Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N#N.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOCC>[Si:10]([O:9][CH2:8][C:4]1[N:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[CH:6][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCOCC2)n1
Temperature: 70 °C
Yield: 72.3 %

Procedure:
A solution of 2-bromo-6-(tert-butyldimethylsilanyloxymethyl)pyridine (J. Org. Chem.; 1993; 4389-4397) (500 mg, 1.66 mmol), morpholine (173 μl, 2.0 mmol), 1,3-bis(diphenylphosphino)propane (68 mg, 10 mol %) in toluene (20 ml) was degassed with a stream of N2 for 15 min. Sodium tert-butoxide (222 mg, 2.31 mmol) and Pd2(dba)3 (76 mg, 5 mol %) were added and the reaction mixture was heated at 70° C. overnight under N2. After cooling to room temperature, Et2O (100 ml) was added and the solution was washed with brine (25 ml), dried and concentrated under reduced. The mixture was purified by column chromatography on silica using 30% Et2O/iso-hexanes as eluent to yield the desired aminopyridine (370 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 7.40 (1H, dd, J=8.6, 7.4 Hz), 6.75 (1H, d, J=7.4 Hz), 6.38 (1H, d, J=8.6 Hz), 4.56 (2H, s), 3.70 (4H, t, J=5.0 Hz), 3.36 (4H, t, J=5.0 Hz), 0.84 (9H, s), 0.00 (6H, s). m/z (ES+) 309 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][OH:22])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Br[CH2:28][C:29]1[CH:30]=[C:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:28][C:29]3[CH:30]=[C:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:19][CH2:20][CH2:21][OH:22])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COC(=O)Cc1cccc(CBr)c1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCO)Cc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product from step (vii) (2 g), methyl 2-(3-(bromomethyl)phenyl)acetate (1.4 g) and potassium carbonate (2.1 g) in DMF (20 mL) was stirred at rt under nitrogen for 24 h. The mixture was partitioned between DCM/water, the organics separated, washed with water, dried, and evaporated under reduced pressure. The residue was purified by chromotography on silica eluting with DCM/MeOH/Et3N (1000/50/3). Yield 2.43 g of solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[N:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[C:5]=1O)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]2[S:10][CH:11]=[CH:12][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2sccc2c1O
Product: O=[N+]([O-])c1cnc2sccc2c1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To 5-nitrothieno[2,3-b]pyridin-4-ol (607.9 mg, 3.099 mmol), POCl3 (6.00 mL) was added, then the mixture was stirred at 110° C. for 1 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in DCM (50 mL), and a saturated aq. NaHCO3 (50 mL) was added slowly. The organic layer was washed with water (50 mL) and brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 to 50% EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (605.3 mg, 91%). LCMS calc. for C7H4ClN2O2S (M+H)+: m/z=215.0. found 215.0.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.S(Cl)(Cl)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([NH:21][C:6]([C:5]1[S:1][C:2]2[CH2:12][CH2:11][CH2:10][CH2:9][C:3]=2[CH:4]=1)=[O:8])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)c1cc2c(s1)CCCC2
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NC(=O)c1cc2c(s1)CCCC2
Yield: 88.9 %

Procedure:
A mixture of 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (500 g, 2.75 mol, 1.0 equiv) and thionyl chloride (655 g, 5.5 mol, 2.0 equiv) was boiled under reflux for 3 h. Excess thionyl chloride was removed by distillation under reduced pressure. The residue was taken up in dichloromethane (1.0 L) and a solution of tert-butylamine (402 g, 5.5 mol, 2.0 equiv) in dichloromethane (500 mL) was added with stirring while the temperature of the mixture was kept below 10° C. The resulting solution was stirred at 25° C. for 16 h. Most of the solvent was removed under reduced pressure. The residue was chilled in an ice-bath and 2M KOH solution was introduced slowly to adjust the pH to 11 with stirring. The suspension was filtered and the solid was collected, washed three times with water, and dried in vacuo to afford 117a as a white solid (580 g, 80%, over two steps). MS: [M+H]+ 238. 1H NMR (500 MHz, CDCl3) δ 7.02 (s, 1H), 5.77 (s, 1H), 2.65 (t, J=6.0 Hz, 1H), 2.47 (t, J=6.0 Hz, 1H), 1.74-1.70 (m, 4H), 1.35 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([C:22]1[N:23]=[CH:24][N:25](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:26]=1)=[O:21])[CH:14]=[CH:13]2>>[NH:25]1[CH:26]=[C:22]([C:20]([C:15]2[CH:14]=[CH:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH:16]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:21])[N:23]=[CH:24]1
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: Brc1ccccc1
Product: COc1ccc2cc(C(O)(c3ccccc3)c3c[nH]cn3)ccc2c1

