Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=5)=[C:36]([C:49]([F:52])([F:51])[F:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:62])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:62])=[C:36]([C:49]([F:52])([F:50])[F:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methylpyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.2 g) was dissolved in dichloromethane (50 ml), and to the solution was added 3-chloroperbenzoic acid (0.69 g) under ice-cooling and the mixture was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1 g) as pale brown oil.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C([O-])(=O)C.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[NH:14][C:15]1[C:16]2[CH:23]=[C:22]([CH:24]=O)[NH:21][C:17]=2[N:18]=[CH:19][N:20]=1>O.CO>[CH3:2][O:3][N:4]=[CH:24][C:22]1[NH:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([NH:14][C:13]3[CH:26]=[CH:27][CH:28]=[C:11]([Cl:10])[CH:12]=3)[C:16]=2[CH:23]=1
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 4 h

Procedure:
69.3 mg (0.83 mmol) of O-methylhydroxylamine hydrochloride and 69.3 mg (0.845 mmol) of sodium acetate in 1 ml of water are added to 163.3 mg (0.5 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage1.6) in 1 ml of methanol. The suspension is heated to boiling for 4 h, cooled and filtered, and the residue is washed with water/isopropanol and finally diethyl ether. 4-(3-Chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde O-methyl oxime is obtained; HPLC: tRet(Grad20)=11.3; TLC-Rf=0.31 (CH2Cl2/methanol 10:1) FAB-MS: (M+H)+=302.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[O:11][CH2:12][CH2:13][O:14]C1CCCCO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccccc2OCCOC2CCCCO2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OCCOc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of 2-[2-(2-benzyloxyphenoxy)ethoxy]tetrahydropyran (4.90 g) in tetrahydrofuran (25 ml) and methanol (25 ml) was added 6N hydrochloric acid (15 ml), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give 2-(2-benzyloxyphenoxy)ethanol (3.07 g, yield 84%).
Reaction SMILES: O[CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].P(Br)(Br)[Br:18]>C(OCC)C>[CH2:2]([Br:18])[CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCBr
Yield: 216.5 %

Procedure:
A solution of 2.00 g (9.0 mmol) of (E,E)-farnesol in 20 ml of dry diethyl ether at 0° C. under argon in the dark was treated dropwise with a solution of 735 μl (4.0 mmol, 0.45 eq.) of PBr3 in 4 ml of dry diethyl ether. The resultant mixture was stirred at 0° C. for one hour, then quenched with H2O and separated. The organic phase was washed with 15 ml of NaHCO3, 15 ml of H2O, and 15 ml of brine, dried over MgSO4 and evaporated to provide 2.47 g of crude farnesyl bromide as a clear oil.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[CH:8][N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][NH:1][C:28](=[O:30])[CH3:29])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: CC(=O)Cl
Reactant: NOCCCCn1cnc2c(N)nc3c(c21)CCCC3
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NOCCCCn1cnc2c(N)nc3c(c21)CCCC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the 1-[4-(aminooxy)butyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine from Part C (200 mg, 0.73 mmol) and triethylamine (512 μL, 3.56 mmol) in pyridine (25 mL) was added acetyl chloride (57 μL, 0.80 mmol). The solution was stirred for 30 minutes at ambient temperature, and additional acetyl chloride (1 equivalent) was added. After 1 hour, water was added and the mixture was extracted with dichloromethane (2×). The aqueous layer was concentrated under reduced pressure to yield a white solid that was purified by chromatography (silica gel, gradient elution with 0-10% methanol in dichloromethane with a small amount of concentrated ammonium hydroxide added) to provide 30 mg of N-[4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]acetamide as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:19]2[C:7]([CH2:8][C:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[CH2:18]2)=[C:6]([C:20]([O:22][CH3:23])=[O:21])[C:5]=1[C:24]([O:26][CH3:27])=[O:25].I[CH3:29].CO>CN(C=O)C>[CH3:3][C:4]1[N:19]2[C:7]([CH2:8][C:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]([CH3:29])[C:10]=3[CH2:18]2)=[C:6]([C:20]([O:22][CH3:23])=[O:21])[C:5]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CI
Reactant: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1[nH]c3ccccc3c1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1c(c3ccccc3n1C)C2
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (0.63 g, 26.5 mmol) in dry DMF (150 ml) was added portionwise dimethyl 3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate (6 g, 17.7 mmol) at 0° C. to 5° C. After being stirred for 15 min, iodomethane (2.5 g, 17.7 mmol) was added and the reaction mixture and was stirred for additional 1 h in an ice bath. After being stirred at room temperature for 9 h, methanol was added into the reaction mixture and then evaporated to dryness in vacuo. The residue was recrystallized from MeOH to give dimethyl 3,6-dimethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate, 5.8 g (94%); mp 240-241° C. 1H NMR (DMSO-d6) δ 2.45 (3H, s, Me), 3.73 (6H, s, COOMe and Me), 3.74 (3H, s, COOMe), 4.16 (2H, t, J=3.4 Hz, CH2), 5.27 (2H, t, J=3.4 Hz, CH2), 7.05-7.09 (1H, m, ArH), 7.17-7.21 (1H, m, ArH), 7.48 (1H, d, J=8.2 Hz, ArH), 7.53 (1H, d, J=7.8 Hz, ArH). Anal. Calcd for (C20H20N2O4): C, 68.17; H, 5.72; N, 7.95. Found: C, 67.79; H, 5.73; N, 7.84.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:2]1
Reactant: C1CCNC1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCc1c[nH]c2ccccc12)N1CCCC1

