Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19](N)=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:23].[CH2:24]=O.[OH-].[Na+]>C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([N:2]([CH3:1])[CH3:24])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:23]
Reactant: C=O
Reactant: Nc1ccc(-c2cc(=O)c3cc(Br)ccc3o2)cc1
Reactant: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)c1ccc(-c2cc(=O)c3cc(Br)ccc3o2)cc1

Procedure:
Sodium cyanoborohydride (74.5 mg, 1.19 mmol) was slowly added dropwise to an acetic acid solution (10 ml) that contained compound 5 (75 mg, 0.237 mmol) and paraformaldehyde (71.1 mg, 2.37 mmol), while stirring. The obtained mixture was stirred at room temperature for 3 hours. After completion of the reaction, 50 ml of a 1 N sodium hydroxide aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with 50 ml (25 ml×2) of chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain a product of interest, 6-bromo-4′-dimethylaminoflavone (compound 7) in the form of a yellow crystal. Yield: 70 mg (yield constant: 85.7%) 1H NMR (300 MHz, CDCl3) δ8.34 (s, 1H), 7.72-7.82 (m, 3H), 7.43 (d, J=9.0 Hz, 1H), 6.70-6.77 (m, 3H), 3.08 (s, 6H). MS m/z 345 (M+).
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1.[CH2:14]1[N:19]2[CH2:20][N:21]3[CH2:23][N:17]([CH2:18]2)[CH2:16][N:15]1[CH2:22]3>C(Cl)(Cl)Cl>[Br-:1].[C:8]1([C:5]2[CH:4]=[C:3]([CH2:2][N+:15]34[CH2:16][N:17]5[CH2:23][N:21]([CH2:20][N:19]([CH2:18]5)[CH2:14]3)[CH2:22]4)[O:7][N:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: BrCc1cc(-c2ccccc2)no1
Solvent: ClC(Cl)Cl
Product: [Br-]
Product: c1ccc(-c2cc(C[N+]34CN5CN(CN(C5)C3)C4)on2)cc1

Procedure:
A 90 g. portion of the product of Example 1 was dissolved in 1.5 l. of chloroform and 70 g. of hexamethylenetetramine was added. The mixture was stirred at reflux temperature for 4 hours, and was filtered hot. The solids were dried under vacuum to obtain 143 g. of impure product, m.p. 159°-160°, which contained about 93 percent product and 7 percent hexamethylenetetramine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:2]=1.CI.[OH-].[Na+].[C:20](O)(=O)C>O.C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11]([S:14][CH3:20])=[N:12][CH:13]=2)[CH:2]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CI
Product: CSc1ncc(Cc2cccnc2)c(=O)[nH]1

Procedure:
A solution of 5-(3-pyridylmethyl)-2-thiouracil (11.0 g), methyl iodide (7.1 g) and sodium hydroxide (4.2 g) in water (150 ml) and ethanol (150 ml) was stirred at 65° for 40 minutes, allowed to cool and acetic acid was added to pH5. The solution was partially evaporated, cooled and filtered to give 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone, m.p. 247°-9° (ex. ethanol-acetic acid).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][N:8]=1)(=O)=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[O:24]1[CH2:25][CH2:26][N:21]([CH2:6][C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(COS(C)(=O)=O)nc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
A mixture containing (5-(tert-butoxycarbonylamino)pyridin-2-yl)methyl methanesulfonate (114; 1.70 g), morpholine (48; 1.0 g, 11.3 mmol) and K2CO3 (2.30 g, 16.9 mmol) in acetonitrile (30 mL) was stirred at room temperature for 12 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=1:1 to 1:3) to afford tert-butyl 6-(morpholinomethyl)pyridin-3-ylcarbamate 115 (1.20 g, 71% for two steps).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[CH:8]=[C:7]2[C:16]1[N:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1.[CH2:35]([O:37][C:38]([C:40]1(Br)[CH2:43][CH2:42][CH2:41]1)=[O:39])[CH3:36]>CN(C)C=O>[CH2:35]([O:37][C:38]([C:40]1([O:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][C:12]=2[O:13][CH3:14])[N:9]([CH3:15])[CH:8]=[C:7]3[C:16]2[N:24]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[CH:17]=2)[CH2:43][CH2:42][CH2:41]1)=[O:39])[CH3:36]
Reactant: COc1cc2c(cc1O)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: CCOC(=O)C1(Br)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2cc3c(-c4cc5cccnc5n4S(=O)(=O)c4ccc(C)cc4)cn(C)c3cc2OC)CCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium hydride (43 mg, 60% dispersion in mineral oil) was added to a stirred solution of 2-(5-hydroxy-6-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [400 mg, Reference Example 28(a)] in dry dimethylformamide (20 mL) under a nitrogen atmosphere at ambient temperature. The mixture was allowed to stir for 1 hour then treated with ethyl-1-bromocyclobutanecarboxylate (216 μl) and stirring was continued overnight. Additional portions of sodium hydride (43 mg, 60% dispersion in mineral oil) and ethyl 1-bromocyclobutanecarboxylate (216 μl) were then added, then the mixture was heated at 50° C. for 5 hours. The cooled reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, then with brine, then dried over magnesium sulfate and then evaporated. The yellow residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (2:3, v/v) to give the title compound (266 mg) as a yellow oil. MS: 576 (MH+). HPLC (METHOD A): RT=11.07 minutes.
Reaction SMILES: [C:1]1([CH2:7][C:8](=C)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[CH2:27](O)CC>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:2]2[C:1]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:22]1
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCCO
Product: COc1ccccc1N1CCN(Cc2ccccc2CCC(=O)O)CC1
Temperature: 25 °C

