Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[I:7].[H-].[Na+].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl.O>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:18])([CH3:17])[CH3:10])[C:6]=1[I:7]
Reactant: Ic1nc[nH]c1I
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(I)c1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
4,5-Diiodoimidazole (prepared according to D. S. Carver, S. D. Lindell, and E. A. Saville-Stones, Tetrahedron, 1997, 53, 42, 14481-14496) (10.1 g, 31.6 mmol) was added portionwise to a room temperature suspension of sodium hydride (1.38 g, 31.6 mmol, 55% *in mineral oil) in dry DMF (45 ml). The reaction mixture was stirred at room temperature for 90 min, then cooled to 0° C. and treated slowly with a solution of 2-(trimethylsilyl)-ethoxymethylchloride (6.81 ml, 34.7 mmol) in DMF (10 ml). After 2 h stirring at 0° C., the reaction mixture was poured onto a mixture of H2O (200 ml) and AcOEt (50 ml). The mixture was filtered and the mother liquor was extracted 3 times with AcOEt. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed (silica, elution with hexane/AcOEt=9:1) to provide the title compound (9.44 g, 66.4%) as a pale yellow oil. MS: m/e=450.0 (M+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]2[NH:12][CH:11]=[CH:10][C:6]=2[CH:7]=[N:8][CH:9]=1.[CH3:13]I>CN(C=O)C.C(Cl)Cl>[Br:3][C:4]1[C:5]2[N:12]([CH3:13])[CH:11]=[CH:10][C:6]=2[CH:7]=[N:8][CH:9]=1
Reactant: CI
Reactant: Brc1cncc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ccc2cncc(Br)c21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Sodium hydride (0.25 g, 6.2 mmol) is added under ice bath cooling to a mixture of 7-bromo-1H-pyrrolo[3,2-c]pyridine (0.8 g, 4.1 mmol) in DMF (10 ml). The mixture is stirred for 30 minutes before methyl iodide (0.25 ml, 4.1 mmol) is added. The mixture is warmed to RT and stirred for 17 h. The mixture is diluted with DCM and extracted with a saturated aqueous sodium hydrogencarbonate solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 0.61 g (71%). HPLC-MS: tR=0.88 min (METHOD—1).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[O:9])[CH2:3]1.[CH3:22][O:23][C:24]1[N:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][O:23][C:24]1[N:29]=[C:28]([C:30]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([C:10]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)[N:11]=3)=[O:9])[CH2:3][C@H:2]2[CH3:1])=[O:31])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(-n2cnc(C(=O)N3CCN[C@H](C)C3)n2)c1
Reactant: COc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(C)c4)n3)C[C@H]2C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 86 mg (0.30 mmol) ((R)-3-methyl-piperazin-1-yl)-(1-m-tolyl-1H-[1,2,4]-triazol-3-yl)-methanone, 46 mg (0.30 mmol) 6-methoxy-pyridine-2-carboxylic acid, 0.11 g (0.33 mmol) TBTU and 80 μL (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]#[N:14].O.[SH2:16].[Na].Cl.C(NCC)C>CN(C=O)C.O>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13](=[S:16])[NH2:14]
Reactant: N#CCCc1ccc2c(n1)NCCC2
Reactant: S
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCNCC
Solvent: O
Product: NC(=S)CCc1ccc2c(n1)NCCC2
Temperature: 55 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
Reagents 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propanenitrile (100 mg), sodium hydrogen sulfide hydrate (360 mg), diethylamine hydrochloride (530 mg) were mixed in DMF (10 mL). The mixture was warmed to 55° C. and stirred at this temperature for about 24 h. The mixture was allowed to cool and then diluted with water (30 mL) followed by extraction with ethyl acetate (3×25 mL). The extracts were combined and washed with water (3×20 mL). The organic phase was dried (magnesium sulfate) and filtered. The solution was concentrated and column purification (CHCl3: MeOH=10:1) to yield a yellow solid 101 mg (89%). 1H NMR (DMSO-d6) δ 9.30 (d, 2H), 7.10 (d, 2H), 6.35 (m, 2H), 3.25 (m, 2H), 2.80 (m, 2H), 2.75 (m, 2H), 2.64 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.CS[C:13](=[NH:15])[NH2:14]>>[O:7]1[CH:8]=[CH:9][N:10]=[C:6]1[S:5][CH2:4][CH2:3][CH2:2][NH:1][C:13]([NH2:15])=[NH:14]
Reactant: NCCCSc1ncco1
Reactant: CSC(=N)N
Product: N=C(N)NCCCSc1ncco1