Procedure:
681 mg (3.60 mmol) 3-(1H-indol-3-yl)-propionic acid, 0.3 mL (3.60 mmol) pyrrolidine, 1.13 g (3.50 mmol) TBTU and 0.98 mL (7.00 mmol) triethylamine in 5.0 mL DMF were stirred overnight at RT. The mixture was purified by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: Br.Br[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].C(=O)([O-])[O-].[Na+].[Na+].[C:20]1(OB(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.OO>C(O)C.C1(C)C=CC=CC=1>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(CCN)cc1Br
Reactant: OB(O)Oc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(CCN)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tetrakis triphenylphosphine palladium (7 g), 3-bromo-4-methoxyphenethylamine hydrobromide (62.2 g) and toluene (400 ml) was stirred under nitrogen with 2M aqueous sodium carbonate solution (200 ml) and then a solution of phenyl boric acid (26.8 g) in ethanol (100 ml) was added. The mixture was heated under reflux for 48 hours then cooled and treated with 30% aqueous hydrogen peroxide solution (10 ml). The mixture was stirred at ambient temperature for 1 hour. The aqueous layer was separated and extracted with ether. The ether extracts were combined with the original organic phase. Distillation yielded 4-methoxy-3-phenylphenethylamine which was used without further purification.
Reaction SMILES: CN(C)C=[O:4].[F-].[K+].Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Cl)=[O:19]>C1(C)C=CC=CC=1>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]2[O:4][C:21]3[C:20](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18](=[O:19])[C:10]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: CN(C)C=O
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=c1c2ccccc2oc2ccc([N+](=O)[O-])cc12

Procedure:
A mixture of 900 mL of dimethyl formamide, 165 mL of toluene, 65.6 g (1.13 mol) of anhydrous potassium fluoride, and 74.6 g (0.252 mol) of (2-chloro-5-nitrophenyl)(2-chlorophenyl)methanone was stirred and heated to reflux. It was dried by distilling out 170 mL of distillate, and then heated under reflux overnight. It was cooled in an ice bath and diluted with 1 l of water and 100 mL of hexane. After 1 hr the gold-colored precipitate was collected and dissolved in 300 mL of methylene chloride. The solution, after separation of water, was dried over sodium sulfate and concentrated in vacuo. The residue was slurried in ether (cold) to leave crude 2-nitroxanthene-9-one. The ether solution was concentrated in vacuo and the residue recrystallized from methanol to give the product, 60°-64°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[NH:7].[Cl:9][C:10]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:11]=1[CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15]>>[NH2:17][CH2:16][C:13]1[C:14]([NH2:15])=[N:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:8][C:12]=1[C:11]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:10]=1[Cl:9]
Reactant: N=C(N)c1cccs1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2cccs2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=351.2 (M+H+), was prepared from thiophene-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:21]([O:23][C:24](Cl)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(Oc2ccccc2)(c2ccccc2)CC1
Product: CCOC(=O)N1CCC(Oc2ccccc2)(c2ccccc2)CC1