Procedure:
In a similar manner to that described in Example 6-(i), the reaction of bromo benzene (0.85 ml) with (6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) was carried out. The reaction mixture was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=3:1→2:1) to give the titled compound (0.98 g) as a pale yellow powder.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:18]([Cl:19])=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][C:10]=1[Cl:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C:9]1[C:10]([Cl:20])=[CH:11][C:12]([CH2:13][OH:14])=[CH:17][C:18]=1[Cl:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1c(Cl)cc(CO)cc1Cl
Temperature: 25 °C
Yield: 25.9 %

Procedure:
To a stirred and cooled (0° C.) solution of 7.70 g (23.0 mmol) of the product of Step A dissolved in 50 mL of anhydrous THF was added 23.0 mL (23.0 mmol) of a 1M solution of lithium aluminum hydride in THF. After the addition was complete the reaction mixture was allowed to warm to room temperature and stirred 3.5 hours. The stirred reaction was then quenched by dropwise addition of 0.88 mL water, then 0.88 mL of 15% NaOH, and finally 2.62 mL water. The reaction mixture was then filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1N HCl, sturated NaHCO3, dried (MgSO4), and evaporated in vacuo to afford 1.83 g (26%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=Cc1ccc(Cl)cc1F
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cc(Cl)ccc2C=O)C1

Procedure:
The title compound was prepared from 4-chloro-2-fluoro-benzaldehyde and (R)-tert-butyl pyrrolidin-3-ylcarbamate as described in Example 70, Step 1 (30.0 mg, 81%). 1H NMR 400 MHz (CDCl3) δ 9.98 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 6.89-6.79 (m, 2H), 4.77 (s, 1H), 3.57 (dd, J=10.7, 6.0 Hz, 2H), 3.34 (s, 1H), 3.25-3.18 (m, 1H), 2.28 (td, J=12.9, 7.0 Hz, 1H), 2.00 (td, J=12.5, 6.4 Hz, 2H), 1.46 (s, 9H). LCMS (ESI, an/z): 325 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:5]1=2.[ClH:25].C1C2C3C=CC=CC=3N(CC(O)=O)C=2CCNC1>>[ClH:25].[CH2:13]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]([CH2:3][CH2:2][OH:1])[C:5]=2[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Agent: Cl
Agent: O=C(O)Cn1c2c(c3ccccc31)CCNCC2
Product: OCCn1c2c(c3ccccc31)CCNCC2
Yield: 48 %

