Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5][C:4]([CH3:12])([CH3:11])[O:3]1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1.S(Cl)(Cl)=O>C(Cl)Cl>[N:14]1([C:8]([CH:6]2[CH2:5][C:4]([CH3:12])([CH3:11])[O:3][C:2]([CH3:1])([CH3:13])[CH2:7]2)=[O:10])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC1(C)CC(C(=O)O)CC(C)(C)O1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)CC(C(=O)n2nnc3ccccc32)CC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2,6,6-tetramethyl-tetrahydro-pyran-4-carboxylic acid (1.4 g, 6.8 mmol) and benzotriazole (2.4 g, 20.3 mmol) in 34 mL of DCM was added thionyl chloride (0.55 mL, 7.4 mmol) dropwise and the mixture was allowed to stir for 8 hrs at RT. The mixture was filtered to remove the ppt and the filtrate washed with saturated NaHCO3 (2×40 mL) and then brine (50 mL). The organic layer was dried over Na2SO4 and concentrated to give 1.9 g (97%) of a white ppt.
Reaction SMILES: [CH3:1][C:2]1[C:15](=[O:16])[N:14]=[C:13]2[N:4]([C@@H:5]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:7]([O:12]2)[CH2:6]3)[CH:3]=1.[N-:17]=[N+:18]=[N-:19].[Li+]>CN(C)C(=O)C>[N:17]([C@@H:7]1[C@@H:8]([CH2:10][OH:11])[O:9][C@@H:5]([N:4]2[CH:3]=[C:2]([CH3:1])[C:15](=[O:16])[NH:14][C:13]2=[O:12])[CH2:6]1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 130 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
2,3'-Anhydrothymidine (0.673 g, 3.0 mmol), lithium azide (0.4 g, 9.0 mmol) and N,N-dimethylacetamide (7.5 ml) were heated together with stirring at 130° C. for 16 hr. The products were then worked-up and chromatographed on silica gel to give 3'-azido-3'-deoxythymidine (0.64 g, 80%). identical to authentic material.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].Br[CH2:26][C:27](=[O:41])[CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:16]([N:15]1[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=[C:6]1[CH:2]([NH:1][CH2:26][C:27](=[O:41])[CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])[CH:3]([CH3:5])[CH3:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(NCC(=O)CCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A suspension of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (1.0 g, 2.93 mmol), 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (867 mg., 2.93 mmol, prepared as described in WO 89/10360), and potassium carbonate (405 mg, 2.93 mmol) in DMF (14 mL) was stirred at room temperature for 80 minutes. The reaction was diluted with water and the resulting white solid (1.6 g.) was used in the subsequent step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:37][CH:38]3[CH2:42][CH2:41][O:40][CH2:39]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: CS(=O)(=O)OCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of 2-[(2-cyclopropylethyl)oxy]-8-(methoxy)-1H-purin-6-amine trifluoroacetic acid salt (2.89 g), potassium carbonate (4.41 g) and dry DMF (32 ml) was heated at 60° C. under nitrogen for 90 minutes. Tetrahydro-3-furanylmethyl methanesulfonate (1.869 g, isomer 1) was then added and stirring continued at 70° C. for 1 h, then at 90° C. for 2 h. The solvent was evaporated and the residue treated with water and extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a hydrophobic frit and evaporated to a brown oil. This was purified on a 360 gm C18 column using water (+0.1% formic acid)/acetonitrile (+0.05% formic acid). Appropriate fractions were combined and evaporated, yield 814 mg.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7]([OH:9])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:7]([C:6]2[S:5][C:4]([CH2:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:3][C:2]=2[CH3:1])=[O:9])[CH2:57][CH2:58]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(=O)O
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: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(=O)NC1CCOCC1
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4-methyl-2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (80 mg, 0.24 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (86 mg, 0.27 mmol), N,N-diisopropyl ethyl amine (210 μL, 1.21 mmol) and 4-aminotetrahydropyran (27 mg, 0.27 mmol). The resulting reaction mixture was stirred overnight and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 8:2 to 1:1) afforded the title compound (97 mg, 97%) as a white solid. MS: m/e=413.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>O1CCCC1>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3,4-difluorophenyl)-carbamic acid tert-butyl ester (Tetrahedron, (1992), 48(35), 7373) (15.1 g) in tetrahydrofuran (120 ml) at 0° C. was added potassium tert-butoxide (94 ml of a 1.0 M solution in tetrahydrofuran) dropwise. After stirring for 2 hr methyl bromoacetate (9.1 ml) was added dropwise and ice-bath removed and reaction mixture stirred at room temperature overnight. Reaction mixture concentrated under reduced pressure, diluted with ethyl acetate and washed with water and brine, dried (Na2SO4) and concentrated to leave the sub-title compound as a brown oil (18.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]=[C:13]([C:15]([O:17]CC)=O)[O:12][N:11]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>C(O)C>[Br:9][C:6]1[CH:5]=[C:4]([C:10]2[N:14]=[C:13]([C:15]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=3)=[O:17])[O:12][N:11]=2)[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Solvent: CCO
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Yield: 53.1 %

