Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][CH:3]([CH2:5][OH:6])[OH:4].[CH2:7]([OH:10])[CH2:8][OH:9].[CH:11](=[O:14])[CH2:12][OH:13]>CO>[CH2:11]([OH:14])[C@@H:12]([OH:13])[C@@H:7]([OH:10])[C@H:8]([OH:9])[C@@H:5]([OH:6])[C@@H:3]([OH:4])[CH:2]=[O:1]
Reactant: O=CC(O)CO
Reactant: O=CCO
Reactant: OCCO
Solvent: CO
Product: O=C[C@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Using the above described procedure of Example 1, glucose (Example 2) was cleanly decarbonylated by one equivalent of chlorotris(triphenylphosphine)rhodium to yield arabinitol (88%) in about 4 hours. Similarly, arabinose (Example 3) yielded erythritol (84%). Glyceraldehyde (Example 4), which has a higher free aldehyde content (ca. 2% in aqueous solution at room temperature), yielded ethylene glycol (95%) in just 30 minutes under the same conditions. Similar results were observed with glycol aldehyde, which yielded methanol (83%) and glucoheptose which yielded glucitol (88%) (Example 5). A practical demonstration of the utility of this reaction is provided by the one-step conversion of commercially available 2-deoxyribose (Example 6) into the much less accessible 1-deoxyerythritol (30 min., >90%). This is particularly significant in that the best known synthesis of 1-deoxyerythritol requires seven steps from glucose [Chaby, R., et al., Tetrahedron, 27:3197-3205 (1971)].
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Br:23])[CH:14]=1)=O)(=O)[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].ClC1C=C(C2[N:36]=C(CCC(OC)=O)OC=2)C=C(C(F)(F)F)C=1>>[Br:23][C:15]1[CH:14]=[C:13]([C:11]2[N:36]=[C:1]([CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:9][CH:10]=2)[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: COC(=O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Reactant: COC(=O)CCC(=O)OCC(=O)c1cc(Br)cc(C(F)(F)F)c1
Product: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Yield: 47 %

Procedure:
The title compound was prepared from 2-(3-bromo-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (Reference Example 43) by a procedure similar to the one described for methyl 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 36) to provide methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (3.62 g, 47%) as a yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@@H:6]([CH2:8][OH:9])[NH2:7])[CH3:3].N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)CC(=O)OCC1C=CC=CC=1.COC(=O)[C@H](CC1C=CC=CC=1)N[C:42](=[O:55])[C@:43]([NH2:54])([CH2:50][C:51](=[O:53])[OH:52])[NH:44][C:45](=[O:49])[CH:46]([CH3:48])[CH3:47]>>[CH2:2]([O:4][C:5](=[O:10])[C@@H:6]([CH2:8][OH:9])[NH:7][C:42](=[O:55])[C@:43]([NH2:54])([CH2:50][C:51](=[O:52])[OH:53])[NH:44][C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C
Reactant: CCOC(=O)[C@H](N)CO
Agent: Cl
Agent: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Product: CCOC(=O)[C@@H](CO)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C

Procedure:
This compound was prepared from 1.7 g D-serine ethyl ester hydrochloride, 3.6 g Z-Asp(OBzl) and 1.8 g N-t-butoxycarbonyl-α-aminoisobutyric acid N-hydroxysuccinimide ester in a manner similar to Example 20 (A), (C), (D) and (E). Yield: 1.2 g, m.p.: 175°-178° C.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19].C(OCC)(=O)C>O>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:19]
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 237.3 %