Procedure:
Reacting 2-(3-aminopropylthio)oxazole with S-methylisothiourea by the procedure of Example 1 gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:3]=1.[CH2:12]([O:19][CH2:20][C:21](Cl)=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CC(C)=O.O>[NH2:11][S:8]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:9])=[O:10]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cccc(NC(=O)COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A suspension of 1-aminobenzene-3-sulfonamide (1 g; 5.8 mmol; 1 eq) in a mixture of acetone (10 mL) and water (10 mL) is stirred at room temperature until complete dissolution. Benzyloxyacetyl chloride (1.4 mL; 8.7 mmol; 1.5 eq) is added at 0° C. followed by the addition of NaHCO3 (1.4 g) over 15 min. After 30 min, the reaction mixture is allowed to stir at room temperature for 2 h. The reaction mixture is then filtered off and the solid residue is washed with MeOH and ACN. The filtrate is concentrated to dryness, affording 1.8 g (97%) of the title compound as a brown foam. 1H NMR (DMSO-d6) δ 8.25 (br s, 1H), 7.81-7.75 (m, 1H), 7.55-7.48 (m, 2H), 7.42-7.28 (m, 8H), 4.62 (s, 2H), 4.13 (s, 2H). HPLC (max plot) 91%; Rt 2.53 min. UPLC/MS: (ES+) 321.2; (ES−) 319.2.
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Oc1ncnc2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ncccc12
Yield: 32 %

Procedure:
The solution of 4-hydroxypyrido[2,3-d]pyrimidine (2.00 g, 13.6 mmol) in POCl3 (40 mL) was refluxed for 2 hours. After cooling, the excess POCl3 was removed under vacuum. The residue was quenched with saturated NaHCO3 and extracted with ethyl acetate (3×100 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 4-chloropyrido[2,3-d]pyrimidine (0.72 g, 32%). 1H NMR (CDCl3, 400 MHz) δ 9.35 (m, 1H), 9.30 (s, 1H), 8.66 (m, 1H), 7.73 (m, 1H). MS (APCI+) [M+H]+166.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([S:8][C@@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1.[H-].[Na+].I[CH3:30].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([S:8][C@@H:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][N:11]([CH3:30])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](Sc1cc(Cl)ccc1C#N)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@@H](Sc1cc(Cl)ccc1C#N)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the product from Example 4 step (a) (92 mg) in THF (5 ml) was added sodium hydride (60% in oil; 10 mg) followed by iodomethane (60 μl). The mixture was stirred at room temperature for 2 days then poured into water and extracted with diethyl ether (three times). The combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated off to give the sub-title compound (100 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12]Br.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][NH:21][C:19]1[CH:18]=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=2[CH3:32])=[C:15]([Cl:14])[CH:20]=1
Reactant: FC(F)(F)c1ccc(CBr)c(Br)c1
Reactant: Cc1cc(C(F)(F)F)ccc1-c1ccc(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(F)F)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2Br)cc1Cl
Temperature: 80 °C

Procedure:
2-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene, prepared as described in Example 34 (2.5 g, 7.9 mmol), 2-chloro-2′-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-amine (2.5 g, 8.7 mmol), and K2CO3 (1.6 g, 11.8 mmol) were diluted with DMF (20 mL) and heated to 80° C. After 3 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]1[C@H:24](O)[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/[N:56]=[N:57]/C(OCC)=O)=O>C1(C)C=CC=CC=1.[Zn](N=[N+]=[N-])N=[N+]=[N-]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][C@H:12]1[C@@H:24]([N:27]=[N+:56]=[N-:57])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: c1c[nH]cn1
Reactant: C[C@@H](O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [N-]=[N+]=N[Zn]N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](N=[N+]=[N-])[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 51.6 %

