Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[CH2:2]([O:4][C:5](=[O:18])/[C:6](/[O-:17])=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:3].[K+].[C:20]([O:23][C@@H:24]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@@H:29]([O:35][C:36](=[O:38])[CH3:37])[C@@H:28]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[O:27][C@@H:25]1O)(=[O:22])[CH3:21]>CN(C=O)C>[C:36]([O:35][C@H:29]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:24]([O:23][C:20](=[O:22])[CH3:21])[C@@H:25]([O:17]/[C:6](/[C:5]([O:4][CH2:2][CH3:3])=[O:18])=[CH:7]\[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[O:27][C@H:28]1[CH2:39][O:40][C:41](=[O:43])[CH3:42])(=[O:38])[CH3:37]
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CCOC(=O)/C([O-])=C/c1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/c1ccccc1[N+](=O)[O-])O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
The solution of potassium salt of 2-nitrophenylpyruvate B2 (100 mg, 0.36 mmol) in dry DMF (3 mL) was added dropwise over a period of 15 min, to a pre-cooled stirred solution of 2,3,4,6-tetra-O-acetyl-α-D-galactose (149 mg, 0.36 mmol) in dry DMF (2 mL) at 0° C. under nitrogen atmosphere. The temperature was gradually raised to room temperature. Reaction mixture was allowed to stir for 15 h, and the reaction was quenched with chilled, saturated aq. NaCl (25 mL). Extraction with ethyl acetate (3×30 mL), drying (MgSO4), concentration under reduced pressure, and purification by flash chromatography (SiO2, hexane-benzene-acetone-methanol, 5:4:5:1) to isolate the pure resultant compound C3 in 50% yield.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=2[O:5][C:4]=1/[N:17]=[CH:18]/[N:19](C)C)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])N>C(#N)C.C(O)(=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([NH:2][C:1]2[C:3]3[C:11]4[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=4[O:5][C:4]=3[N:17]=[CH:18][N:19]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: CCOC(=O)N1CCc2c(oc(/N=C/N(C)C)c2C#N)C1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)N1CCc2c(oc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Reaction time: 20 h
Yield: 22.3 %

Procedure:
Ethyl 3-cyano-2-{[(1E)-(dimethylamino)methylidene]amino}-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 37A (1.20 g, 4.14 mmol) and 3-chloro-4-fluoroaniline (1.20 g, 8.27 mmol) were heated in a mixture of acetonitrile (20 mL) and acetic acid (10 mL) in a microwave oven for 30 min to 160° C. The mixture was then concentrated in vacuo, diluted with water, basified with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The residue was triturated with dichloromethane and left to stand for 20 h. The precipitate was collected by suction filtration. Subsequently, the solid was triturated with methanol. The crystals were collected by suction filtration and washed with diethyl ether to yield 360 mg (22%) of the title compound. A second batch of 159 mg (10%) was obtained from the mother liquor after purification by preparative HPLC.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:46][CH2:45][CH2:44][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([O:36]CC1C=CC=CC=1)=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13]S(C1C=CC(C)=CC=1)(=O)=O)=[O:5])[CH3:3].C1(OC)C=CC=CC=1>>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:46][CH2:45][CH2:44][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([OH:36])=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:13])[NH2:24])=[O:5])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)OCc2ccccc2)cc1
Solvent: COc1ccccc1
Product: C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
The solution of 250 mg (0.330 mmol) of Boc-Ala-Arg(Tos)-Pro-Ala-OBzl (SEQ ID NO: 7), 1 ml of anisole and 2 ml of HF was stirred at 0° C. for 2 h. The reaction mixture was evaporated under reduced pressure to remove HF. To the residue 2 ml of HF were added and the solution was stirred at 0° C. for another 1 h. The reaction mixture was evaporated under reduced pressure to remove HF. The residue was triturated with ether and the resulted solid was purified on the Sephadex G-10 column. The collected fractions were lyophilized to provide 80 mg (58%) of the title compound. Mp. 157–159° C., FAB-MS (m/e) 415[M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:16][C@@H:17]([CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:18][NH:19]C(=O)OCC[Si](C)(C)C)=[O:15])[CH2:9]1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].C(Cl)Cl>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:16][C@@H:17]([CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:18][NH2:19])=[O:15])[CH2:9]1
Reactant: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CNC(=O)OCC[Si](C)(C)C)CC2CCCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN)CC2CCCCC2)C1
Reaction time: 0.5 h