Procedure:
71.6 g (0.5 mol) of 1-aminocyclohexanecarboxylic acid was added to a solution of 20 g (0.5 mol) of sodium hydroxide in 250 ml of water, and the mixture was stirred at 80° C. for 2 hours. The mixture solution was cooled by ice-water, and 71.8 g (0.2 mol) of 2-furancarbonyl chloride and a solution of 24 g (0.6 mol) of sodium hydroxide in 100 ml in water were simultaneously added thereto for approximately 1 hour. The reaction solution was slowly returned to room temperature, and it was stirred overnight. After 80 ml of ethyl acetate was added to the reaction solution and the mixture was stirred for 1 hour, the insolubles were removed by filtration. The aqueous layer was separately collected, and 49 ml of concentrated hydrochloric acid was added thereto under ice-cooling. The precipitated crystal was collected by filtration and dried under reduced pressure to obtain 112.6 g (95%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.C1([S:11]([N:14]2[C:26]3[CH2:25][N:24]([CH2:27][CH:28]([CH:37]4[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]4)[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23][CH2:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])C=CC=CC=1.[C-:44]#[N:45].[K+]>CO.O1CCCC1.O>[C:15]1([S:11]([N:14]2[C:26]3[CH2:25][N:24]([CH2:27][CH:28]([CH:37]4[CH2:38][CH2:39][C:40]([N:2]([CH3:3])[CH3:1])([C:44]#[N:45])[CH2:41][CH2:42]4)[O:29][Si:30]([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:32])[CH3:31])[CH2:23][CH2:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)OC(CN1CCc2c(n(S(=O)(=O)c3ccccc3)c3ccccc23)C1)C1CCC(=O)CC1
Reactant: CNC
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1(C#N)CCC(C(CN2CCc3c(n(S(=O)(=O)c4ccccc4)c4ccccc34)C2)O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40% aqueous dimethylamine solution (596 μl, 4.73 mmol) was added to a mixture of 4 M hydrochloric acid (256 μl) and methanol (153 μl), while cooling with ice. A solution of the product from stage 6 (557 mg, 0.98 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml) was added to the mixture. Potassium cyanide (153 mg, 2.36 mmol) and water (2 ml) were then added. The suspension was stirred at room temperature overnight and thereafter diluted with water (20 ml). The mixture was extracted with diethyl ether (5×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1.N[OH:13]>O1CCCC1>[OH:13][NH:2][CH:3]=[N:4][C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1
Reactant: CN(C)C=Nc1cnccn1
Reactant: NO
Solvent: C1CCOC1
Product: ONC=Nc1cnccn1
Temperature: 80 °C

Procedure:
A solution of N,N-dimethyl-N′-pyrazin-2-ylimidoformamide (189 g) from Step A in tetrahydrofuran (400 mL) was treated drop wise with 50% aqueous solution of hydroxylamine (245.7 mL) at 0° C., then warmed up to 80° C. for 2.5 h. Tetrahydrofuran was removed by rotoevaporation and the resulting aqueous mixture kept cold in a refrigerator. The resulting solid was filtered and rinsed with cold diethyl ether to yield the desired product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[C:24]([O:28][C:29]([NH:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[C:24]([O:28][C:29]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([NH:36]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:37][CH:38]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-tert.butoxycarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16](NC(C)(C)C)=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:24].O.[OH-].[Na+]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]([OH:17])=[O:24])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ncccc1CCc1cccc(Cl)c1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide (1.0 mole, 317 g), sulfuric acid (325 mL) and water (300 mL) are refluxed at about 130° C. for approximately 2 hours. Completeness of the reaction is determined by thin layer chromatography. The reaction mixture is cooled to about 35° C. and added to ice (2 kg). The mixture is then brought to about pH 11 with 50% sodium hydroxide. Additional ice (1 kg) is added, followed by ethyl acetate (1 liter) and hexane (525 mL). The mixture is acidified to about pH 4 with sulfuric acid and stirred for about 1 hour. Crude product is isolated by filtration, washed with water and hexane and optionally dried at about 50° C. Then the crude product is dissolved in ethyl acetate by refluxing at about 75° C. After treating the solution with decolorizing carbon (5 g), the filtrate is concentrated and cooled to about 15° C. Purified product is isolated by filtration, washed with hexane: ethyl acetate (3:1) and dried at about 50° C. A second crop may be obtained by concentrating the mother liquor and recrystallizing from ethyl acetate as described above. The yield of product is shown to be 60%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15]O)[CH:6]=[CH:5]2.[Cl-:19].ClC=[N+](C)C.CN([CH:28]=[O:29])C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][Cl:19])[CH:6]=[C:5]2[CH:28]=[O:29]
Reactant: CC(C)(CO)Cn1ccc2cc(Br)ccc2c1=O
Reactant: CN(C)C=O
Reactant: [Cl-]
Agent: C[N+](C)=CCl
Solvent: O
Product: CC(C)(CCl)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A solution of 6-bromo-2-(3-hydroxy-2,2-dimethylpropyl)isoquinolin-1(2H)-one (Example 2a, 0.92 g) dissolved in DMF (5 ml) was treated with (chloromethylene)dimethylammonium chloride (1.90 g) in a sealed tube. The resulting mixture was stirred at 80° C. for 20 h. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (300 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution with 50% diethyl ether in isohexane) to afford the subtitle compound (0.50 g) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:9])[C:7]2=[CH:30][CH:31]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:9])[C:7]2=[CH:30][CH:31]=1
Reactant: [H][H]
Reactant: CCOc1cc(C(CC(=O)OC)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)OC)N2C(=O)c3ccc(N)cc3C2=O)ccc1OC
Yield: 92 %