Procedure:
A solution of the ethyl 3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate (78 mg, 0.2 mmol) plus 4-trifluoromethoxybenzyl amine (57 mg, 0.3 mmol) in ethanol (3 mL) was refluxed for 6 hours. The resulting solution was evaporated in vacuo and the residue was dissolved in ethyl acetate (2.5 mL) and washed with 1 N hydrochloric acid (2 mL), then water (2 mL). The organic layer was evaporated to dryness in vacuo and purified by preparative HPLC to give the title compound (57 mg, 53%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 4.55 (2H, d), 7.38 (2H, d), 7.51 (2H, d), 10.07 (1H, t), 10.95 (1H, s, br). LCMS (10 cm_apci_formic) tR 4.14 min; m/z 534/536/538 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.C[O:23][C:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([Cl:33])[Cl:32])=[CH:27][CH:26]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:32][CH:31]([Cl:33])[C:28]1[CH:27]=[CH:26][C:25]([C:24]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:9][C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:13]=[CH:12][N:11]=3)[CH:4]=2)=[O:23])=[CH:30][CH:29]=1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: COC(=O)c1ccc(C(Cl)Cl)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2ccc(C(Cl)Cl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 45 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 4-methyl-N*3*-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diamine (2.00 g mg, 7.21 mmol) in toluene (22 ml) at 45° C. under an atmosphere of argon is added sequentially 4-dichloromethyl-benzoic acid methyl ester (1.90 g, 8.67 mmol) and AlMe3 (2 M in toluene, 12.6 ml, 25.2 mmol). The resulting brown solution is stirred at 45° C. for a period of 3.5 hrs. The reaction mixture is then cooled to 0° C. and quenched by slow addition of a saturated aqueous solution of Rochelle salt (70 ml) which causes the precipitation of the crude product. t-Butyl methyl ether (150 ml) and methylene chloride (100 ml) are added sequentially to the suspension which are then washed with aqueous saturated NaHCO3 (100 ml) and aqueous saturated NaCl (100 ml). The aqueous phases are back-extracted with t-butyl methyl ether (100 ml). The crude product, which is contained in the combined organic phases, is filtered off with suction, washed with t-butyl methyl ether and dried in vacuo. Yield: 3.35 g of the title compound, 84% of theory, as beige crystals, (HPLC: 91% area).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([CH:36]([CH3:38])[CH3:37])[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:12][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([NH:35][CH2:34][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH:36]([CH3:38])[CH3:37])=[O:11]
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Reactant: COc1cccc(C(CN)C(C)C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(CNC(=O)Cc2c(Cl)cncc2Cl)C(C)C)c1
Yield: 97.9 %

Procedure:
By working in a way similar to that described in example 30 but using (3,5-dichloro-pyridin-4-yl)-acetic acid (4.62 g, 22.4 mmoles), carbonyldiimidazole (4 g, 24.64 mmoles), THF (60 ml) and 2-(3-methoxy-phenyl)-3-methyl-butylamine (4.33 g, 22.4 mmoles), obtained as described in example 37, 8.36 g of the title compound were obtained (yield: 97.9%), m.p.: 94-95° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=O>C(O)C>[NH2:1][C:2]1[S:3][C:6]2[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]=2[N:4]=1
Reactant: NC(N)=S
Reactant: CC1CCC(=O)C(Br)C1
Solvent: CCO
Product: CC1CCc2nc(N)sc2C1
Temperature: 25 °C

Procedure:
Thiourea (22.3 g., 0.29 mole) was slurried in 275 ml. of ethanol. 2-Bromo-4-methylcyclohexanone was added and the mixture heated to reflux for 75 minutes. The reaction mixture was cooled to room temperature and the crude product recovered as the hydrobromide salt by filtration. The crude salt was dissolved in warm water, filtered and made basic with ammonium hydroxide to precipitate the free base as an oil, which crystallized on cooling. Purified 2-amino-4,5,6,7-tetrahydro-6-methylbenzthiazole (25.2 g., m.p. 98°-100° C.) was obtained by recrystallization from cyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[O:15]([C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:30]3[CH2:31][CH2:32][N:27]([C:25]4[CH:26]=[C:17]([O:15][CH3:16])[CH:18]=[C:19]5[C:24]=4[N:23]=[CH:22][CH:21]=[CH:20]5)[CH2:28][CH2:29]3)[C:7]=2[CH:14]=1
Reactant: COc1ccc2occ(CCI)c2c1
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Product: COc1cc(N2CCN(CCc3coc4ccc(OC)cc34)CC2)c2ncccc2c1

