Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])([C:14]([F:18])([F:17])[CH:15]=C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:30]=[O+][O-].[BH4-].[Na+].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])([C:14]([F:17])([F:18])[CH2:15][OH:30])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CC(F)(F)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCc2ccccc2)(C(F)(F)CO)C1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-allyl)-piperidine-1-carboxylic acid tert-butyl ester (15.1 g) in chloroform/methanol (150 ml/150 ml) cooled to −78° C. was flowed ozone air for 30 minutes. To the reaction mixture was added sodium borohydride (4.2 g) in small batches, and then the mixture was warmed to 0° C. and stirred at the same temperature for additional 50 minutes. To the mixture were added saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and the mixture was extracted with chloroform. The separated aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1 to 2/1) to give the titled compound (13.6 g).
Reaction SMILES: [OH:1][C:2]1[N:3]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH2:27][CH2:28][NH:29][CH3:30])[CH:22]=[CH:21]3)[C:4]([C:7]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:16])=[CH:9][C:8]=2[OH:17])=[N:5][N:6]=1.[O:31]=[C:32]1[CH:36]=[CH:35][C:34](=[O:37])[N:33]1[CH2:38][CH2:39][CH2:40][C:41]([OH:43])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C.O.C(OCC)(=O)C>[OH:17][C:8]1[CH:9]=[C:10]([OH:16])[C:11]([CH:13]([CH3:14])[CH3:15])=[CH:12][C:7]=1[C:4]1[N:3]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH2:27][CH2:28][N:29]([CH3:30])[C:41](=[O:43])[CH2:40][CH2:39][CH2:38][N:33]2[C:34](=[O:37])[CH:35]=[CH:36][C:32]2=[O:31])[CH:22]=[CH:21]3)[C:2]([OH:1])=[N:6][N:5]=1
Reactant: O=C(O)CCCN1C(=O)C=CC1=O
Reactant: CNCCn1ccc2cc(-n3c(O)nnc3-c3cc(C(C)C)c(O)cc3O)ccc21
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(ccn3CCN(C)C(=O)CCCN3C(=O)C=CC3=O)c2)c(O)cc1O
Reaction time: 12 h
Yield: 46.2 %

Procedure:
The benzylether [5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-(2-(methylamino)ethyl)-1H-indol-5-yl)-4H-1,2,4-triazol-3-ol; 294 mg, 0.5 mmol) was dissolved in 6 ml degassed ethyl acetate and ethanol (1:1). 50 mg Pd/C (10%) was added and the mixture stirred under hydrogen (balloon) at rt for 6 h. After filtration the solvent was removed and the crude purified by chromatography on silica with DCM/MeOH (5-20%)/NH4OH (0.5%) to yield 203 mg (0.5 mmol) 4-(5-hydroxy-4-(1-(2-(methylamino)ethyl)-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol. This amine (203 mg) was added to 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoic acid (110 mg, 0.6 mmol), EDC (154 mg, 0.8 mmol) and HOBt (108 mg, 0.8 mmol) in 9 ml DCM/DMF (2:1) at rt. The mixture was stirred for 12 h and then ethyl acetate and water added. The aq. Phase was extracted twice with ethyl acetate and the combined organic extracts washed with brine and dried over MgSO4. The crude was purified by chromatography on silica with DCM/MeOH (0-8%) to yield 133 mg (0.23 mmol) N-(2-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-1H-indol-1-yl)ethyl)-4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylbutanamide.