Procedure:
2-(2,3,4,5-Tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanol hydrochloride was prepared from tert-butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate by the procedure used to prepare 2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-ylacetic acid hydrochloride in 48% yield. 1H NMR (300 MHz, CDCl3) δ 3.22, 3.37, 3.44-3.52, 3.80, 4.30, 7.07, 7.15, 7.37, 7.48; MS (ESI+) for C14H18N2O m/z 231.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][CH2:9][O:8]1.[OH-].[Na+]>O.CO>[O:8]1[CH2:9][CH2:10][CH2:11][O:12][CH:7]1[CH2:6][CH2:5][CH2:4][C:3]([OH:13])=[O:2]
Reactant: COC(=O)CCCC1OCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCC1OCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[1,3]Dioxan-2-yl-butyric acid methyl ester (6.8 g, 0.036 mol) was added to a stirred solution of sodium hydroxide (1.87 g, 0.047 mol) in water (30 ml) and methanol (30 ml). The mixture was stirred for 18 h at room temperature and then the solvent evaporated. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml) and cooled to 0° C. The mixture was acidified with hydrochloric acid (1M) to pH 2 and the layers separated. The aqueous layer was further extracted with cold ethyl acetate (100 ml) and the combined organic layers washed with brine (100 ml) and then dried (Na2SO4). The solvents were evaporated and the crude solid (5.56 g) was used in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:21][OH:22].C(=O)([O-])O.[Na+]>C(O)C>[OH:22][NH:21][C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][C:6]([S:9](=[O:10])(=[O:11])[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:5][CH:4]=1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1NS(=O)(=O)c1ccc(C(=N)NO)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of 4-cyano-N-o-tolyl-benzenesulfonamide (214 mg, 0.629 mmol) in ethanol (3 mL), hydroxylamine hydrochloride (437 mg, 6.29 mmol) and sodium hydrogen carbonate (528 mg, 6.29 mmol) were added and the resulting suspension was stirred at 60° C. for 18 hrs. Subsequently the reaction mixture was filtered. The precipitate was washed with ethanol and the combined eluents were evaporated under reduced pressure. The residue was dried under high vacuum (45° C., 3 hrs) to give N-hydroxy-4-o-tolylsulfamoyl-benzamidine (345 mg, 0.56 mmol, 89% crude yield, purity 49.6%) as beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][Si:10]([CH3:14])([CH3:13])[C:11]#[CH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.C1CCCCC1.[Cu]I.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>[CH3:9][Si:10]([C:11]#[C:12][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1)([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: Oc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cncc(O)c1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 2.0 g (11.6 mmol) 5-bromo-3-hydroxy-pyridine and 2.3 mL (16.2 mmol) 1-trimethylsilyl-ethyne to using 66 mg (0.3 mmol) CuI, 303 mg (1.2 mmol) triphenylphosphine, 243 mg (0.3 mmol) PdCl2(PPh3)2 and 19 mL (139 mmol) triethylamine in 20 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate and small amounts of cyclohexane, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a DCM/MeOH gradient. Yield: 2.0 g (91%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH2:16].N1C=CC=CC=1>CO>[NH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: NCCCN
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])cnc1NCCCN

Procedure:
2-Chloro-3-methyl-5-nitropyridine (15.5 g), 1,3-diaminopropane (30 ml) and pyridine (10 ml) were stirred together and, after the initial exotherm had subsided, the mixture was heated under reflux for 1.5 hr. On cooling the mixture was treated with methanol and the bulk of crystalline bi-product filtered off. The solution was stripped, the residue taken up in water and the pH adjusted to 6.5 with hydrochloric acid. After filtering through `Hyflo` the solution was extracted with chloroform. The pH was raised to 14, (NaOH) and extracted with ether. After drying (K2CO3), the ether extracts were stripped to give a yellow solid which was triturated with ether/pentane to give 2-(3-aminopropylamino)-3-methyl-5-nitropyridine, (12.9 g; 68%) m.p. 93°-95° C.
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Cl:5])/[Cl:3].Cl.[C:11]([NH:15][NH2:16])([CH3:14])([CH3:13])[CH3:12]>CO>[C:11]([N:15]1[C:6](=[O:7])[C:4]([Cl:5])=[C:2]([Cl:3])[CH:1]=[N:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NN
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Agent: Cl
Solvent: CO
Product: CC(C)(C)n1ncc(Cl)c(Cl)c1=O