Procedure:
2-(Trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropylcarbamate (85.3 mg, 0.14 mmol) was dissolved in 6 mL 1:1 TFA/CH2Cl2 (6 mL) and stirred for 30 min. LC-MS showed the reaction was complete. After concentration, (3R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)-N—((S)-1-amino-3-cyclohexylpropan-2-yl)piperidine-1-carboxamide trifluoroacetic acid salt was isolated by prep HPLC. LC-MS (3 min) tR=1.56 min, m/z 446 (M+1). 1H NMR (CD3OD) δ 7.37-7.25 (m, 5H), 4.30 (d, 1H), 4.03 (m, 1H), 4.97-4.90 (m, 2H), 3.50-3.39 (m, 2H), 3.27 (s, 3H), 3.00 (dd, 1H), 2.85-2.75 (m, 3H), 1.81-0.82 (m, 22H).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].C(N(CC)C(C)C)(C)C.[CH:51]([NH:54][CH2:55][CH:56]1[CH2:60][CH2:59][CH2:58][O:57]1)([CH3:53])[CH3:52]>C(Cl)Cl>[CH:51]([N:54]([CH2:55][CH:56]1[CH2:60][CH2:59][CH2:58][O:57]1)[C:2](=[O:3])[NH:1][C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])([CH3:53])[CH3:52]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Reactant: CC(C)NCC1CCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)N(CC4CCCO4)C(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.3 %

