Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([OH:6])=O)[CH3:3].C(N1CCOCC1)C.C(OC(Cl)=O)C(C)C.[CH2:30]([O:37][C:38](=[O:41])[CH2:39][NH2:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O>O1CCCC1.CN(C=O)C>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:2]([C:4]([NH:40][CH2:39][C:38]([O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:41])=[O:6])[CH3:3]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
1.9 g of Boc-(D)Ala-OH and 1.3 ml of N-ethylmorpholine are dissolved in 50 ml of absolute tetrahydrofuran and 1.3 ml of chloroformic acid iso-butyl ester added dropwise at a temperature of -15°. After 5 minutes, a solution of 3.4 g of glycine-benzylester-tosylate and 1.3 ml of N-ethylmorpholine in 50 ml of DMF is added. After 1 hour's stirring at -10°, the reaction mixture is evaporated and the residue taken up in acetic acid. The solution is repeatedly washed with dilute citric acid and potassium bicarbonate. The title compound is crystallised from ether. M.P. 88°.
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:4]([Zn+])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][N:11]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1N1CCCCC1C)C(=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1>>[CH3:10][NH:11][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[C:4]1[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Cc1cccnc1[Zn+]
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Br-]
Product: CNc1cnccc1-c1ncccc1C

Procedure:
The title compound was prepared in analogy to example 55, intermediate, from 3-methyl-2-pyridylzinc bromide (CAS RN 308795-91-7) and (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b). Light yellow sticky solid (93%). MS (ESI): m/z=200.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[NH2:17].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[NH:17][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:11]
Reactant: COC(=O)[C@H](N)Cc1ccc(O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2,6-dichlorobenzoylchloride (0.68 mL) in CH2Cl2 (5 mL) was added to a solution of an ice-cold solution of D-tyrosine methyl ester HCl salt (1.0 g) and DIEA (2.26 mL) in CH2Cl2 (15 mL). The mixture was stirred at room temperature for 24 h. The mixture was diluted with CH2Cl2 (50 mL) and washed successively with H2O, 1 N HCl and brine. The organic layer was dried (MgSO4) and evaporated, and the residue was recrystallized from EtOAc and hexanes to yield 1.46 g of N-(2,6-dichlorobenzoyl)-D-tyrosine methyl ester. ESMS: m/z 369 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[C:14]3[N:15]=[C:16]([CH3:18])[NH:17][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[C:5](=O)[NH:4][C:3]1=[O:24].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[C:14]3[N:15]=[C:16]([CH3:18])[NH:17][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[C:5](=[S:34])[NH:4][C:3]1=[O:24]
Reactant: Cc1nc2c([nH]1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1nc2c([nH]1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
The title product was prepared from the product of step (iv) (0.1 g) and Lawesson's reagent (0.378 g) according to the method of example 34 step (iv). Purification was by chromatography eluting with 0-5% methanol in dichloromethane followed by reverse phase HPLC using a 40 mm Novapak column eluting with 15-85% methanol in 0.1% aqueous ammonium acetate gradient over 9 min.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:9])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(OCc2ccccc2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Add benzyl bromide (1 mL, 8.38 mmol) to a solution of 6-chloropyridin-2-ol (2 g, 15.4 mmol), potassium carbonate (3.41 g, 24.7 mmol) in DMF (20 mL) heat to 80° C. and stir for two hours. Quench reaction mixture with water, then extract three times with 20 mL EtOAc. Combine the organic washings and wash with water (20 mL); dry over sodium sulphate; filter; collect the filtrate; and concentrate under vacuum. Purify via normal phase silica gel flash column chromatography using a gradient of 0-50% ethyl acetate in petroleum ether to give the title compound as a clear oil. MS: (m/z): 220 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][O:3][C:4]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)C(C)(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(OCc1ccc(-c2ccc(Cl)cc2)cc1)c1ccccc1
Reaction time: 1 h

Procedure:
Sodium hydride (1.05 g., 50% w/w dispersion in mineral oil), was added to a stirred solution of ethyl 2-hydroxy-2-phenylpropionate (3.48 g.) at 4° C. in dimethylformamide (100 ml.). After 1 hour, 4-(4-chlorophenyl)benzyl chloride (4.74 g.) was added and stirring was continued at 4° C. for 1 hour and then at room temperature for 20 hours. The mixture was neutralised by cautious addition of N-hydrochloric acid and then extracted with ether. The extracts were washed with water, dried (MgSO4) and evaporated to give ethyl 2-[4-(4-chlorophenyl)benzyloxy]-2-phenylpropionate as an oil (7.9 g.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CCOCC>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]#[C:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: C#Cc1ccccc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 90 °C
Yield: 95.3 %