Procedure:
A solution of mucochloric acid (33.8 g, 200 mmol) and tert.-butylhydrazine hydrochloride (24.9 g, 200 mmol) in methanol (400 mL) was stirred at reflux overnight. Methanol was removed in vacuo and the residue was partitioned between ether and water. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 100% hexanes). Product-containing fractions were combined and the title compound was crystallized from ether/hexanes (yield: 10.0 g, 22.6%). mp 63-64° C. 1H NMR (300 MHz, CDCl3) δ 1.65 (s, 9H), 7.73 (s, 1H). MS (DCI/NH3) m/z 221 (M+H)+, 238 (M+NH4)+.
Reaction SMILES: [CH:1]([N:4]=[C:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH:5]([N:4]1[C:1]([CH3:3])=[CH:2][CH:18]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]1=[O:10])([CH3:7])[CH3:6]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)=NC(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Temperature: 185 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
A mixture of isopropyl(1-methylethylidene)amine (7.94 g, 80.0 mmol, prepared according to Newcomb, Martin et al., J. Amer. Chem. Soc., 1990, 112, 5186) and diethyl (ethoxymethylene)malonate (17.31 g, 80.0 mmol) in diphenyl ether (48 mL) was stirred in a sealed tube at 180-190° C. for 18 h. After cooling, the mixture was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=1/1˜1/2) to give 12.5 g (70%) of the title compound as brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([CH3:21])([CH3:20])[CH3:19])=[NH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32]>>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:10][P:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)P(Cl)C(C)C
Reactant: CC(C)(C)c1ccc(C(=N)Nc2ccccc2C(C)(C)C)cc1
Agent: [Li]CCCC
Product: CC(C)P(N=C(Nc1ccccc1C(C)(C)C)c1ccc(C(C)(C)C)cc1)C(C)C

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.54 g of 4-tert-butyl-N1-(2-tert-butylphenyl)benzamidine (Amidine VII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow semi-solid was isolated (1.9 g, 100%).
Reaction SMILES: C([O-])=O.[NH4+:4].[OH:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([C:16](=O)[C:17]([OH:19])=[O:18])([CH2:9]3)[CH2:7]1)[CH2:13]2.[OH-].[NH4+]>SC[C@H]([C@@H](CS)O)O>[NH2:4][C@@H:16]([C:8]12[CH2:14][CH:12]3[CH2:11][CH:10]([CH2:15][C:6]([OH:5])([CH2:13]3)[CH2:7]1)[CH2:9]2)[C:17]([OH:19])=[O:18]
Reactant: [NH4+]
Reactant: O=C(O)C(=O)C12CC3CC(CC(O)(C3)C1)C2
Agent: O=C[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [OH-]
Product: N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 105.5 %

Procedure:
A 266 ml solution was prepared containing ammonium formate (16.74 g, 0.2654 moles) and (3-hydroxy-adamantan-1-yl)-oxo-acetic acid (29.76 g, 0.1327 moles) and brought to pH 8.0 with 12.7 ml concentrated ammonium hydroxide. AND (372 mg, 0.561 mmoles) and dithiothreitol (81.8 mg, 0.530 mmoles) were added, then the solution was added to the bottle containing the Escherichia coli extract. The bottle was maintained at 400 on a shaker at 40 rpm. Concentrated ammonium hydroxide was added periodically to maintain pH 8.0 After 38 hours, the solution contained 31.5 grams (0.140 moles, 100% yield) (S)-amino-(3-hydroxy-adamantan-1-yl)-acetic acid as measured by HPLC analysis and no R-enantiomer of the amino acid.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:25]([O:32][C:33](=[O:44])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:43])[C@H:40]([CH3:42])[NH2:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:25]([O:32][C:33](=[O:44])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:43])[C@H:40]([CH3:42])[NH:41][C:3](=[O:4])[C@@H:2]1[CH2:6][CH2:7][CH2:8][NH:1]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 2.5 h

Procedure:
Ac-L-proline (3.05 g, 19.41 mmol) was dissolved in drytetrahydrofuran (100 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and an internal thermometer. The solution was cooled to -15° C. and N-methylmorpholine (2.13 ml, 19.41 mmol) was added followed by isobutylchloroformate (2.51 ml, 19.41 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Five minutes after the addition was completed, a solution of L-alanyl-L-proline benzyl ester hydrochloride (6.08 g, 19.41 mmol) in chloroform (70 ml) was added followed by a second portion of N-methylmorpholine (2.13 ml, 19.41 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. The reaction mixture was then allowed to slowly warm to room temperatureand stirred at room temperature for 2.5 hours. Thereaction mixture was concentrated to a small residue on a rotary evaporator, diluted with chloroform (500 ml) and poured into a separatory funnel where it was washed with 0.2N hydrochloric acid (3×200 ml) and 5% sodium bicarbonate (200 ml). The organic layer was dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and chromatographed using methylene chloride-methanol as an eluent to give Ac-L-prolyl-L-alanyl-L-proline benzyl ester; Rf: 0.35 (CH3OH/CH2Cl2 --7:93).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C(=O)=[O:13].C(O)(C)C.[Li]CCCC.CN(CCN(C)C)C>C1COCC1>[C:9]1([OH:13])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=C=O
Reactant: Brc1ccc2ccncc2c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Oc1nccc2ccccc12
Reaction time: 0.67 h