Procedure:
2-Isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (125 mg, 0.22 mmol), N,N-diisopropylethylamine (0.06 mL, 0.34 mmol), isopropyl-(tetrahydro-furan-2-ylmethyl)-amine (315 mg, 2.2 mmol), and methylene chloride (3 ml) were combined and stirred at room temperature for 18 hours. The reaction was concentrated to dryness in vacuo. The crude material was dissolved in a solution of tetrahydrofuran (4 mL) and methanol (1 mL). To the mixture was added 0.2 mL 50% w/v aqueous potassium hydroxide and the combined mixture stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate, and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated to dryness in vacuo. The crude material was purified by preparative HPLC to give 15 mg (27 μmol, 12%) of 2-[3-isopropyl-3-(tetrahydro-furan-2-ylmethyl)-ureido]-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide. 1H-NMR (250 MHz, CDCl3) δ 11.90 (s, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.72-7.52 (m, 4H), 7.30 (t, J=7.1 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H); MS: m/z 556.4 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:4][C:3]=1[CH:17]([CH3:19])[CH3:18].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.[Cl-].[CH3:44][O:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([N:54]=[N:55][C:56]2[CH:61]=[CH:60][C:59]([CH2:62][NH3+:63])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)=[O:47].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl.CO>[OH:1][C:2]1[C:3]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:5]([CH2:11][CH2:12][CH2:13][C:14]([NH:63][CH2:62][C:59]2[CH:58]=[CH:57][C:56](/[N:55]=[N:54]/[C:51]3[CH:52]=[CH:53][C:48]([C:46]([O:45][CH3:44])=[O:47])=[CH:49][CH:50]=3)=[CH:61][CH:60]=2)=[O:16])=[CH:6][C:7]=1[CH:8]([CH3:9])[CH3:10]
Reactant: CC(C)c1cc(CCCC(=O)O)cc(C(C)C)c1O
Reactant: COC(=O)c1ccc(N=Nc2ccc(C[NH3+])cc2)cc1
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(/N=N/c2ccc(CNC(=O)CCCc3cc(C(C)C)c(O)c(C(C)C)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
Acid 8 (164 mg, 1.00 mmol), benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (BOP, 884 mg, 2.00 mmol) and DMAP (12 mg, 0.10 mmol) were dissolved in methylene chloride (10 mL) and stirred at room temperature for 10 min. A solution of compound 4 (366 mg, 1.2 mmol) and triethylamine (505 mg, 5.0 mmol) in methylene chloride (15 mL) was added, and the reaction mixture was stirred at room temperature for 48 h. Aqueous work-up and chromatography on silica gel using chloroform and chloroform-methanol (3%) step-gradient as an eluent afforded pure 9 (296 mg, 57%) as orange crystals. 1H NMR (360 MHz, CDCl3): δ 8.18 (d, J=8.6 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H), 7.91 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 6.85 (s, 2H), 5.83 (t, J=9.1 Hz, 1H), 4.73 (s, 1H), 4.53 (d, J=5.9 Hz, 2H), 3.96 (s, 3H), 3.11 (septet, J=6.9 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H), 2.29 (t, J=7.6 Hz, 2H), 1.99 (q, J=7.6 Hz, 2H), 1.24 (d, J=6.9 Hz, 12H). 13C NMR (90.55 MHz, CDCl3): δ 173.23, 166.90, 155.42, 152.23, 148.52, 142.66, 133.99, 133.57, 132.17, 130.98, 128.85, 128.38, 123.87, 123.73, 123.01, 121.65, 120.13, 52.73, 43.56, 36.51, 35.45, 28.02, 27.51, 23.15. HRMS (m/z): [M+H]+ calcd. for C31H37N3O4 516.2857. found 516.2863.
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O1CCOCC1.Cl[CH2:16][C:17]([C-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1)=O.[CH-:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1.[Fe+2:29]>O>[CH:19]1([CH2:17][C:16]([C-:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)=[S:6])[CH2:23][CH2:22][CH2:21][CH2:20]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:29]
Reactant: SC1CCCC1
Reactant: O=C(CCl)[c-]1cccc1
Agent: [Fe+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: S=C(CC1CCCC1)[c-]1cccc1
Yield: 8.7 %

Procedure:
Cyclopentylmercaptan (ca 1.5g, 0.015M) was added to a solution of sodium hydroxide (0.6g, 0.015M) in water (3 ml). Dioxan (45 ml) was added, followed by chloroacetylferrocene (3.9g, 0.015M), and the mixture was heated at 100° for 2 hours with stirring. On cooling, water was added to the reaction mixture which was then extracted with chloroform. The organic layer was washed with dilute sodium hydroxide and water before it was dried over anhydrous magnesium sulphate and evaporated to an oil on a rotary evaporator. The product was isolated after column chromatography on silica gel using gradient elution with 1-21/2% (v/v) ethyl acetate in petroleum ether (60-80). Orange needles (0.40g) of the title compound were obtained mp = 78°-9°.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28](Br)[S:29][C:30]=2[NH:31]C(OC(C)(C)C)=O)=[O:25])[CH2:13][CH2:12]1)C1C=CC=CC=1.[F:42][C:43]1[CH:48]=[C:47]([CH3:49])[CH:46]=[CH:45][C:44]=1B(O)O>>[NH2:31][C:30]1[S:29][C:28]([C:44]2[CH:45]=[CH:46][C:47]([CH3:49])=[CH:48][C:43]=2[F:42])=[N:27][C:26]=1[C:24]([NH:23][C:22]1[CH:21]=[N:20][N:19]([CH3:40])[C:18]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:11]([NH2:10])[CH2:12][CH2:13]1)=[O:25]
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Product: Cc1ccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](N)CC3)c(N)s2)c(F)c1
Yield: 20.5 %