Procedure:
Compound 5 (30 mg, 2 μmol Pd), 1-(4-bromo-phenyl)ethan-1-one (0.20 g, 1 mmol), phenylacetylene (0.16 g, 1.5 mmol), and triethylamine (3 mL) were sequentially added into a 15 mL septum-sealed test tube under protection of nitrogen. The mixture was then heated at 90° C. for 72 h. After it was cooled to the room temperature, 8 mL of anhydrous ether was added to precipitate compound 5. The mixture was centrifuged and the upper liquid layer was transferred via a syringe into a 20 mL round-bottom flask. Repeated the above precipitation procedure once. The combined liquid layer was concentrated under reduced pressure to give an oily residue. A saturated ammonium chloride solution (5 mL) was then added. The resulting mixture was extracted by ethyl acetate (10 mL×3), dried over anhydrous magnesium sulfate, filtrated, and concentrated to give a crude product. The crude product was further purified by column chromatography (silica gel, hexane/ethyl acetate=4/1) to give 0.21 g (98% yield) of 1-(4-acetylphenyl)-2-phenylethyne. 1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 7.33–7.35 (m, 3H), 7.52–7.54 (m, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.2 Hz, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][NH:9][C:10](=[O:27])[C@H:11]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[NH:12]C(OC(C)(C)C)=O)[CH3:2].[ClH:30].C(OCC)(=O)C>C(OCC)(=O)C.C(OCC)C>[ClH:30].[CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][NH:9][C:10](=[O:27])[C@H:11]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[NH2:12])[CH3:2]
Reactant: CCOC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1CCCCC1
Yield: 86.8 %

Procedure:
To the solution of thus obtained N-t-butoxycarbonyl-β-cyclohexyl-L-alanyl-glycyl-glycine ethy lester (506.2 mg, 1.22 mmol) in ethyl acetate (1 mL) under ice-cold condition, add 4M hydrogen chloride/ethyl acetate (3.0 mL, 12 mmol) with stirring, and then the reaction mixture was stirred for 4.5 hours at room temperature. Diethylether (12 mL) was added and the mixture was stirred under ice-cold condition, then the precipitate was collected by filtration to obtain hygroscopic crude crystals. The crude crystals were suspended in diethylether (10 mL)and collected by filtration to obtain β-cyclohexyl-L-alanyl-glycyl-glycine ethyl ester hydrochloride (370.3 mg) as colorless crystalline powder (yield 86%).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@H:16]([NH2:20])([CH2:18][CH3:19])[CH3:17].C([BH3-])#N.[Na+]>CO>[C@H:16]([NH:20][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)([CH2:18][CH3:19])[CH3:17]
Reactant: CC[C@@H](C)N
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC[C@@H](C)NCc1ccc(Oc2ccccc2)cc1
Reaction time: 18 h
Yield: 76.4 %

Procedure:
4-Phenoxybenzaldehyde (8.13 g, 41 mmol) and (R)-sec-butylamine (3 g, 41 mmol) were dissolved in methanol (137 mL) under nitrogen at room temperature. Sodium cyanoborohydride (2.58 g) was added, and stirring was continued for 18 hours. The solvent was removed, and the residue was suspended in ether, washed with brine and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 8.0 g (77%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15].C1(C)C=CC=CC=1.[BH4-].[Na+]>CO>[CH2:1]([NH:9][CH2:10][CH2:11][NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H](NCCN)C(C)(C)C
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1)C(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A solution of benzaldehyde (23 g, 217 mmol) and the product of Example 111-3 (50 g, 217 mmol, 1 equivalent) in 50:50 mixture of toluene and methanol (total volume=1400 mL), stirred at 50° C. overnight, cooled to −3° C., treated with NaBH4 (16.6 g, 434 mmol, 2equivalents) slowly over 5 hours, and stirred at room temperature for 16 hours. The reaction mixture was quenched with a saturated NaHCO3 solution (1400 mL) and extracted with ethyl acetate (1.3 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (850 mL). The organic layers were combined, washed with brine (900 mL), and concentrated. The residue was dissolved in heptanes (700 mL), decanted inorganic salt, distilled to oil and chased to yield 69.4 g of crude material. 1H NMR (CDCl3): δ 7.05-7.3(m, 7H), 3.75(d, 2H), 2.4-2.8(m, 5H), 1.4(s, 9H), 0.87(s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH:41]=[CH:42][C:43]([O:47][CH2:48][CH2:49][CH2:50][O:51][CH3:52])=[N:44]2)=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][C:43]([O:47][CH2:48][CH2:49][CH2:50][O:51][CH3:52])=[N:44]3)=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1ccc2ccc(CCl)cc2n1
Product: COCCCOc1ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc2n1