Procedure:
2-(Phenylmethyl)propenoic acid (Mannich and Ganz, Chem. Ber., 1922, 55, 3486) (2.00 g, 12.35 mmol) and 1-(2-methoxyphenyl)piperazine (2.37 g, 12.35 mmol) in propanol (25 ml) were heated under reflux for 18 hours, cooled to room temperature, and evaporated in vacuo. The residue was triturated with acetone and ether to give the product (0.80 g) as a colourless powder, m.p. 155°-158°. (Found: C, 71.6; H, 7.4; N, 7.6. C21H26N2O3 requires C, 71.2; H, 7.3; N, 7.9%.)
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[CH:6]([O:9][B:10](OC(C)C)[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>>[CH:1]([B:10]([O:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:6]([CH3:8])[CH3:7])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]C(C)CC
Product: CCC(C)B(OC(C)C)OC(C)C
Temperature: 50 °C

Procedure:
Following the method of Example 1, reaction of sec-butyllithium (208 mL, 250 mmol) and triisopropoxyborane (47.0 mL, 250 mmol), with solvents removed at 0° C. and 15 mm Hg and oil bath temperature maintained at 50° C., yielded sec-butyldiisopropoxyborane, 42.0 g (206 mmol, 90%), bp 138°-140° C. (754 mm Hg); proton NMR (neat) δ4.35 (septet, J=18 Hz, 2H), 1.09 (d, J=18 Hz, 12H), 0.8 (bm, 9H); boron NMR (neat) δ+79.5 ppm (s).
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]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:42][C:43]1[N:47]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH:46]=[N:45][N:44]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[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]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH2:42][C:43]5[N:47]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH:46]=[N:45][N:44]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)Cn1cnnc1CCl
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CC(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(OCc4nncn4CC(C)C)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-(4-hydroxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g), 3-chloromethyl-4-isobutyl-4H-1,2,4-triazole hydrochloride (0.15 g) and potassium carbonate (0.4 g), N,N-dimethylformamide (5 ml) was added, and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, 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/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methoxy]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 27) (0.31 g) as yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([OH:28])=O)[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:5]2=[CH:4][CH:3]=1.Cl.CN.C[CH2:41][N:42]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([NH:42][CH3:41])=[O:28])[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(F)cc1C1CC(=O)N(CC(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CN1C(=O)CC(c2cc(F)ccc2C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (70 mg, 0.13 mmol) prepared in example 146d, Methylamine hydrochloride (11 mg, 0.16 mmol), EDC.HCl (31 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol) and DIPEA (69 mg, 0.533 mmol) in DMF (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-(methylamino-carbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (29 mg as a white solid.
Reaction SMILES: CCCCC.[C:6]([Li])([CH3:9])([CH3:8])[CH3:7].C1COCC1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]([CH3:44])=[C:32]([CH3:43])[C:33]4[O:37][C:36]([CH3:39])([CH3:38])[C:35](=[O:40])[C:34]=4[C:41]=3[CH3:42])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>O>[C:6]([C:35]1([OH:40])[C:34]2[C:41]([CH3:42])=[C:30]([N:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=4)[CH2:29][CH2:28]3)[C:31]([CH3:44])=[C:32]([CH3:43])[C:33]=2[O:37][C:36]1([CH3:39])[CH3:38])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]C(C)(C)C
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(C(C)(C)C)C(C)(C)O4)CC2)cc1
Temperature: 0 °C
Yield: 33 %