Procedure:
Following the procedures from Example 210 and shown in FIG. 3, using ((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester and 2-fluoro-4-methyl-phenylboronic acid as starting materials, 211 was obtained in 20.5% yield over two steps: 1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.14 (t, J=8.2 Hz, 1H), 7.47 (s, 1H), 7.36 (broad s, 2H), 7.22-7.14 (m, 2H), 3.66 (s, 3H), 3.45-3.05 (m, 7H), 2.36 (s, 3H), 1.98-1.78 (m, 3H), 1.72-1.54 (m, 3H); MS (ESI) m/z: 444.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2cccc(Cl)c2)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2cccc(CBr)c2)c1
Yield: 93.4 %

Procedure:
3'-Chloro-3-methyl[1,1'-biphenyl] (7.0 g, 0.035 mole) and N-bromosuccinimide (6.4 g, 0.035 mole) in 100 ml of carbon tetrachloride were irradiated for 4 hours with white light to afford 3-bromomethyl-3'-chloro[1,1'-biphenyl] (9.2 g). The nmr spectrum was consistent with that expected for the named compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=O)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:21]([CH:22]=O)=[CH:20][CH:19]=[CH:18][N:17]=1.[OH-].[K+]>C(O)C>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:22]=[CH:12][C:11]=1[CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14]
Reactant: CC(=O)CCCNC(=O)OC(C)(C)C
Reactant: Nc1ncccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1ccc2cccnc2n1

Procedure:
A mixture of 11-4 (5.0 g, 24.8 mmol), 1-3, 2-amino-3-formylpyridine (3.6 g, 29.8 mmol) and 20% KOH (1 ml) in absolute ethanol (100 mL) was heated at reflux for 8 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/methanol) to give 11-6 as a yellow oil.
Reaction SMILES: C(O[C:5](=O)[C@:6]([NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:20])C1C=CC=CC=1)N)N)C#C.[C:31](#N)[CH3:32].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.C(Cl)(Cl)(Cl)Cl>[CH:5]([C:6]1([NH:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][CH2:9][CH2:10][NH:12][C:13]1=[O:20])=[C:31]=[CH2:32]
Reactant: C#CCOC(=O)[C@@](N)(CCC(N)NC(=O)c1ccccc1)NC(=O)c1ccccc1
Reactant: CC#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C=CC1(NC(=O)c2ccccc2)CCCNC1=O
Reaction time: 2 h

Procedure:
An 11.04 g aliquot of 2,5-di(benzoylamino)ornithine propargyl ester was added to 80 ml of dry acetonitrile, 21.97 ml of triethylamine, 12.48 carbon tetrachloride and 30.69 g of triphenylphosphine. After about 2 hours at room temperature, 50 ml of methanol were added and the solution left at room temperature overnight. The reaction mixture was concentrated in vacuo, and to this residue was added 80 ml of tetrahydrofuran and 40 ml of 10% acetic acid and stirring. After 24 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and 10% HCl. The organic layer was extracted several times with 10% HCl after which the combined aqueous fractions were washed exhaustively with methylene chloride. The pH of the aqueous portion was adjusted to 10 with concentrated sodium hydroxide to induce lactam formation. On cooling, a precipitate formed which was filtered and recrystallized from methanol-ethyl acetate to give the title compound, mp 203°-204° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[NH:35]1[CH2:38][CH:37]([OH:39])[CH2:36]1.CS(C)=O>CN1C(=O)CCC1>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:35]4[CH2:38][CH:37]([OH:39])[CH2:36]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: OC1CNC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CC(O)C4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and azetidin-3-ol hydrochloride in NMP. [α]D20=+12.2° (c=0.51, DMSO), ES-MS m/e (%): 443 (M+H+, 100).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:29])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:24]([CH2:25]O)=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.[CH2:30]([N:32](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:29])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:24]([CH2:25][C:30]#[N:32])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCN(CC)CC
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2ncccc2CO)cc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2ncccc2CC#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a mixture of [2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]-3-pyridyl]methanol (2.12 g), triethylamine (1.09 g) and ethyl acetate (150 mL) was dropwise added methanesulfonyl chloride (1.24 g) under ice-cooling and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (30 mL) was added an aqueous solution (3 mL) of sodium cyanide (0.66 g) at room temperature and the mixture was stirred at room temperature for 3 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.63 g, 75%) of 2-[2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]1[OH:41])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]4[OH:41])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(N[C@@H]1CCCC[C@@H]1O)c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@@H]3CCCC[C@@H]3O)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-((1R,2S)-2-hydroxycyclohexyl)benzenesulfonamide. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.33 (s, 2H), 8.15-8.11 (m, 1H), 7.98 (m, 1H), 7.69-7.64 (m, 1H), 7.61-7.56 (m, 1H), 7.42-7.32 (m, 3H), 3.70-3.63 (m, 1H), 3.09-3.03 (m, 1H), 1.70-1.61 (m, 1H), 1.60-1.44 (m, 3H), 1.42-1.24 (m, 3H), 1.22-1.10 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Si]([C:13]#[CH:14])(C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:13]#[CH:14])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C#Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.2 %