Procedure:
7-Bromoisoquinoline (40 mg, 0.193 mmol, 3 equiv) was dissolved in THF (1 mL, 0.19 M) and cooled down to −72° C. (dry ice-isopropanol bath), after which n-BuLi (88 μL, 2.3 M, 0.19 mmol, 3 equiv) was added dropwise. After 40 minutes, TMEDA (88 μL, 0.58 mmol, 9 equiv) was added into the solution. After 10 minutes, O-TBS-estrone (25 mg, 0.065 mmol, 1 equiv) in THF (0.3 mL, 0.22 M in THF) was added dropwise into the reaction solution. After 40 minutes, the reaction was quenched by the addition of sat. aq. NaHCO3 (5 mL). The aqueous layer was extracted four times (4×10 mL) with EtOAc, washed with sat. aq. NaCl (20 mL), dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, 30% EtOAc:hexanes) afforded isoquinolinol Compound 28 (25 mg, 74%) as a yellow foam: Rf=0.31 (1:1 EtOAc:DCM); [α]D=+16.9° (c 0.54, CH2Cl2); IR (neat) νmax=3210, 1496, 1285, 1251, 837 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.28 (s, 1H), 8.51 (d, J=4.8 Hz, 1H), 7.88 (d, J=7.8 Hz, 2H), 7.79 (d, J=8.9 Hz, 1H), 7.65 (d, J=5.6 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.55-6.50 (m, 2H), 2.87-2.73 (m, 2H), 2.59 (ddd, J=5.1, 9.8, 14.8 Hz, 1H), 2.25 (ddd, J=4.4, 12.5, 17.1 Hz, 1H), 2.10-2.00 (m, 2H), 1.96-1.91 (m, 1H), 1.79 (td, J=4.0, 11.2 Hz, 1H), 1.75-1.65 (m, 2H), 1.50 (dddd, J=2.2, 10.8, 12.7, 21.6 Hz, 1H), 1.47-1.32 (m, 1H), 1.33-1.22 (m, 2H), 1.15 (s, 3H), 0.95 (s, 9H), 0.57 (td, J=4.1, 12.8 Hz, 1H), 0.16 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 153.2, 152.8, 145.2, 142.9, 137.6, 134.6, 132.8, 130.8, 127.9, 125.9, 125.3, 125.2, 120.0, 119.8, 117.0, 86.1, 48.3, 47.4, 43.3, 39.5, 38.9, 33.7, 29.6, 27.4, 26.1, 25.7, 24.2, 18.1, 14.8; HRMS (ESI-TOF) calcd for C33H43NO2Si [M+H]+: 514.3136; found: 514.3140.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[O:21][C:20]=23)[CH:23]=1
Reactant: COc1cc(-c2cc3nccc(-c4cccc(C(=O)O)c4)c3o2)cc(OC)c1OC
Reactant: COCCN
Product: COCCNC(=O)c1cccc(-c2ccnc3cc(-c4cc(OC)c(OC)c(OC)c4)oc23)c1
Yield: 62 %

Procedure:
Starting from 3-[2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridin-7-yl]benzoic acid (0.062 mmol) and 2-methoxyethylamin (0.069 mmol) the product is prepared analogously to “A43” and obtained as colorless solid in a yield of 62%. HPLC (method A): Rt 2.53 min (purity 98.8%); LCMS (ESI+) (method E): Rt 1.78 min, M+H+ 463.2 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.84 (s, 1H), 8.79-8.72 (m, 1H), 8.60 (d, J=5.1, 1H), 8.28 (d, J=8.3, 1H), 8.03 (d, J=7.9, 1H), 7.78 (s, 1H), 7.75-7.70 (m, 2H), 7.35 (d, J=16.3, 2H), 3.93 (s, 6H), 3.74 (s, 3H), 3.54-3.43 (m, 4H), 3.28 (s, 3H).