Procedure:
(S, R)-1-benzyloxycarbonyl-2-(1-hydroxyethyl)-4-tert-butyloxycarbonyl-piperazine (7.6 g) was dissolved in 208 mL of toluene. While stirring, imidazole (3,5 g), triphenylphospine (15.31 g), and Zn(N3)2.pyr2 (14.11 g) were added in that order. The mixture was cooled to 0° C. and diethylazodicarboxylate (10.2 g) was added dropwise. The mixture was warmed to room temperature and stirred for 1 hour, then decanted into a separatory funnel and extracted with 2×360 mL of ethyl acetate. Any solids in the reaction flask were dissolved with 1N HCl, poured into the separatory funnel, and extracted with 2×760 mL of ethyl acetate. The combined organics were washed with 760 mL each of saturated NaHCO3 and brine, dried with Na2SO4, and concentrated. The residue was purified by flash chromatography, eluting with 4:1 hexanes-ethyl acetate to provide 4.19 g of the title compound. Mass spectrum (ESI) 334.1 (M−55).
Reaction SMILES: [O-:1]Cl=O.[Na+].[N:5]([C:8]1[N:9]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]([CH:14]=[O:15])=[C:11]([Cl:13])[N:12]=1)=[N+:6]=[N-:7].CC(=CC)C>O.C1COCC1.CC(O)(C)C>[N:5]([C:8]1[N:9]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]([C:14]([OH:1])=[O:15])=[C:11]([Cl:13])[N:12]=1)=[N+:6]=[N-:7]
Reactant: [O-][Cl+][O-]
Reactant: C[Si](C)(C)CCOCn1c(N=[N+]=[N-])nc(Cl)c1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(N=[N+]=[N-])nc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaClO2 (21.7 g, 240 mmol) and NaH2PO4.2H2O (19.9 g, 144 mmol) in H2O (51 mL) was added to a stirred solution of 2-azido-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carbaldehyde (7.2 g, 24.0 mmol) and 2-methyl-2-butene (144 mL of a 2M solution in THF, 2887 mmol) in THF (72 mL) and t-BuOH (17 mL). The reaction mixture was stirred at RT for 1 h and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and dried to provide 2-azido-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid as a clear oil that was assumed to be quantitative and used without further purification. The above acid (1.40 mmol) was stirred in a solution of TFA (2.15 mL, 27.9 mmol) in CH2Cl2 (2 mL) for 1 h at RT. Sat'd NaHCO3 was added and the mixture was washed with EtOAc. The aqueous layer was isolated, acidified with 1N HCl and extracted thoroughly with EtOAc. The organic layer was dried (Na2SO4), filtered, concentrated, and triturated with hexanes and again with diethyl ether to provide the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.33 (br. s., 1H), 12.77 (br. s., 1H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][NH:3]1.[CH3:24][S-:25].[Na+].O>CN1CCCC1=O>[O:1]=[C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[C:18]([S:25][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: C[S-]
Reactant: O=c1[nH]cccc1CN1CCC(CCc2cccnc2Cl)CC1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1ncccc1CCC1CCN(Cc2ccc[nH]c2=O)CC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
168 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in Example 117 and 354 mg of sodium thiomethoxide were suspended in 5 ml of 1-methyl-2-pyrrolidinone, and the mixture was stirred at 150° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (methanol:ethyl acetate=1:19), to give 20 mg of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2](SC)=[C:3]([C:6]#[N:7])[C:4]#[N:5].[CH3:10][NH:11][CH3:12]>CN(C)C=O>[NH2:1][C:2]([N:11]([CH3:12])[CH3:10])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: CSC(N)=C(C#N)C#N
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)C(N)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.1 %

Procedure:
Into a pressure bottle were placed 5.6 g of 3-amino-2-cyano-3-(methylthio)propenenitrile and 3 ml of dimethylformamide, and the mixture was cooled to 0°. A volume of 5.4 ml (3.6 g) of dimethylamine was condensed in a dry-ice trap and added to the pressure bottle. The bottle was sealed and the reaction mixture was heated, with stirring, at 100° for 3-4 hours (in subsequent runs, the heating time was reduced to 80 minutes without reducing the yield). After this time, the mixture was allowed to cool to ambient temperature, where it stood for two days. The pressure bottle was cooled to 0° and opened. The mixture was allowed to attain ambient temperature, then was poured into 300 ml of ice-water, causing a white solid to precipitate. The slurry was stirred for 30 minutes. The solid product was collected by filtration and washed with cold water to give 5.1 g of 3-amino-2-cyano-3-(dimethylamino)propenenitrile, m.p. 228°-229°. The nmr was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH2:32])[CH2:11][C:12]([CH3:31])([CH3:30])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH:18]([C:26]([NH:28][CH3:29])=[O:27])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4].[CH:36](OC1C=CC([N+]([O-])=O)=CC=1)=[O:37].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(NC(C)=O)C1)=O)CCC>>[CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH:32][CH:36]=[O:37])[CH2:11][C:12]([CH3:30])([CH3:31])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH:18]([C:26]([NH:28][CH3:29])=[O:27])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(C(=O)NC)Oc2ccccc21
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(NC(C)=O)Cc2ccccc21)NC(=O)OC(C)(C)C
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)NC)Oc2ccccc21)NC=O