Procedure:
To a solution of methyl 3-(4-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate (2.3 g, 5.4 mmol) in 25 mL of ethyl acetate was added 0.25 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford a yellow solid. The crude product was purified by flash column chromatography (silica gel, 20% ethyl acetate/methylene chloride). The resulting solid was dried in vacuo (60° C.,<1 mm) to afford 1.98 g (93%) of methyl 3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate as a yellow solid: mp 65-67° C.; 1H NMR (CDCl3)δ 7.56-7.48 (m, 1H); 7.15-6.93 (m, 3H), 6.85-6.71 (m, 2H), 5.70 (dd, J=6.1, 9.7 Hz, 1H), 4.35 (br s, 2H), 4.09 (q, J=7 Hz, 2H), 3.83 (s, 3H), 3.72 (dd, J=9.7, 16.4 Hz, 1H), 3.62 (s, 3H), 3.23 (dd, J=6.1, 16.4 Hz, 1H), 1.44 (t, J=7 Hz, 3H); 13C NMR (CDCl3)δ 171.2, 168.3, 168.2, 152.3, 148.9, 148.1, 134.6, 131.4, 125.1, 120.3, 120.2, 117.9, 112.6, 111.2, 108.4, 64.3, 55.9, 51.8, 50.4, 38.1, 14.7; HPLC (Waters Radial-Pak Phenyl column, 1.8×100 mm, 1 mL/min, 240 mm, 55/45, acetonitrile/0.1% aqueous phosphoric acid) 3.5 min, 100%; Anal. Calcd. for C21H22N2O6.0.29 H2O. Theoretical: C, 62.49, H, 5.63, N, 6.94. Found: C, 62.53; H, 5.62; N, 6.78.
Reaction SMILES: [Cl-:1].[N:2]1([S:7]([NH:10][C@H:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])(=[O:9])=[O:8])[CH:6]=[CH:5][N:4]=[CH:3]1.[O:22](C)[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[S:23]([O-:25])(=[O:24])=[O:22].[Cl-:1].[CH3:21][O:20][C:18](=[O:19])[CH2:17][C@@H:11]([NH:10][S:7]([N:2]1[CH:6]=[CH:5][N+:4]([CH3:26])=[CH:3]1)(=[O:9])=[O:8])[CH2:12][N+:13]([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)C[C@H](C[N+](C)(C)C)NS(=O)(=O)n1ccnc1
Reactant: COS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C[C@H](C[N+](C)(C)C)NS(=O)(=O)n1cc[n+](C)c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-(1H-imidazole-1-sulfonamido)-4-methoxy-N,N,N-trimethyl-4-oxobutan-1-aminium chloride in DCM (5 mL), cooled at 0° C., is added methyl triflate (1.05 equiv). After being stirring for 2 h at 0° C., the reaction mixture is concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26](SC)=[N:25][C:24]2=[O:30])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Al]>CC#N>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:25][C:24]2=[O:30])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:16])([F:17])[F:15]
Reactant: COc1cc(C=C2SC(SC)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Reactant: C1COCCN1
Agent: [Al]
Solvent: CC#N
Product: COc1cc(C=C2SC(N3CCOCC3)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
A solution of 4-[2-Methoxy-4-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile (88 mg, 0.2 mmol) in CH3CN (1 mL) was treated with morpholine (0.4 mmol) and heated to 60° C. in an aluminum heating block for 10 h. The solvent was removed in vacuo and the crude reaction mixture was purified by silica gel chromatography (EtOAc/CH2Cl2) to afford the title compound. 1H NMR (400 Hz, CDCl3) δ 7.95 (d, 1H), 7.79 (s, 1H), 7.66 (dd, 1H), 7.19 (m, 3H), 6.76 (d, 1H), 4.10 (m, 2H), 3.84 (m, 4H), 3.78 (s, 3H), 3.64 (m, 2H); LC/MS (m/z) [M+1]+490.3 (calculated for C23H19F3N3O4S, 490.47).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[C:18]([Br:19])=[CH:17][S:16][CH:15]=1.CN([CH:23]=[O:24])C>C1COCC1>[Br:13][C:14]1[C:18]([Br:19])=[CH:17][S:16][C:15]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Brc1cscc1Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1scc(Br)c1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
To a solution of diisopropylamine (1.3 g, 12.5 mmol) in 15 mL of anhydrous THF was added n-BuLi (4.0 mL, 2.5 M in hexane) at −78° C. After the mixture was stirred at −78° C. for 0.5 h 3,4-dibromothiophene (2 g, 8.3 mmol) in anhydrous THF (20 mL) was added. The mixture was stirred at −78° C. for 15 min., a solution of DMF (670 mg, 9.2 mmol) in THF (5 mL) was added. After being stirred at this temperature for 0.5 h, the mixture was stirred at room temperature for 2 hours. The mixture was quenched with NH4Cl saturated solution, diluted with water, extracted with EtOAc, concentrated, and purified by column chromatography to give 3,4-dibromothiophene-2-carbaldehyde (1.0 g, yield 45%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:16].[Na+]>CC(C)=O.CCCCCC>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][I:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: ICc1cccc(Oc2ccccc2)c1
Reaction time: 8 h