Reaction SMILES: [CH3:1][CH2:2][CH:3]=[CH2:4].[CH2:5](O)C(C)C>>[CH3:4][CH:3]([CH:2]=[CH2:1])[CH3:5].[CH3:4][CH2:3][CH:2]=[CH2:1]
Reactant: CC(C)CO
Agent: C=CCC
Product: C=CC(C)C
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
The reactor which had been thoroughly dried and purged with nitrogen was charged with 77.0 mmol of diisobutylaluminum monochloride and 8.0 kg of liquefied 3-methylbutene-1 . The contents were heated to 70° C., and 9.05 g of the solid titanium trichloride catalyst complex as obtained in Preparation Example 1 was introduced under pressure into the reactor to start the polymerization. The polymerization was carried out while successively feeding butene-1. After 3.5 hours, 300 ml of isobutyl alcohol was introduced under pressure to stop the polymerization. The amount, of butene-1 supplied was 400 g. Subsequently the surplus unreacted monomer was removed from the reactor, and then 8.0 kg of n-hexane was introduced into the reactor. The resulting mixture was stirred at 50° C. for 30 minutes and then allowed to stand. The supernatant liquid was withdrawn, and the catalyst component in the polymer was removed by washing. This operation was repeated five times. Then, 0.2 parts of Irgafos PEPQ and 0.2 parts of Irganox 1010 were added, and the resulting mixture was dried to obtain 4.3 kg of a white powdery 3-methylbutene-1 /butene-1 copolymer.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[N:20]([CH3:21])[C:19]4[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=4[N:17]=3)=[CH:11][CH:10]=2)C=CC=CC=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:21][N:20]1[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]=[C:16]1[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=1
Reactant: Cn1c(Oc2ccc(N=C(c3ccccc3)c3ccccc3)cc2)nc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(Oc2ccc(N)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a suspension of N-(diphenylmethylidene)-4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline (810 mg) in THF (10 mL) was added 1 N HCl aq (10 mL) at room temperature, and the mixture was stirred at room temperature for 1 h. The mixture was neutralized with sat. NaHCO3 aq. and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5%-100% AcOEt in hexane) to give 4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline (440 mg) as colorless crystals.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29].[B:30](OC)([O:33]C)[O:31]C>O1CCCC1>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:13]([B:30]([OH:33])[OH:31])[CH:18]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COCCOCOc1ccc(C(C)(C)C)cc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCOCOc1ccc(C(C)(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
n-Butyllithium in hexane (2.5 M, 4.2 mL, 10.5 mmol) was added dropwise to a solution of give 2-bromo-4-(tert-butyl)-1-((2-methoxyethoxy)methoxy)benzene (3.0 g, 9.46 mmol) and trimethyl borate (1.2 mL, 10.76 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 20 minutes then at 0° C. for an additional 20 minutes. The reaction was then quenched by the addition of water (20 mL) and the mixture extracted with ether (100 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure to give (5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)phenyl)boronic acid (2.61 g, 98% yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([CH:9]([C:14]([CH3:16])=[CH2:15])[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[N:8]([C:9](=[C:14]([CH3:15])[CH3:16])[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:3])[CH3:2]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.1 %

Procedure:
To a solution of 1.07 g (3 mmol) (2R) methyl 2-((3S,4S)-4-acetoxy-3-t-butyloxycarbonylaminoazetidine-2-on-1-yl)-3-methylbut-3-enoate in 30 ml of methylene chloride, at room temperature 0.3 ml of triethylamine is added and the reaction mixture stirred for 6 hours at room temperature. The reaction mixture is first washed with 15 ml of 1N hydrogen chloride in water and then with 15 ml of saturated sodium chloride solution. The organic layer is dried over sodium sulfate and the solvent removed in vacuo, leaving 1.07 g (100%) of a noncrystalline solid (title compound). IR spectrum in methylene chloride: 3420, 3000, 1790, 1760, 1725, 1505, 1385, 1365, 1215 and 1150 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:22].Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[C@@H:9]([CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1cscn1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
A solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(thiazol-4-yl)propanoic acid (Compound SP726) (800 mg, 2.94 mmol) in tetrahydrofuran (20 ml) was added dropwise to a suspension of sodium hydride (470 mg, 11.8 mmol, 60%) in tetrahydrofuran (30 ml) under a nitrogen atmosphere. Subsequently, iodomethane (1.67 g, 11.8 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was adjusted to pH 4 with 6 mol/1 aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was dried over sodium sulfate and then concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate) to afford (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(thiazol-4-yl)propanoic acid (Compound SP727) (560 mg, 67%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](Cl)=[O:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:26]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(F)c(F)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,4-difluorobenzoyl chloride, there is obtained ethyl N-(3,4-difluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 406 (3), 377 (17), 194 (100), 141 (38);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[S:17][C:13]=2[N:12]2[C:27]([CH3:30])=[N:28][N:29]=[C:11]2[CH2:10][N:9]=1.[OH-].[K+].[CH:33](I)([CH3:35])[CH3:34]>COCCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:33]([CH3:35])[CH3:34])=[CH:22][CH:21]=3)[S:17][C:13]=2[N:12]2[C:27]([CH3:30])=[N:28][N:29]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(CCc3ccc(O)cc3)cc1C(c1ccccc1Cl)=NC2
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1nnc2n1-c1sc(CCc3ccc(OC(C)C)cc3)cc1C(c1ccccc1Cl)=NC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
A mixture of 0.5 g of thienotriazolodiazepine compound obtained in Example 5, 0.2 g of potassium hydroxide and 0.62 g of isopropyl iodide in 20 ml of 2-methoxyethanol is stirred at 90° C. for 4 hours, and then the resulting mixture is concentrated to dryness. The residue is dissolved in 50 ml of chloroform, washed with water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from isopropyl ether-ethyl acetate to give 0.3 g of 4-(2-chlorophenyl)-2-[2-(4-isopropoxyphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine as colorless crystals, melting at 121°-124° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[P:6](O)([O:10][C@H:11]1[CH2:15][O:14][C@@H:13]2[C@H:16]([O:19][N+:20]([O-:22])=[O:21])[CH2:17][O:18][C@H:12]12)([O:8][CH3:9])=[O:7].S(Cl)([O:27][CH2:28][Cl:29])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[P:6]([O:10][C@H:11]1[CH2:15][O:14][C@@H:13]2[C@H:16]([O:19][N+:20]([O-:22])=[O:21])[CH2:17][O:18][C@H:12]12)([O:8][CH3:9])([O:27][CH2:28][Cl:29])=[O:7]
Reactant: O=S(=O)(Cl)OCCl
Reactant: COP(=O)(O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: COP(=O)(OCCl)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium bicarbonate (289 mg, 3.44 mmol) followed by tetrabutylammonium hydrogensulfate (29.2 mg, 0.086 mmol) were added to a vigorously stirred 0° C. mixture of methyl (3S,3aS,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl hydrogen phosphate (245 mg, 0.859 mmol) in dichloromethane (5 mL) and water (7.5 mL), and the mixture was stirred at 0° C. for 10 minutes. Chloromethyl chlorosulfate (0.106 mL, 1.03 mmol) in dichloromethane (2.5 mL) was added, and the mixture was stirred at room temperature for overnight. The organic phase was removed, dried and concentrated. Chromatography over silica, eluting with 20-60% ethyl acetate/hexane afforded the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 5.72-5.64 (m, 2H), 5.36 (td, J=5.5, 2.8 Hz, 1H), 5.02 (t, J=5.2 Hz, 1H), 4.93 (quintet, J=3.6 Hz, 1H), 4.63 (dd, J=12.1, 4.8 Hz, 1H), 4.18 (dd, J=11.0, 7.3 Hz, 1H), 4.00 (dd, J=11.4, 2.8 Hz, 1H), 3.94 (dq, J=11.1, 2.4 Hz, 1H), 3.90 (dd, J=11.3, 5.6 Hz, 1H), 3.83 (d, J=11.4 Hz, 3H); LC-MS: m/z 334.0 (M+H).