Procedure:
140 mg of 5(S)-amino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[2(R,S)-methylaminocarbonyl-3,4-dihydro-2H-1,4-benzoxazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (Example 28)) are reacted with 100 mg of 4-nitrophenyl formate in a manner analogous to that described in Example 17): Rf (S)=0.33; FAB-M S: (M+H)+ =519.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1CCN>C(#N)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH2:11][CH2:12][NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: NCCc1c(F)cccc1F
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Fc1cccc(F)c1CCNC(=S)n1ccnc1
Yield: 124.7 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (9.5 g, 48 mmol) and 2-(2,6-difluorophenyl)ethylamine (7.54 g, 48 mmol) in acetonitrile (100 mL) was stirred at room temperature for 20 h. The solution was concentrated under reduced pressure and the resulting precipitate was collected by filtration and triturated with hexane to provide 16 g of crude titled product as a brown solid:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[F:10][C:11]([F:39])([F:38])[C:12]1[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[CH:29]=[C:28](F)[CH:27]=[CH:26][C:25]=2[N+:31]([O-:33])=[O:32])[CH:19]=1>CN(C)C=O.C(OCC)(=O)C>[F:38][C:11]([F:10])([F:39])[C:12]1[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[CH:29]=[C:28]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:27]=[CH:26][C:25]=2[N+:31]([O-:33])=[O:32])[CH:19]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(OC3CCOCC3)ccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 114 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tetrahydro-2H-pyran-4-ol (220 mg, 2.11 mmol, 3.00 equiv, 98%) in N,N-dimethylformamide (5 mL). This was followed by the addition of sodium hydride (86 mg, 3.58 mmol, 5.00 equiv), in portions at room temperature. The resulting solution was stirred for 10 min at room temperature. To this was added N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide (300 mg, 0.70 mmol, 1.00 equiv, 98%). Then the resulting solution was stirred for an additional 2 h at 80° C. in an oil bath. The resulting solution was diluted with 200 mL of ethyl acetate, and washed with 2×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/methanol (20/1). The product was obtained as 400 mg (97%) of a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][NH2:32])[CH:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][NH:32][C:21]([C:17]2[S:16][C:15]([C:12]3[CH:13]=[CH:14][N:10]([CH2:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH:25]=1
Reactant: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)O
Reactant: NCCc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)NCCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
To a solution of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (0.1 g, 0.30 mmol) in methylene chloride (5 mL) was added 2-pyridin-3-yl-ethylamine (0.04 g, 0.33 mmol), benzotriazol-1-yloxytris(dimethylamino)-hexafluorophosphate (0.146 g, 0.33 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.60 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (50 mL), washed with water (50 mL) and brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel eluting with 50% ethyl acetate, 50% hexane to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (2-pyridin-3-yl-ethyl)-amide as a white solid (0.095 g, 73%). 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=2 Hz, 2H), 7.58 (d, J=4 Hz, 1H), 7.25-7.28 (m, 1H), 7.14 (d, J=2 Hz, 1H), 6.90-7.03 (m, 4H), 6.70 (d, J=2 Hz, 1H), 5.96-6.03 (m, 1H), 4.34 (t, J=7 Hz, 2H), 3.65-3.73 (m, 2H), 3.17 (t, J=7 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 2.68 (s, 3H). MS (M+H)+=436.2; Rt=1.28 min; HRMS (M+H)+=436.16.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10][NH2:11].[CH3:13][C:14]([CH3:21])([CH2:18][CH:19]=O)[CH2:15][CH:16]=O>>[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10][N:11]1[CH:19]=[CH:18][C:14]([CH3:21])([CH3:13])[CH:15]=[CH:16]1
Reactant: CC(C)(CC=O)CC=O
Reactant: CN(C)CCN
Solvent: c1ccccc1
Product: CN(C)CCN1C=CC(C)(C)C=C1

Procedure:
In 100 ml of benzene 3.30 ml (0.03 mole) of N,N-dimethylethylenediamine was combined with 3.84 g (0.03 mole) of 3,3-dimethylglutaraldehyde under nitrogen. The reaction mixture was warmed to reflux and water azeotroped off via a Dean-Stark trap. After 15 hours the benzene was evaporated in vacuo giving 5.76 g of crude product as a brown liquid. The crude product was distilled to yield 2.41 g of the title compound as a clear liquid, bp 60° C./0.2 mm Hg.