Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][C:17](Cl)=[O:18].Cl>[OH-].[Na+]>[O:18]=[C:17]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH2:16]1
Reactant: O=C(O)[C@@H](CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared according to the method described by H. H. Otto, Helvetica Chimica Acta, 2004, 87, 90. To an ice cooled solution of N -(phenylmethyl)-D-serine (8.90g, 45.59mmol) in 2N NaOH solution (50 mL) was added chloroacetyl chloride (4.36 mL, 54.71 mmol), dropwise over 15 minutes. The reaction was stirred for 30 minutes before adding 30% NaOH solution (4.5 g in 15 mL) and stirring at R.T. for 2 and ½ hours. It was cooled in an ice bath before adding c.HCl solution to pH<1. solid precipitated out. Filtered. Suspended in isopropanol and heated at reflux for 10 minutes. Filtered hot. Solvent evaporated to afford a pale yellow solid. Triturated with Et2O to afford the title compound as a cream solid in 29% yield.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].C(=O)([O-])[O-].[Ca+2].[H][H]>O>[CH2:2]([OH:1])[C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
24 g of Raney-nickel obtained by the method described above was added to 300 g of an aqueous solution containing 100 g of 6-deoxy L-mannose in a 1-L glass autoclave with an agitator and a thermometer, to which water was added to a final reaction volume of 600 g. So as to adjust the reaction mixture to pH 7, then, calcium carbonate was added. Reaction was progressed while the temperature was retained at 50° C.; the hydrogen pressure was retained at 12 kg/cm2 (gauge pressure); the agitation speed was retained at 700 rpm. The reaction mixture was analyzed by HPLC. Consequently, 6-deoxy L-mannose was decreased to 1% in the 8-hour reaction, to produce 6-deoxy L-mannitol.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C(N)CCC.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:15](I)[CH:14]=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:17]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:18]=1
Reactant: COC(=O)Cc1ccc(Br)cc1I
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCCCN
Product: COC(=O)Cc1ccc(Br)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 118.1 %

Procedure:
Trimethylsilylacetylene (0.319 ml, 2.25 mmol), palladium acetate (12 mg, 56.3 μmol), triphenylphosphine (30 mg, 0.113 mmol), n-butylamine (0.334 ml, 3.38 mmol) and copper iodide (43 mg, 0.225 mmol) were added to a solution of methyl (4-bromo-2-iodophenyl)acetate (400 mg, 1.13 mmol) obtained in Example (85-1) in tetrahydrofuran (6 ml), and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=15/1) to give crude methyl (4-bromo-2-trimethylsilanylethynylphenyl)acetate (434 mg).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH:11]1[C:19]2[N:18]3[C:20]([CH:23]4[CH:27]([CH3:28])[CH2:26][CH:25]([NH2:29])[CH2:24]4)=[CH:21][N:22]=[C:17]3[CH:16]=[N:15][C:14]=2[NH:13][CH:12]=1>CN(C=O)C>[CH:11]1[C:19]2[N:18]3[C:20]([C@@H:23]4[C@H:27]([CH3:28])[CH2:26][C@H:25]([NH:29][S:5]([CH2:4][CH2:3][C:2]([F:10])([F:9])[F:1])(=[O:7])=[O:6])[CH2:24]4)=[CH:21][N:22]=[C:17]3[CH:16]=[N:15][C:14]=2[NH:13][CH:12]=1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: CC1CC(N)CC1c1cnc2cnc3[nH]ccc3n12
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](NS(=O)(=O)CCC(F)(F)F)C[C@@H]1c1cnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 144 h
Yield: 5.1 %

Procedure:
3,3,3-Trifluoropropane-1-sulfonyl chloride (0.194 g, 0.987 mmol, Matrix) was added dropwise to a solution of TEA (0.31 mL, 2.2 mmol) and 3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine (0.28 g, 1.1 mmol, Preparation #53) in DMF (10 mL). The resulting mixture was stirred at ambient temperature for about 144 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water (20 mL each). The layers are separated and the organic layer was washed with brine (30 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified by using General Procedure AA (Table 2, Method 9, Rt=17.7 min, or =negative) to give N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (0.021 g, 4.6%) as a white solid: LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z 416 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[CH:12][C:11](Br)=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH:15]1([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=2)(=[O:21])=[O:20])[CH2:17][CH2:16]1.C(Cl)Cl.CC#N>C([O-])([O-])=O.[Na+].[Na+].COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:13]=[CH:12][C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([S:19](=[O:20])(=[O:21])[NH:18][CH:15]3[CH2:16][CH2:17]3)[CH:23]=2)=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: O=S(=O)(NC1CC1)c1cccc(B(O)O)c1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CON(C)C(=O)c1cc(-c2cccc(S(=O)(=O)NC3CC3)c2)cnc1N