Procedure:
To a solution of 3-phenoxybenzyl chloride (10.0 g, 45.7 mmol) in 200 ml acetone was added sodium iodide (7.6 g, 507 mmol). The mixture was stirred at temperature overnight. The mixture was diluted with 300 ml hexane and the organic layer was washed twice with 5% sodium bicarbonate, once with brine and then dried over MgSO4. Evaporation of the filtrate gave a light yellow oil. The product was used in next step without purification. 1H NMR (CDCl3) 4.4 (s, 2H), 6.8-7.4 (m, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>>[CH3:18][N:19]([CH3:23])[C:20](=[S:21])[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:16][CH:15]=1
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1cccc(C(=O)c2ccc(O)cc2)c1
Product: CN(C)C(=S)Oc1ccc(C(=O)c2cccc(C#N)c2)cc1
Yield: 93.2 %

Procedure:
Following the procedure described in Preparation I and starting from 27 g (0.121 mol) of 3-cyanophenyl 4-hydroxyphenyl methanone and 17.2 g (0.138 mol) of dimethylthiocarbamoyl chloride, 35 g (yield: 88%) of O-4-(3-cyanobenzoyl)phenyl dimethylthiocarbamate melting at 160° C. are obtained.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]#[N:17])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[OH:18][CH2:19][C:20](=O)[CH3:21].O>C1COCC1.C(OCC)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[O:18][CH:19]=[C:20]([CH3:21])[N:17]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Reactant: CC(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1coc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
17 mL 2 mol/L aqueous sodium hydroxide solution was dropped to 6.7 g 4-cyano-piperazine-1-carboxylic acid tert-butyl ester and 2.5 mL 1-hydroxy-propan-2-one in 10 mL THF. The reaction was stirred 12 h at RT and over night at 75° C. The reaction was cooled, water was added and the mixture was diluted with diethylether. The precipitate was filtered to give 1.32 g of the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)=O.C(OC(C1N(C)C2C(C=1)=CC=CC=2)=O)C>>[CH3:16][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)[CH:13]=[C:5]1[CH2:3][NH:2][CH3:1]
Reactant: CNC(=O)c1cc2ccc(OC)cc2n1C
Agent: CCOC(=O)c1cc2ccccc2n1C
Product: CNCc1cc2ccc(OC)cc2n1C
Yield: 95 %