Reaction SMILES: CNC.[CH3:4][N:5]([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1.[BH4-].[Na+]>C(O)C>[CH3:16][N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:4]
Reactant: CN(C)Cc1ccc([N+](=O)[O-])cc1
Agent: CNC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)Cc1ccc(N)cc1
Temperature: 60 °C

Procedure:
Using the procedure of Example 1, dimethylamine Compound 4a1 was used in place of Compound 1n2 and carried forward to prepare dimethyl-(4-nitrobenzyl)-amine Compound 4a2. Stannous chloride (28.1 g, 148 mmol) was added to a solution of Compound 4a2 (5.33 g, 29.6 mmol) in ethanol (200 mL) and heated to 60° C. Sodium borohydride (0.560 g, 14.8 mmol) in ethanol (80 mL) was added dropwise. Two hrs later the reaction mixture was added to ice water. The slurry was filtered through Celite 545 and the filtrate cake rinsed with ether. The collected liquors were brought to pH 11 with 1N NaOH and extracted with ether. The combined organic layers were washed with water, dried over MgSO4 and filtered. The dried organic solution was then reduced in vacuo to provide 4-dimethylaminomethyl-phenylamine Compound 4a which was used in the next step without further purification. MS 207 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]#[N:17])[N:10]=[C:9]1[CH:18]([N:22]([CH2:32][CH2:33][NH2:34])[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:36]1([C:41](N)=[NH:42])C=CC=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]#[N:17])[N:10]=[C:9]1[CH:18]([N:22]([CH2:32][CH2:33][NH:34][C:41]([NH2:42])=[NH:36])[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N(CCN)C(c2nc(C#N)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N(CCNC(=N)N)C(c2nc(C#N)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To a solution of N-[1-(1-benzyl-4-cyano-5-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propyl]-N-(2-amino-ethyl)-4-methyl-benzamide (75 mg, 0.16 mMol) in DMF (1.5 mL) was added 1H-pyrazole-1-carboxamidine hydrochloride (25 mg, 0.17 mMol) and diisopropylethyl amine (57 μL, 0.33 mMol). The reaction was stirred at RT for 16 h, quenched with water (2 mL) and diluted with methylene chloride (2 mL). The aqueous layer was adjusted to pH 7 and extracted with methylene chloride (2×5 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated. Purification of the residue by reverse phase HPLC furnished the title compound (38 mg, 37%) as a white powder. MS (ES) m/e 500.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[C:33](=[O:44])[N:34]([CH3:43])[C:35]2[C:40]([C:41]=1[NH2:42])=[CH:39][CH:38]=[CH:37][N:36]=2.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18](=[O:20])[NH:31][C:32]2[C:33](=[O:44])[N:34]([CH3:43])[C:35]3[C:40]([C:41]=2[NH2:42])=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCCC(C(=O)O)C1)OCc1ccccc1
Reactant: Cn1c(=O)c(N)c(N)c2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(NC(=O)C2CCCC(NC(=O)OCc3ccccc3)C2)c(N)c2cccnc21
Temperature: 0 °C
Yield: 12.2 %

Procedure:
3-Benzyloxycarbonylamino-cyclohexanecarboxylic acid (0.277 g, 1.0 mmol), TEA (0.10 g, 1.0 mmol), and HOBt (0.135 g, 1.0 mmol) were added sequentially to a stirred solution of 3,4-diamino-1-methyl-1H-[1,8]naphthyridin-2-one (0.19 g, 1.0 mmol) in DMF (8 mL) at room temperature. The solution was cooled to 0° C. and EDCI (0.19 g, 1.0 mmol) was added. The resulting solution was allowed to stir, with warming to room temperature, for 17 h. The mixture was diluted with water (5 mL) and extracted with CH2Cl2, dried with MgSO4, and concentrated. The residue was purified by flash chromatography eluting with 5% MeOH in CH2Cl2 to give [3-(4-amino-1-methyl-2-oxo-1,2-dihydro-[1,8]naphthyridin-3-ylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester (55 mg, 12% yield), and 60 mg (32%) of unreacted diamine. 1H-NMR (CDCl3): δ 8.59 (m, 1H), 8.21 (m, 1H), 7.91 (m, 1H), 7.33 (m, 6H), 7.20 (dd, 1H, J=8.0, 4.8), 5.51 (m, 2H), 5.12 (m, 2H), 4.76 (m, 1H), 4.10 (m, 1H), 3.81 (s, 3H), 2.60 (m, 1H), 2.33 (m, 1H), 1.93-2.05 (m, 3H), 1.73 (m, 2H), 1.45 (m, 2H). MS: calculated for C24H27N5O4+H 450.2; found: 450.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:35])[CH2:10][C:11]([C:13]1[C:14](O)=[C:15]([CH:23]2[CH2:27][CH2:26][N:25]([CH3:28])[CH:24]2[CH2:29][O:30]C(=O)C)[C:16]([O:21][CH3:22])=[CH:17][C:18]=1[O:19][CH3:20])=[O:12].C([O-])(O)=O.[Na+]>Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:35][C:14]2[C:13]([C:11](=[O:12])[CH:10]=1)=[C:18]([O:19][CH3:20])[CH:17]=[C:16]([O:21][CH3:22])[C:15]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][OH:30]