Procedure:
A suspension of 2-Amino-5-bromo-N-methoxy-N-methyl-nicotinamide (0.2 g, 0.77 mmol), N-cyclopropyl 3-boronobenzenesulfonamide (0.2 g, 0.84 mmol), Pd(dppf)Cl2.DCM (0.063 g, 0.077 mmol) in 2M Na2CO3 (1 ml) and DME (3 ml) is heated at reflux for 1 hour. The crude reaction mixture is subjected to column chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA). All the acetonitrile is removed in vacuo, and the aqueous solution remaining is adjusted to basic pH using NaHCO3. The product is extracted into DCM, and dried (MgSO4). Concentration and drying in vacuo at 40° C. yields the title compound. [M+H]+ 726
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:17](=[O:18])[CH2:16][N:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:13]=[C:8]12)#[CH:2].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:17](=[O:18])[CH2:16][N:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:13]=[C:8]12)[CH3:2]
Reactant: C#Cc1cccc2c1CCN1C(=O)CN=C(c3cccc(OC)c3)C=C21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cccc2c1CCN1C(=O)CN=C(c3cccc(OC)c3)C=C21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
9-ethynyl-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 40-2. A solution of 37-1 (700 mg, 1.69 mmol) in MeOH (20 mL) was treated with K2CO3 (467 mg, 3.38 mmol) and the mixture was stirred at RT for 18 h. The mixture was concentrated in vacuo, and the residue taken up in AcOEt and washed with H2O. The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was re-crystallized from heptane/AcOEt to provide the title compound (410 mg) as brown crystals. UPLC-MS: MS 343.3 (M+H+); UPLC rt 1.03 min.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:38]([NH2:40])=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[NH:51]([C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67])[C@H:52]([C:63]([OH:65])=O)[CH2:53][CH2:54][CH2:55][NH:56][C:57](=[NH:62])[NH:58][N+:59]([O-:61])=[O:60].[N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O.C1CCC(N=C=NC2CCCCC2)CC1>[Pd].O1CCCC1.CN(C=O)C>[NH:51]([C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67])[C@H:52]([C:63]([NH:1][CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:38]([NH2:40])=[O:39])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])=[O:65])[CH2:53][CH2:54][CH2:55][NH:56][C:57](=[NH:62])[NH:58][N+:59]([O-:61])=[O:60]
Reactant: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Reactant: NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)N[N+](=O)[O-]
Reaction time: 6 h

Procedure:
In 30 ml. of DMF was dissolved 1.0 g. of Z-β-Ala-Phe-Phe-Tyr-NH2, and using Pd-black as a catalyst, catalytic reduction was carried out for 6 hours. The catalyst was filtered off. To the filtrate was added a solution of Z-Arg(NO2)-ODNP in tetrahydrofuran (the dinitrophenyl ester prepared from 0.52 g. of Z-Arg(NO2)-OH and 0.30 g. of 2,4-dinitrophenol in 10 ml. of tetrahydrofuran by the DCC process). The mixture was stirred for 13 hours and the solvent was distilled off. To the residue was added 50 ml. of water and the resulting powder was collected byy filtration and dried. Yield 1.01 g. (74.9 %); melting point: 192°-194°; [α]D22 -11.1° (c=1.02 %, DMF).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([N:23]6[CH:27]=[C:26]([C:28]([O:30]CC)=[O:29])[CH:25]=[N:24]6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([N:23]6[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[N:24]6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cnn(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Ethyl 1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxylate (0.42 g, 1.0 mmol) was dissolved in methanol (10 mL), and was treated with an aqueous solution of lithium hydroxide (0.048 g, 2.0 mmol) in water (5 mL). The mixture was stirred at 50° C. for 2 h, cooled to RT, neutralized with 1N HCl (2 mL). The volatiles were removed under reduced pressure. The residue was co-evaporated with toluene (3×), and dried to afford the desired product which was directly used in next step. LCMS: (M+H)=397.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N+:11]=[N-:12])[C:3]1=[O:13].[CH3:14][C:15](=[O:18])[C:16]#[CH:17]>C1C=CC=CC=1>[C:15]([C:16]1[CH:17]=[C:4]2[N:11]([C:3](=[O:13])[N:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=32)[N:12]=1)(=[O:18])[CH3:14]
Reactant: CN1C(=O)C(=[N+]=[N-])c2ccccc21
Reactant: C#CC(C)=O
Solvent: c1ccccc1
Product: CC(=O)c1cc2c3ccccc3n(C)c(=O)n2n1