Procedure:
A pentane solution (2.00 mL, 3.08 mmol) containing 1.54 M t-butyllithium was added dropwise to a solution of THF (4 mL) containing 5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one (800 mg, 2.03 mmol) synthesized in Reference Example 42 under argon atmosphere at −70° C. or lower, and then the mixture was warmed to 0° C. The reaction solution was stirred under ice-cooling condition for 30 minutes, and then water was added thereto and extraction was performed using ethyl acetate. The organic layer was washed with water and saturated saline, and then dried using anhydrous sodium sulfate. It was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane-ethyl acetate 100:0 to 8:1) and silica gel column chromatography (hexane-ethyl acetate 100:0 to 8:1), and after that, crystallization was performed using hexane to give 300 mg of the title compound (yield: 33%).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:22])[C:10](=[CH:18]OCC)[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[CH3:7].[C:23]([NH2:29])(=[O:28])[CH2:24][C:25]([CH3:27])=[O:26]>C(O)C>[C:25]([C:24]1[C:23](=[O:28])[NH:29][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:9]([O:8][CH2:6][CH3:7])=[O:22])[CH:18]=1)(=[O:26])[CH3:27]
Reactant: CC(=O)CC(N)=O
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Reaction time: 0.5 h

Procedure:
Sodium acetate (30 g, 0.37 mol) is added to a stirred mixture of diethyl(ethoxymethylene)oxalacetate (87 g, 0.36 mol) and acetoacetamide (36 g, 0.36 mol) in absolute ethanol (300 mL). After stirring the reaction mixture for 30 minutes, the ethanol is distilled off under reduced pressure, the residue acidified to pH 2 with dilute aqueous hydrochloric acid and the resulting solid filtered off. Crystallization from an ethanol-water mixture affords diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate as crystals mp 101°-110° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](OC2C=CC=CC=2)=[CH:6][CH:5]=1)=[O:3].[Br:17]Br>>[Br:17][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: BrBr
Product: O=C(CBr)c1ccccc1

Procedure:
4-Phenoxyacetophenone was brominated with bromine according to Method A to provide the desired α-bromoacetophenone, which was condensed with 2-amino-13,4,-thiadiazole-5-sulfonamide according to method C, to provide compound 87 as an off white, solid. 1H NMR (200 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.71 (s, 2H), 7.90 (d, J=7.9 Hz, 2H), 7.40 (t, J=7.3 Hz, 2H), 7.07 (t, J=7.3 Hz, 1H), 7.08–7.03 (m, 6H).
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[O:1]1[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: OCc1cccc2c1OCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cccc2c1OCC2
Yield: 95.4 %

Procedure:
A solution of 2,3-dihydro-benzofuran-7-methanol (8.13 g, 54.5 mmol) was oxidized using DMSO, oxalyl chloride, and triethyl amine similar to the above procedures to give the product as an oil (7.7 g, 95%).
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:21])[CH:15]=[CH:16][C:17](OC)=[O:18].CCCCCC.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:23][Si:2]([CH3:1])([CH3:22])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:21])[CH:15]=[CH:16][CH2:17][OH:18]
Reactant: COC(=O)C=C[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C[C@H](C=CCO)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -95 °C
Reaction time: 1 h

Procedure:
A 3.66 g amount of methyl(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-pentenoate was placed in a 500 ml eggplant-shaped flask, and 100 ml of hexane and 40 ml of toluene were then added to dissolve it. The solution was cooled to -95° C., then 12.2 ml of diisobutylaluminum hydride was slowly added and the solution stirred at the same temperature for 1 hour. Next, a further 24 ml of diisobutylaluminum hydride was added, followed by stirring for 2 hours. The consumption of the material was confirmed by thin layer chromatography, then the excess reducing agent was broken down by methanol and a saturated aqueous solution of sodium sulfate and then 300 ml of ethyl acetate and 80 ml of a saturated aqueous solution of ammonia chloride were added for separation. Extraction was performed from the aqueous layer by 100 ml of ethyl acetate, then the organic layer was washed with saturated saline and was dried by anhydrous magnesium sulfate. The desiccant was filtered out, then the filtrate was concentrated under reduced pressure to obtain a crude product in an amount of 3.61 g. This was purified by a silica column (hexane/ethyl acetate=19/1 to 4/1) to obtain (4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-y l]-2-penten-1-ol in an amount of 3.31 g (98%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C@@H:12]1[CH2:16][O:15][CH2:14][C@H:13]1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([O:20][CH2:21]C)=[CH2:19].C(N(CC)CC)C>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C@H:12]1[C@H:13]([O:17][CH2:21][O:20][CH2:18][CH3:19])[CH2:14][O:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COCC
Reactant: O[C@@H]1COC[C@H]1OCCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCO[C@@H]1COC[C@H]1OCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
Trans-4-[2-(benzyloxy)ethoxy]tetrahydrofuran-3-ol (2.20 g, 9.23 mmol) synthesized in (18a), ethyl vinyl ether (3.33 g, 46.2 mmol), and pyridinium paratoluene sulfonate (231 mg, 0.92 mmol) were dissolved in dichloromethane (22 ml), followed by stirring at room temperature for one hour. Triethylamine (187 mg, 1.84 mmol) was then added, and the resulting mixture was directly purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V) to give trans-3-[2-(benzyloxy)ethoxy]-4-(ethoxymethoxy)tetrahydrofuran (2.88 g, yield 100%). This compound (1.55 g, 5.00 mmol) was dissolved in methanol (30 ml), to which 20% palladium hydroxide-carbon (155 mg) was added, followed by stirring at room temperature for one hour under a hydrogen atmosphere. The resulting solution was concentrated under reduced pressure to give the desired title compound (725 mg, yield 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:12][C@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:18]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Temperature: 140 °C
Yield: 68.5 %