Reactant: COc1cc(OC)c(C2CCN(C)C2COC(C)=O)c(O)c1C(=O)CC(=O)c1ccc(Cl)cc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(Cl)cc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Reaction time: 3 h

Procedure:
To a solution of n-BuLi (15% in hexane, 0.9 mL, 2 mmol) in THF (10 mL), maintained at 0° C. under nitrogen atmosphere, hexamethyldisilazane (0.44 mL, 2 mmol) was added dropwise and stirred for 15 min. To this, a solution of the compound of example (67) (0.6 g, 1 mmol) in THF (10 mL) was added dropwise, maintaining the temperature at 0° C. After the addition, the reaction was allowed to warm to room temperature and stirred for 2.5 hrs. The reaction mixture was acidified with dilute HCl, and basified with 10% sodium bicarbonate to pH 8 to 9. The aqueous layer was extracted with chloroform (3×25 mL). The organic layer was washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and dried under vacuum to yield acetic acid 3-{3-[3-(2-bromo-4-chlorophenyl)-3-oxo propionyl]-2-hydroxy-4,6-dimethoxyphenyl}-1-methyl-pyrrolidin-2-ylmethyl ester as a brown solid (1.2 g). This ester was dissolved in conc. HCl (10 mL) and stirred for 3 hrs. to effect cyclisation. At the end of 3 hrs, the reaction mixture was basified with solid NaHCO3 to pH 8 to 9. The aqueous layer was extracted with chloroform (25×3 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and dried over vacuum. The residue was purified by column chromatography with 3% methanol in chloroform and 0.1% ammonia as eluent to yield the compound, (+)-trans-2-(2-bromo-4-chloro phenyl)-8-(2-hydroxymethyl-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one as a yellow solid.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:11]([N:13]([CH3:38])[C@H:14]([C:18]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:24]=1)=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccc(F)cc1
Yield: 90.6 %

Procedure:
A mixture of Z-Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.73 g, 2.61 mmol) and 10% palladium/carbon (340 mg) in methanol (50 ml) was stirred at room temperature in a hydrogen atmosphere for 17 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=100:10:1) to give Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.25 g, 91%). EI-MS:528 (M+)
Reaction SMILES: [CH3:1][C:2]#[N:3].C([Li])CCC.C[O:10][C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:16]2)=O.Cl>C1(C)C=CC=CC=1.CCCCCC>[O:10]=[C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([Si:22]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:31])[CH3:30])[CH:23]([CH3:24])[CH3:25])[CH:17]=[CH:16]2)[CH2:1][C:2]#[N:3]
Reactant: COC(=O)c1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)CC#N)ccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.9 %

Procedure:
To a solution of 393 μL of anhydrous CH3CN (7.5 mmol) in 6 mL of dry toluene cooled down to −78° C., 5.35 mL of butyllithium in hexane solution (1.6 N) were added dropwise. The mixture was left stirring at −78° C. for 20 minutes and then a solution of 500 mg of 1-triisopropylsilanyl-1H-indole-5-carboxylic acid methyl ester (1.5 mmol) in 2 mL of dry toluene were added and the reaction allowed to reach room temperature. Upon reaction completion after about 20 minutes the mixture was cooled down to 0° C. and HCl 2N was added to pH 2. The organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure, affording 490 mg of title product which was used in the next step without further purification (yield=96%).