Procedure:
To an oven-dried flask under N2 was added 1-bromo-3-iodobenzene (5.00 g, 17.73 mmol), anhydrous, degassed THF (100 mL), dichlorobis(triphenyl-phosphine)palladium(II) (620 mg, 0.88 mmol), copper(I) iodide (100 mg, 0.53 mmol), TEA (7.15 g, 71 mmol), and TMS acetylene (1.91 g, 20 mmol). After stirring overnight at rt, the reaction was washed with brine (100 mL), organic layer separated, concentrated under reduced pressure, adsorbed to silica gel and purified by column chromatography (5% EtOAc in hexanes) to afford the desired product (3.57 g, 80%) as a clear oil. This was dissolved in 100 ml 1:1 THF:MeOH and to this was added water (10 mL), and K2CO3 (5.87 g, 43 mmol). After stirring overnight at rt, the reaction was washed with brine (100 mL), adsorbed to silica gel and purified by LC (5% EtOAc in hexanes) to afford the alkyne (1.92 g, 75%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.10 (s, 1H), 7.17 (t, J=7.69 Hz, 1H), 7.38-7.44 (m, 1H), 7.45-7.48 (m, 1H), 7.61-7.62 (s, 1H).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[N:14]=[C:15]([C:19](Cl)(Cl)Cl)[NH:16][C:17]=1[Cl:18].C(N(CC)CC)C>O1CCOCC1>[Cl:12][C:13]1[N:14]=[C:15]([C:19]2[O:11][C:8]([O:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:9][N:10]=2)[NH:16][C:17]=1[Cl:18]
Reactant: NNC(=O)Oc1ccccc1
Reactant: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1nc(-c2nnc(Oc3ccccc3)o2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
16.7 g (0.11 mol) of carbazic acid phenyl ester were added in portions, at room temperature, to a solution of 25.4 g (0.1 mol) of 4,5-dichloro-2-trichloromethyl-imidazole in 200 ml of dioxane. After the slightly exothermic reaction had subsided, the mixture was gradually warmed to the boil and boiled for a further 2 hours under reflux. It was then cooled to room temperature and 20.2 g (0.2 mol) of triethylamine were added dropwise. The mixture was stirred for a further 2 hours at 50° C., the insoluble constituents were filtered off and the filtrate was evaporated in vacuo. The residue was treated with water and the product was filtered off, washed with water and dried. 21.5 g (72.5% of theory) of 2-(4,5-dichloro-imidazol-2-yl)-5-phenoxy-1,3,4-oxadiazole were obtained. Melting point: 109° C. (from toluene).