour, residue was dissolved in 2 ml ethyl acetate, and 2-3 drop perchloric acid (HClO4) diluted with 1 ml water was added. The reaction mixture was stirred at 25-30° C. for 24 hrs and reaction mass was dumped into water, and extracted with ethyl acetate. The layers were separated and washed the organic layer with 10% sodium bicarbonate solution and then water. It was dried over sodium sulfate, concentrated on rotavapor to obtain yellow colored oily compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([O:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([CH3:36])[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([O:11][CH2:12][CH2:13][N:7]4[C@H:6]4[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]34)[CH:10]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCO3
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CCO3)c(C)c1
Yield: 73.3 %

Procedure:
Tert-butyl(6bR,10aS)-5-(4-methoxy-2-methylphenyl)-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate (0.16 g, 73%) was prepared by the general method of Example 89, step C from tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate (0.20 g, 0.50 mmol), 4-methoxy-2-methylphenyl boronic acid (0.17 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 437 (base, M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:2]1.C1C(=O)N([Br:23])C(=O)C1.CCN(C(C)C)C(C)C.[CH3:33][C:34]([O:37][C:38]([O:40]C(OC(C)(C)C)=O)=O)([CH3:36])[CH3:35]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:23][C:2]1[N:1]([C:38]([O:37][C:34]([CH3:36])([CH3:35])[CH3:33])=[O:40])[C:9]2[C:4]([C:3]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccccc12
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
Ethyl 2-(1H-indol-3-yl)acetate (15 g, 73.9 mmol) was dissolved in DCM (750 mL). At ambient temperature, NBS (13.15 g, 73.9 mmol) was added to the reaction mixture in 5 portions approximately 2 minutes apart. After the last addition of NBS, iPr2NEt (28 mL, 162 mmol) was added slowly to the reaction mixture and stirred for 5 minutes. Boc2O (33.8 g, 155 mmol) was added followed by DMAP (900 mg). After stirring at 16 h, the reaction was partitioned between DCM and H2O. The organics were washed with aqueous 1N HCl and dried over sodium sulfate. After removal of solvent, the crude product was purified by silica gel chromatography to provide tert-butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (16.3 g, 58%). MS (m/z) 382 [M+H]+.