Procedure:
To a solution of 5.0 g (0.0288 mole) of 1-methyl-3-diazooxindole in 200 ml of benzene there is added 2.38 g (0.035 mole) of 3-butyn-2-one and the solution refluxed overnight.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:19]2S[CH:21]=[CH:22][CH:23]=2)[C:8]2[C:9](=[O:18])[C:10]([CH3:17])=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=2[CH3:14])[CH:2]=1>C(O)C.[Ni]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:8]2[C:9](=[O:18])[C:10]([CH3:17])=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=2[CH3:14])[CH2:19][CH2:23][CH2:22][CH3:21])[CH:2]=1
Reactant: CC1=C(C)C(=O)C(C(c2cccnc2)c2cccs2)=C(C)C1=O
Agent: [Ni]
Solvent: CCO
Product: CCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1cccnc1
Yield: 72.7 %

Procedure:
The solution of 1.2 g (3.7 mmol) of 2-[(3-pyridyl)(2-thienyl)methyl]-3,5,6-trimethyl-1,4-benzoquinone in 20 ml of ethanol was refluxed by heating in the presence of 24 g of Raney nickel (W-6) for 5 hours. After cooling the catalyst was removed by filtration, and the filtrate was concentrated and redissolved in ethyl acetate and shaken with the solution of 1.2 g of ferric chloride in 10 ml of water. The mixture was made weakly alkaline with sodium hydrogen carbonate, from which the organic layer was separated, washed with water, dried, and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate-isopropyl ether (1:1)), to give 0.8 g (72.5%) of 2-[1-(3-pyridyl)pentyl]-3,5,6-trimethyl-1,4-benzoquinone (Compound No. 7).
Reaction SMILES: [Cl:1][C:2]1[C:27]([OH:28])=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1.[C:29]([O:34]C)(=[O:33])[C@H:30]([CH3:32])O>>[Cl:1][C:2]1[C:27]([O:28][C@H:30]([CH3:32])[C:29]([OH:34])=[O:33])=[CH:26][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)=[CH:11][C:10]=3[CH2:23][CH2:24][CH3:25])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)[C@H](C)O
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O)cc12
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2cc(Cl)c(O[C@H](C)C(=O)O)cc12