Procedure:
Analogously to Method D, 0.300 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy) propoxy]phenyl}piperidine-1-carboxylate and 0.181 g of 7-chloromethyl-2-(3-methoxy-propoxy)quinoline are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=6.33.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([CH3:23])[C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>C1COCC1>[OH:31][C:29]([CH3:32])([CH3:30])[CH2:28][N:27]1[CH2:21][C:14]2[C:15](=[CH:20][C:11]([CH2:10][C:9]3[CH:25]=[CH:26][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[C:12]([CH3:24])[C:13]=2[CH3:23])[C:16]1=[O:17]
Reactant: CC(C)(O)CN
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(C)c1C=O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1C)CN(CC(C)(C)O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-3,4-dimethylbenzoate (0.11 g) in THF (4.00 mL) was added 1-amino-2-methylpropan-2-ol (0.03 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with methanol (4.0 mL). Sodium triacetoxyborohydride (0.11 g) was added thereto under argon atmosphere, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]2[N:35]([CH:36]=1)[C:18]1[N:19]([C:28]3[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[C:20](=[O:27])[C:21]3[C:26]([C:17]=1[N:16]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3>ClCCl>[Cl:34][C:31]1[N:30]=[CH:29][C:28]([N:19]2[C:18]3[N:35]4[CH:36]=[C:12]([NH:11][CH:1]=[O:2])[CH:13]=[CH:14][C:15]4=[N:16][C:17]=3[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:27])=[CH:33][CH:32]=1
Reactant: O=CO
Reactant: Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Formic acid (5.0 equiv., 1.390 mmol, 0.064 g) was added to a cooled (0° C.) solution of acetic anhydride (2.0 equiv., 0.552 mmol, 0.050 g) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 1 h. Compound 53 (1.0 equiv., 0.276 mmol, 0.100 g) was added and the resulting suspension was stirred at room temperature for 6 h. The precipitate was filtered off and successively washed with isopropanol and isopropyl ether affording N-[6-(6-chloro-pyridin-3-yl)-5,6-dihydro-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl]-formamide (57) (0.060 g, yield=56%, purity (LC)=96%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:14](O)=[O:15]>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>[C:20]([O:19][C:17](=[O:18])[NH:12][CH2:13][C:14](=[O:15])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: NCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC(=O)NCCCCc1ccccc1
Reaction time: 16 h

Procedure:
Phenylbutylamine (8.2 g, 52 mmol) is added to a mixture of BOC-Gly-PNB (14.82 g, 50 mmol) in dioxane (60 mL) and 1 M K2CO3 (60 mL). The mixture is stirred 16 h and then diluted with CH2Cl2 and washed with a saturated NaHCO3 solution until the organic phase is colorless. The organics are dried (MgSO4) and concentrated to provide [(4-phenyl-butylcarbamoyl)-methyl]-carbamic acid tert-butyl ester which is used as is without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)(=[O:25])=[O:24])=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:32][C:33](=O)[CH2:34][CH2:35][CH3:36].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23]([N:26]5[CH2:27][CH2:28][N:29]([CH:34]([CH2:35][CH3:36])[CH2:33][CH3:32])[CH2:30][CH2:31]5)(=[O:24])=[O:25])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCCC(C)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCNCC3)ccc1OCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCC(CC)N1CCN(S(=O)(=O)c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Reaction time: 20 h
Yield: 24.3 %