Procedure:
A suspension of 2-bromo-5-trifluoromethyl-pyridine (2.37 g; 10.0 mmol; 1.0 eq.), (R)-2-methylpiperazine (2.00 g; 20.0 mmol; 2.0 eq.) and DIEA (1.94 g; 15.0 mmol; 1.5 eq.) in 4 mL of DMA was heated at 140° C. for 14 h. The mixture was cooled to room temperature. After evaporation of the solvent under vacuum, the residue was dissolved in a 1/1 mixture of DCM/Et2O. A 4N solution of HCl was added (10 mL) then the resulting precipitate was collected and washed with Et2O. The solid was then poured to an aq. solution of NaOH (5N, 20 mL) and the resulting mixture was extracted with Et2O (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give the title compound as an orange solid (1680 mg, 69%) used without further purification for is the next steps. M+(ESI): 246.3. HPLC (Condition A), Rt: 1.0 min (HPLC purity: 99.9%).
Reaction SMILES: [NH2:1][C:2](=[N:36][N+:37]([O-:39])=[O:38])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+]([NH:43][C:44]([NH:46][C:47](N)=[O:48])=[O:45])([O-])=O.C(N(C(C)C)CC)(C)C>CO>[NH2:43][C:44]([NH:46][C:47]([NH:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:26][C:24](=[O:25])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:36][N+:37]([O-:39])=[O:38])[NH:8][C:9](=[O:23])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:33][CH:32]=1)=[O:48])=[O:45]
Reactant: NC(=O)NC(=O)N[N+](=O)[O-]
Reactant: NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: NC(=O)NC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reaction time: 14 h

Procedure:
A mixture of 0.53 g (0.997 mMol) of (R)-N5 -[amino(nitroimino)-methyl]-N-[[4-(aminomethyl)phenyl]methyl]-N2 -(diphenylacetyl)-ornithinamide, 0.16 g (1.08 mMol) of nitrobiuret, 50 ml of methanol and 0.2 ml of diisopropylethylamine was refluxed for 5 hours with stirring. The same amount of nitrobiuret and diisopropylethylamine was added again and the mixture was refluxed for a further 3 hours. The crystals obtained after leaving the mixture to stand for 14 hours at ambient temperature were suction filtered, washed thoroughly with methanol and diethylether and dried in vacuo. 0.51 g (83% of theory) of colourless crystals were obtained, Mp. 214-218° C.
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([CH:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][C:21]([O:23]C)=[O:22])[C:15]=2[CH:31]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](#[N:34])[CH3:33]>Cl>[NH:1]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([CH:19]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][C:21]([OH:23])=[O:22])[C:15]=2[CH:31]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:34][C:32]1[CH:4]=[CH:3][CH:2]=[CH:7][C:33]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([CH:19]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][C:21]([OH:23])=[O:22])[C:15]=2[CH:31]=1)=[O:9]
Reactant: COC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)Nc3ccccc3)cc21
Reactant: CC#N
Agent: Cl
Product: Nc1ccccc1C(=O)Nc1ccc2ncn(C(CC(=O)O)c3ccccc3)c2c1
Product: O=C(O)CC(c1ccccc1)n1cnc2ccc(NC(=O)Nc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of methyl 3-{6-[(anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (90 mg, 210 μmol) in a mixture of hydrochloric acid (20 mL of a 5N solution) and acetonitrile (10 mL) was stirred at room temperature for 72 hours. The solution was evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=3.77 min, MH+ 401].