Procedure:
9.0 g of 1-methyl-4-phenoxy-4-phenylpiperidine are added in portions of 100 ml of chloroformic acid ethyl ester at 80° C.; severe foaming is observed during this addition. When the addition has ended, the mixture is boiled under reflux for 3 hours, excess chloroformic acid ethyl ester is distilled off in vacuo, and 120 ml of water and 15 ml of concentrated ammonia are added to resulting solid residue. This mixture is stirred thoroughly, and the precipitate is filtered off and rinsed with water. The 1-ethoxycarbonyl-4-phenoxy-4-phenylpiperidine (m.p. 117° to 118° C., from ethanol) thus obtained is boiled under reflux with a solution of 15 g of potassium hydroxide in 150 ml of n-butanol for 4 hours; after cooling, 300 ml of water are added to the solution, and the obtained mixture is extracted twice with diethyl ether. The combined organic phases are dried over sodium sulfate and concentrated. The title compound remains as a brownish oil. The hydrochloride melts at 192° C. (from ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17]C)=[O:16])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:19])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([OH:17])=[O:16])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(Br)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cn1cccc1C(=O)O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144.5 %

Procedure:
To a solution of crude methyl 1-[2-(4-bromophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (2.39 g, 2.47 mmol) in THF (30 mL) and water (20 mL) was added lithium hydroxide monohydrate (0.63 g, 15.1 mmol). The dark solution was stirred at room temperature. The outcome of the reaction was monitored by LCMS and after 1 h another portion of lithium hydroxide monohydrate (300 mg) was added to the reaction mixture. After 16 h the reaction mixture was diluted with a aqueous solution of NaOH (1M) (50 mL) then extracted with CH2Cl2 (100 mL). The pH of the aqueous fraction was adjusted to 1 with aqueous HCl (1M) and then extracted with CH2Cl2 containing 10% of propan-2-ol (3×75 mL). The organic extracts (from acidic aqueous) were combined, dried (MgSO4) and concentrated in vacuo to give crude (˜50% pure) 1-[2-(4-bromophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid as a yellow solid (1.10 g, yield 72%) The crude material was used without purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Li+].[OH-].O.Cl>[Cl-].[Na+].O.CO>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21](=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A mixture of methyl 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoate (520 mg, 1.25 mmol), LiOH (261 mg, 6.23 mmol), water (3 mL) and methanol (6 mL) was stirred at room temperature overnight. The aqueous layer was acidified with 2 N HCl to PH<1. Brine (30 mL) was added to the solution. The aqueous layer was extracted with a mixture of DCM:IPA (4:1) twice. The combined organic layers were dried over sodium sulfate, filtered and then concentrated under vacuum to give 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid as a white solid (350 mg, 70%): LC-MS m/z 404 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([CH2:22][OH:23])[N:3]=1>C(Cl)Cl>[CH:22]([C:4]1[N:3]=[C:2]([OH:1])[C:7]([C:8]([NH:10][CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=1)=[O:23]
Reactant: O=C(NCc1cccc2ccccc12)c1cnc(CO)nc1O
Solvent: ClCCl
Product: O=Cc1ncc(C(=O)NCc2cccc3ccccc23)c(O)n1

Procedure:
A mixture of step B product, 2-20-c, (2.22 g, 7.2 mmol) and Dess-Martain reagent (3.35 g, 7.9 mmol) in DCM (80 mL) was stirred at the ambient temperature for 1 h. The reaction solution was evaporated under vacuum to give a residue, which was purified by column chromatography with the eluent DCM:MeOH=60:1˜30:1 to afford the crude compound, 2-20-d, (1.84 g, 84%) as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:30])[NH:17][C:18]2[S:26][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[CH:11][CH:10]=1.[CH3:31][C:32]1([CH3:35])[CH2:34][O:33]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:30])[NH:17][C:18]2[S:26][C:21]3[CH2:22][N:23]([CH2:31][C:32]([OH:33])([CH3:35])[CH3:34])[CH2:24][CH2:25][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[CH:13][CH:14]=1
Reactant: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2
Reactant: CC1(C)CO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)CN1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Temperature: 50 °C
Yield: 19.8 %

Procedure:
A solution of compound A4 (200 mg, 0.430 mmol), 2,2-dimethyloxirane (155 mg, 2.15 mmol), and diisopropylethylamine (167 mg, 1.29 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was stirred at room temperature for 2 h and heated to 50° C. in a sealed tube for another 21 h. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 2% to 6% methanol/methylene chloride to afford compound U1 as a yellow solid (36 mg, 20%): 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.19 (s, 1H), 7.70-6.70 (m, 6H), 4.19 (s, 1H), 3.62 (s, 2H), 2.78 (bs, 4H), 2.38 (s, 2H), 1.12 (s, 6H). MS (M+H) 423.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CCOC(C)=O>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][N:11]([C:14](=[O:16])[CH3:15])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Solvent: CCOC(C)=O
Product: CC(=O)N1CCOc2ccc([N+](=O)[O-])cc21
Reaction time: 15 h