Procedure:
A mixture of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-(piperazine-1-sulfonyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (35 mg, 0.08 mmol), pentanone (25 μL, 0.24 mmol), AcOH (9 μL, 0.16 mmol) and 4 Å molecular sieves in DCE (2 mL) was stirred at RT for 1 h before the addition of sodium triacetoxyborohydride (33 mg, 0.16 mmol). The resulting mixture was stirred for 16 h before further pentanone (100 μL, 0.92 mmol) and sodium triacetoxyborohydride (198 mg, 0.96 mmol) were added. The mixture was stirred for 20 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM) to afford 134 (10 mg, 25%) as a white solid. LCMS: RT 3.13 min [M+H]+ 514.4. 1H NMR (CDCl3, 400 MHz): δ 8.95 (1H, d, J=2.36 Hz), 7.88 (1H, s), 7.70 (1H, s), 7.65 (1H, dd, J=8.59, 2.37 Hz), 7.17 (1H, d, J=8.60 Hz), 5.94-5.85 (1H, m), 4.59-4.58 (2H, m), 4.52-4.51 (2H, m), 3.05 (4H, s), 2.61 (4H, s), 2.13-2.10 (1H, m), 1.60 (6H, d, J=6.64 Hz), 1.46-1.35 (2H, m), 1.29-1.27 (2H, m), 0.83 (6H, t, J=7.36 Hz)
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].[H-].[Na+].Br[C:9]1[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16]([N:17]=1)=[C:15]([NH2:18])[N:14]=[CH:13][N:12]=2>CN(C=O)C>[C:1]([CH2:2][S:3][C:9]1[N:10]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:11]2[C:16]([N:17]=1)=[C:15]([NH2:18])[N:14]=[CH:13][N:12]=2)([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: Nc1ncnc2c1nc(Br)n2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1nc(SCC(=O)O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A solution of thioglycolic acid (0.05 mL, 0.68 mmol) and NaH (0.05 g, 1.35 mmol, 60% in oil) in anhydrous DMF (3 mL) was stirred for 30 min at 0° C. under argon, then 23 (0.13 g, 0.45 mmol) in DMF (3 mL) was added. After stirring overnight at room temperature, the reaction mixture was concentrated to dryness, and the crude product was purified by reverse phase HPLC (5-50% ACN in TEAA over 20 min) to give 24 (0.07 g, 50%). Rt (0-10% A in B over 20 min.) 10.36 min.; 1H NMR (DMSO-d6) δ: 4.17 (s, 2H, SCH2), 5.31 (s, 2H, CH2), 7.10 (bs, 2H, NH2), 7.29 (m, 3H, H arom.), 7.35 (m, 2H, H arom.), 8.12 (s, 1H, H2); 13C NMR (DMSO-d6) δ: 34.91 (SCH2), 45.97 (CH2), 119.17 (C5), 127.77, 128.22 and 129.15 (CH), 136.63 (Cq), 147.77 (C8), 152.02 (C4), 152.51 (C2), 154.62 (C6); 169.85 (CO); HRMS (ESI-TOF) m/z calcd for [C14H13N5O2S+H]316.0868; found 316.0855.
Reaction SMILES: Cl[C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[NH4+:23].[OH-]>O1CCOCC1>[NH2:23][C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: [NH4+]
Reactant: C[C@]12C=CC(=O)C(Cl)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 90 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
A mixture of 4-chloroandrosta-1,4,6-triene-3,17-dione (1.585 g, 5 mmole), dioxane (50 ml) and 30% NH4OH aqueous solution (100 ml) is stirred at 90° C. in a pressure vessel during 24 hours. After cooling to room temperature, the reaction mixture is worked up as described in the Example I. There are obtained 370 mg (1.24 mmole, 24% yield ) of the title compound or a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=[N:19][OH:20])[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1nc(C=NO)nc(C(C)(C)C)c1O

Procedure:
A solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde (1.5 g, 6.3 mmol), hydroxylamine hydrochloride (2.2 g, 32.7 mmol), and sodium acetate (2.9 g, 34.9 mmol) in ethanol (20 mL) is heated at reflux for 12 hours. The reaction mixture is poured over water (150 mL) and the precipitate is collected by filtration. Recrystallization from ether/hexane gives the desired 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde oxime as a mixture of isomers (0.62 g, 39%); mp 205°-220° C.
Reaction SMILES: [O:1]1[CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:2]1[CH2:3][CH2:4]2)=O.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:6](=[O:8])[CH:5]3[O:1][CH:2]([CH2:3][CH2:4]3)[C:9]2=[O:10])[CH2:17][CH2:18]1
Reactant: O=C1OC(=O)C2CCC1O2
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Solvent: Cc1ccccc1
Product: O=C1C2CCC(O2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
Tetrahydrofuran-2,5-dicarboxylic anhydride (1.5 g., 10 mmole) was dissolved in 150 ml. of toluene in a 500 ml. round bottom flask equipped with a Dean-Stark trap and condenser. 1-(4-Aminobutyl)-4-(2-pyrimidinyl)piperazine (2.59 g., 11 mmole) was added and the mixture was refluxed for 24 hours. When the analysis failed to detect the expected product, the solvent was removed in vacuum and replaced with xylene. Reflux was continued for 48 hours. The solvent was then removed in vacuum and the residue column chromatographed on 100 g. of silica gel using a gradient elution from pure chloroform to 5% ethanol/chloroform. The relevant fractions were combined and concentrated in vacuum and the product crystallized from isopropanol with the addition of 4N HCl/isopropanol. 1.2 Grams of the title compound was obtained as the dihydrochloride; m.p. 221°-222° C.