Procedure:
N, 1-Dimethyl-6-methoxy-1H-indole-2-carboxamide According to the procedure of Preparation 1(b), except substituting methyl-1-methyl-6-methoxy-1H-indole-2-carboxylate for ethyl-1-methyl-1H-indole-2-carboxylate, the title compound (95%) was prepared as an off-white solid: MS (ES) m/e 219.2 (M+H)+ and 437.4 (2M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)=[O:36])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccccn3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-pyridinecarbonyl chloride: ESMS m/e: 484.6 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC#N>[Br-:1].[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCc1cccc(Br)c1
Solvent: CC#N
Product: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]

Procedure:
A stirred mixture of 3-bromobenzyl bromide (Aldrich) (5.1 g, 20.5 mmoles), triphenylphosphine (54 g, 0.20 moles), and CH3CN (100 mL) was refluxed for 20 hours. The cooled reaction mixture was then concentrated and the residue triturated with hexanes (10×) to remove excess triphenylphosphine. The remaining white solid was collected by filtration and then dried in vacuo to give 11-2 as a white solid.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:17]2[C:21]([CH2:22][O:23][CH2:24][C:25]#[CH:26])=[N:20][N:19]=[C:18]2[CH2:27][NH2:28])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[C:29]1(=[O:43])[N:33]([CH2:34][C:35](Cl)=[O:36])[C:32](=[O:38])[C:31]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:30]12.CN(C)C=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:17]2[C:21]([CH2:22][O:23][CH2:24][C:25]#[CH:26])=[N:20][N:19]=[C:18]2[CH2:27][NH:28][C:35](=[O:36])[CH2:34][N:33]2[C:32](=[O:38])[C:31]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:30]3[C:29]2=[O:43])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: C#CCOCc1nnc(CN)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C#CCOCc1nnc(CNC(=O)CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the above product (817 mg) and 27.5% hydrogen bromide/acetic acid (3 ml) is stirred at room temperature for 1.5 hours. The resultant solution is mixed with dry ether (30 ml) to give a precipitate. The precipitate is washed with dry ether (20 ml) twice to give 5-chloro-2-(3-aminomethyl-5-propargyloxymethyl-4H-1,2,4-triazol-4-yl)-benzophenone hydrobromide. To a suspension of this hydrobromide in dry benzene (20 ml), 2-phthalimidoacetyl chloride (1.6 g) is added at room temperature. The resultant mixture is mixed with dry dimethylformamide (10 ml) and stirred at room temperature for 3 hours. The reaction mixture is poured into saturated aqueous sodium bicarbonate (50 ml)/water (50 ml) and stirred under ice-cooling for 30 minutes. The precipitate is filtered, washed with water and ether in order and dissolved in methylene chloride (about 50 ml). The organic layer is dried over magnesium sulfate and evaporated to remove the solvent. The residue is recrystallized from methylene chloride/ethanol to give 5-chloro-2-[3-(2-phthalimidoacetamidomethyl)-5-propargyloxymethyl-4H-1,2,4-triazol-4-yl]-benzophenone (682 mg) as crystals melting at 245° to 246° C. (decomp.). (4) A solution of the above product (600 mg) and hydrazine hydrate (1.0 ml) in 95% ethanol (10 ml) is refluxed for 2 hours. The precipitate is filtered off, and the filtrate is evaporated under reduced pressure to remove the solvent. The residue is extracted with methylene chloride, and the methylene chloride layer is shaken with 2N hydrochloric acid (50 ml) twice. The hydrochloric acid layer is made alkaline with aqueous ammonia and shaken with methylene chloride thrice. The methylene chloride layer is dried over potassium carbonate to give 5-chloro-2-(3-glycylaminomethyl-5-propargyloxymethyl-4H-1,2,4-triazol-4-yl)-benzophenone hydrate as a colorless oil. The product is crystallized from isopropanol/ether to give crystals melting at 93° to 95° C.