Procedure:
The phenol from Step 6 (0.38 g, 1.0 mmol) and methyl (S)-lactate (0.16 g, 1.5 mmol) was reacted according the general procedure described in Step 11 of Example 1 to give the title compound as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19](O)=O>>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]3[N:17]=[CH:19][NH:18][C:13]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1N
Reactant: O=CO
Product: c1nc2ccc(OCCCN3CCCCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(3-piperidin-1-yl-propoxy)-benzene-1,2-diamine [2.2 g, Intermediate (39)] and formic acid (20 ml) at 100° C. was stirred for 3 hours and then cooled to room temperature and passed through a SCX column. The column was eluted with 7N ammonia in methanol to yield 6-(3-piperidin-1-yl-propoxy)-1H-benzoimidazole [3.45 g, Intermediate (40)] as a dark oil.; LC/MS: 260 (M+H).
Reaction SMILES: C(O[C@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:28].C(OCC)(=O)C.CCCCCC>ClCCl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[Br:28])(=[O:10])[CH3:9]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
1,2,3,4,6-penta-O-acetyl-α-D-glucopyranose (1.0 g, 2.60 mmol) was dissolved in 20 mL of dichloromethane and 1.90 mL of hydrobromic acid (33% in acetic acid) at 0° C., and the reaction was stirred while warming to room temperature. TLC (40% ethyl acetate-hexane) after 18 h showed complete consumption of the starting material and formation of a higher running spot. The reaction was slowly diluted with saturated sodium bicarbonate (25 mL), extracted into dichloromethane (2×100 mL), dried over sodium sulfate, filtered and concentrated to afford 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide which was used without purification.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])([O-])=[O:2].[C:11]([O:15][C:16]([N:18]1[CH2:21][CH2:20][C@H:19]1[CH2:22][O:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([C:30]#[CH:31])[CH:29]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1.O>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH2:5][C:4]1[CH:31]=[C:30]([C:28]2[CH:27]=[N:26][CH:25]=[C:24]([O:23][CH2:22][C@@H:19]3[CH2:20][CH2:21][N:18]3[C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH:29]=2)[O:2][N:1]=1
Reactant: C#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Reactant: COC(=O)CCC[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)on1
Temperature: 60 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of methyl 4-nitrobutyrate (306 μL, 2.4 mmol) and 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-ethynylpyridine (230 mg, 798 μmol) in dry benzene (8.0 mL) were added phenyl isocyanate (0.26 mL, 2.4 mmol) and triethylamine (0.22 mL, 1.6 mmol). The reaction mixture was stirred at 60° C. for 24 h, then diluted with water and stirred vigorously for 2 h. The mixture was extracted with CH2Cl2, and the organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by CC on SiO2 eluting with EtOAc/hexane 1:1 to give the isoxazole (283 mg, 85%). 1H NMR (CD3OD, 400 MHz) δ 8.50 (br s, 2H), 7.62 (s, 1H), 6.53 (s, 1H), 4.55 (br s, 1H), 4.40 (br s, 1H), 4.21 (dd, 1H, J=10.0, 2.4 Hz), 3.91 (t, 2H, J=7.2 Hz), 3.73 (s, 3H), 3.07 (t, 2H, J=7.2 Hz), 2.80 (t, 2H, J=7.2 Hz), 2.38 (m, 2H), 1.42 (s, 9H). 13C NMR (CDCl3, 100 MHz) δ 172.8, 167.1, 163.3, 156.3, 155.4, 139.8, 139.5, 124.3, 117.6, 100.9, 80.0, 69.0, 60.1, 52.0, 47.3, 32.1, 28.8, 21.7, 19.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O.[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21]>C(O)(=O)C.S(=O)(=O)(O)O>[F:16][C:17]([F:25])([F:24])[C:18]([C:19]1[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][C:20]=1[CH3:21])=[O:23]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1sccc1C(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sccc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 18.1 %

Procedure:
To a stirred solution of 30 mg (0.13 mmol) (2-amino-thiophen-3-yl)-(4-fluoro-phenyl)-methanone in 1 ml acetic acid was added 0.017 ml (0.13 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 15 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 8 mg (17%) 2,2,2-trifluoro-1-[4-(4-fluoro-phenyl)-6-methyl-thieno[2,3-b]pyridin-5-yl)-ethanone as a yellow oil. ES-MS m/e (%): 340 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.I[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:17][CH2:16][CH2:15][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][CH2:10]1
Reactant: OCCI
Reactant: Fc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCN1CCN(c2ccccc2F)CC1
Yield: 65.9 %