Procedure:
A solution of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.7 g, 3.89 mmol) in acetic anhydride (1.9 mL) and EtOAc (7 mL) was heater under reflux with stirring. After 15 h, the mixture was concentrated under reduced pressure to give 1-(6-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone as a yellow solid, which was carried on crude without purification: Mass Spectrum (ESI) m/e=223.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][C@@H:12]([OH:29])[CH2:13][O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])[CH3:16]>C(O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][C@@H:12]([OH:29])[CH2:13][O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:16]
Reactant: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution of methyl (2E)-3-{2-[(1R)-1-({(2R)-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]-2-hydroxypropyl}oxy)ethyl]phenyl}prop-2-enoate (127 mg, 0.28 mmol), which had been obtained in Example 1 (1f), in ethanol (2.8 mL) was added with 10% palladium-carbon (wet, 50 wt %, 63 mg), and hydrogenated under atmospheric pressure for 3 hours. The reaction solution was filtered through Celite and washed with ethanol. The solvent was distilled off under reduced pressure to give the title compound as a colorless oily substance (115 mg, yield 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].[CH:16]([O-])([O-])OC.S(=O)(=O)(O)O>CO>[C:13]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:16])=[O:8])([OH:15])=[O:14]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: COC([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Yield: 82.2 %

Procedure:
To a suspension of 3-nitrophthalic acid (211 g) and methyl orthoformate (127 g) in methanol (420 ml) was added conc. sulfuric acid (20 ml) dropwise with stirring. The reaction mixture was heated under reflux for 18 hours and concentrated to dryness. After addition of water (30 ml) to the residue, the mixture was stirred at 3-10° C. for one hour. The precipitated crystals were recrystallized from ethyl acetate-hexane to give pale yellow prisms (185 g, 82%), m.p. 166-1680° C.
Reaction SMILES: [Fe:1](Cl)(Cl)Cl.[NH4+].[P:6]([O-:14])([O:11][CH2:12][CH3:13])([S:8][CH2:9][CH3:10])=[S:7]>O>[P:6]([O-:14])([O:11][CH2:12][CH3:13])([S:8][CH2:9][CH3:10])=[S:7].[Fe+3:1].[CH2:9]([S:8][P:6]([O-:14])([O:11][CH2:12][CH3:13])=[S:7])[CH3:10].[CH2:9]([S:8][P:6]([O-:14])([O:11][CH2:12][CH3:13])=[S:7])[CH3:10]
Reactant: Cl[Fe](Cl)Cl
Agent: CCOP([O-])(=S)SCC
Agent: [NH4+]
Solvent: O
Product: [Fe+3]

Procedure:
A 0.12M solution was prepared by dissolving 11.2 g in 500 ml of water. This dissolution was rapid and formed a colourless clear solution. The iron (III) chloride and the diethyl dithiophosphate ammonium salt reacted to produce iron (III) diethyl dithiophosphate. FIG. 9 shows the molecular structure of the iron (III) diethyl dithiophosphate and the mass spectrum of iron (III) diethyl dithiophosphate produced here.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([SH:8])([CH3:7])[CH3:6].Br[CH2:13][CH2:14][CH2:15][OH:16].Cl>C(O)C>[NH2:3][C@H:4]([C:5]([S:8][CH2:13][CH2:14][CH2:15][OH:16])([CH3:7])[CH3:6])[C:9]([OH:11])=[O:10]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: OCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(SCCCO)[C@@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2N sodium hydroxide (11.3 mL, 22.7 mmol) was added to D-(−)-penicillamine (2.5 g, 16.8 mmol) at 0° C. Once all the solid was dissolved, a solution of 3-bromopropanol (3.03 g, 21.8 mmol) in ethanol (17 mL) was slowly added at 0° C. and the resulting mixture was stirred for 15 h at room temperature. The mixture was treated with 1N hydrochloric acid until pH is ˜6 and the solvents were removed to obtain (2S)-2-amino-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoic acid as a white solid. This solid was used for the next step without further purification; Electrospray Mass Spec 208.1 (M+H)+.