Procedure:
A mixture of 1-(2-fluorophenyl)piperazine (0.50 g), 2-iodoethanol (0.48 g), and potassium carbonate (1.5 g) in dimethylformamide (7 mL) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was purified by preparative thin-layer chomatography (silica gel, eluting with chloroform/methanol, 9:1), giving the title compound as a yellow oil (0.41 g, 65%). 1H NMR (300 MHz, CDCl3) δ7.09-6.90 (m, 4H), 3.67 (t, 2H, J=5.4 Hz), 3.13 (t, 4H, J=4.7 Hz), 2.76 (br s, 1H), 2.71 (t, 4H, J=4.8 Hz), 2.63 (t, 4H, J=5.4 Hz). 13C NMR (75 MHz, CDCl3) δ156.3 (d, J=244.1 Hz), 140.6 (d, J=8.8 Hz), 125.1 (d, J=3.4 Hz), 123.2 (d, J=8.1 Hz), 119.5 (d, J=2.9 Hz), 116.7 (d, J=20.6 Hz), 60.1, 58.4, 53.6 (2C), 51.2 (d, 2C, J=3.0 Hz).
Reaction SMILES: [Na+].C([NH:12][C@H:13]([C:19]([O-:21])=[O:20])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])(OCC1C=CC=CC=1)=O.[H-].[Na+].Br[CH:25]([S:27]([O-:30])(=[O:29])=[O:28])[CH3:26].[Na+]>CN(C)C=O>[NH2:12][C@H:13]([C:19]([OH:21])=[O:20])[CH2:14][CH2:15][C:16]([NH:17][CH2:26][CH2:25][S:27]([OH:30])(=[O:29])=[O:28])=[O:18]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Reactant: CC(Br)S(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H](CCC(=O)NCCS(=O)(=O)O)C(=O)O

Procedure:
3.02 g. (10 mmoles) of carbobenzyloxy-L-glutamine sodium salt (Liebig's Ann. 640, 145 /1961/) are dissolved in 50 ml. of dimethyl formamide, 12 mmoles of sodium hydride are added in the form of an oily dispersion, and the mixture is heated for 2 hours under exclusion of air humidity. Thereafter a solution of 2.11 g. (10 mmoles) of sodium bromoethanesulfonate in 50 ml. of dimethyl formamide is added dropwise, and the mixture is heated for additional 2 hours. The mixture is evaporated in vacuo. The residue is extracted with ether, then the dry substance is dissolved in water, and the solution is passed through a column filled with Dowex 50 ion exchanger. The column is eluted with water. The eluate is evaporated in vacuo, and the residue is dried over solid potassium hydroxide. The obtained substance is subjected to catalytic hydrogenation as described in Example 5. The product is recrystallized from a mixture of ethanol and water. 1.55 g. of gamma-L-glutamyl-taurine are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][O:12][C:13]([CH:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][O:12][C:13]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=C(C=C1CCCCC1)OCCc1cc(F)c(F)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(CC1CCCCC1)OCCc1cc(F)c(F)c(F)c1
Yield: 93.4 %

Procedure:
4-(3',4',5'-Trifluorophenyl)ethoxycarbonylmethylenecyclohexane (18.3 g) was dissolved in ethanol (100 ml), followed by adding Pd/C (5%, 5 g), stirring the mixture, hydrogenating in a hydrogen gas atmosphere until completion of absorption of a hydrogen, filtering off the catalyst after completion of the reaction, and concentrating the solvent under reduced pressure, to obtain 4 -(3',4',5'-trifluorophenyl)ethoxycarbonylmethylcyclohexane (17.2 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH:8]2[CH:10]([OH:11])[CH:4]([CH2:5][N:6]([CH3:12])[CH2:7]2)[CH2:3]1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:12][N:6]1[CH2:5][CH:4]2[CH:10]([O:11][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]([CH2:9][N:2]([CH3:1])[CH2:3]2)[CH2:7]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CC2CN(C)CC(C1)C2O
Solvent: c1ccncc1
Product: CN1CC2CN(C)CC(C1)C2OC(=O)c1ccccc1
Yield: 42.5 %

Procedure:
10 g of 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane-9-ol are dissolved in 50 ml of dry pyridine, and a solution of 11.24 g of benzoyl chloride in 50 ml of dry pyridine is added dropwise, within 30 minutes, to the solution stirred at 5°-10° C. Thereafter the reaction mixture is stirred at room temperature for 3 hours, and the bulk of pyridine is distilled off under vacuo. The residue is taken up in 50 ml of water, the mixture is acidified with 20 ml of concentrated aqueous hydrochloric acid, and the mixture is extracted thrice with 50 ml of ether, each, in order to remove the non-basic substances. The aqueous phase is rendered alkaline with potassium carbonate and extracted thrice with 50 ml of chloroform, each. The chloroform solutions are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The residue is crystallized from n-hexane. 3,7-Dimethyl-9-benzoyloxy-3,7-diazabicyclo[3.3.1]nonane is obtained with a yield of 42.5%; m.p.: 100°-102° C.