Procedure:
8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxy-quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methoxyl-8-piperazino quinoline (243 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 90 mg, (21%); (M+H): 418; 1HNMR (400 MHZ, CDCl3): δ 8.73˜8.71 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H) 8.03˜8.00 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H), 7.50˜6.71 (m, 7H); 3.91 (s, 3H), 3.87 (s, 3H), 3.55˜2.82 (12H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19](#[N:21])[CH3:20]>O1CCCC1>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH2:20][C:19]#[N:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCCOCc1ccccc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)CCCOCc1ccccc1
Temperature: 0 °C
Yield: 81.9 %

Procedure:
In a stream of argon, 248 ml of tetrahydrofuran was added to 26 g (0.65 mole) of 60% sodium hydride, and a solution of 72.2 g (0.325 moles) of ethyl 4-benzyloxybutyrate and 26.7 g (0.65 mole) of acetonitrile in 94 ml of anhydrous tetrahydrofuran was added dropwise over the course of 40 minutes, and the mixture was heated under reflux for 2.5 hours. After cooling, the reaction mixture was poured into ice water, and washed with a 1:1 mixture of hexane and ether. The aqueous layer was acidified with concentrated hydrochloric acid, and extracted with ether. The ether layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting crude 6-benzyloxy-3-ketohexanenitrile was subjected to silica gel column chromatography. The column was eluted with a 1:1 mixture of hexane and ether to give 57.8 g (81.2%) of a pale yellow oily product.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2)[C:8](=[O:10])[CH3:9].Cl.[NH2:39]O.CC([O-])=O.[Na+]>CO.O>[F:36][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[O:23][N:39]=[C:20]([CH3:21])[CH:19]=2)[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)CC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2ccc(Cl)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(c2cc(C)no2)c2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a mixture of N-(3,5-Bis-trifluoromethyl-benzyl)-N-[8-chloro-1-(3-oxo-butyryl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-acetamide (0.13 mmol, 72 mg), hydroxylamine hydrochloride (1.3 mmol, 90 mg) in MeOH (2 mL) was added NaOAc (20 mg) at room temperature. The resulting suspension was stirred vigorously at 70° C. for 12 h. After completion, the mixture was diluted with water (20 mL), extracted with EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated to dryness. Flash chromatography (EtOAc-Hexane as eluent 1:1) afforded the title compound as viscous foam; Rf 0.35 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 564 (M+H2O).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](Cl)(=[O:11])[CH3:10]>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cnc(N)cn1
Solvent: C1CCOC1
Product: CC(=O)Nc1cnc(C)cn1
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of 5-methylpyrazin-2-amine (300 mg, 2.75 mmol) in dried THF (9 mL) were added acetyl chloride (0.21 mL, 2.89 mmol) and TEA (0.75 mL, 5.50 mmol). The reaction mixture was stirred for 3 hours after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (10% to 30% Ethyl acetate/Hexane) as a solvent to afford title compound (360 mg, 86% yield). MS m/z: 152 [M+1].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.CCN(CC)CC.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][C:19](=[O:22])[CH2:20][CH3:21])=[CH:2]1
Reactant: NCc1c[nH]c2ccccc12
Reactant: CCC(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
Compound 25 (1.00 g, 6.84 mmol) and Et3N (1.4 mL, 10.26 mmol) were dissolved in MeOH and cooled to 0° C. Propionyl chloride (633 mg, 6.84 mmol) was added dropwise and the reaction was stirred at room temperature for 4 hours. The volatiles were removed and the residue was taken up in CH2Cl2 (40 mL), washed with 10% citric acid (20 mL), satd. NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried with Na2SO4, filtered and the volatiles were removed to yield 1.33 g of a white, crystalline solid (1.33 g, 96% yield). An analytical sample was recrystallized from EtOAc/hexanes. m.p.=91-92° C. 1H NMR (CDCl3) δ 8.80 (br s, 1H, NH), 7.62 (d, 1H, ArH, J=7.85 Hz), 7.38 (d, 1H, ArH, J=7.2 Hz), 7.20 (3H, ArH), 5.80 (br s, 1H, NH), 4.60 (d, 2H, ArCH2, J=5.1 Hz), 2.20 (q, 2H, COCH2CH3, J=7.6 Hz), 1.14 (t, 3H, COCH2CH3, J=7.6 Hz). 13C NMR (CDCl3) δ 173.6, 136.5, 126.6, 123.3, 122.5, 119.9, 118.8, 112.8, 111.4, 35.2, 29.7, 9.9. IR (KBr) vmax cm−1: 3405, 1891, 1634, 1532, 1097.
Reaction SMILES: [Ba+2].P([O:6][CH2:7][C:8]([C@@H:10]([C@@H:12]([C@H:14]([CH3:16])[OH:15])[OH:13])[OH:11])=[O:9])([O-])([O-])=O>O>[OH:6][CH2:7][C:8]([C@@H:10]([C@@H:12]([C@H:14]([CH3:16])[OH:15])[OH:13])[OH:11])=[O:9]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)C(=O)COP(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O
Product: C[C@H](O)[C@@H](O)[C@@H](O)C(=O)CO
Temperature: 37 °C
Yield: 56.9 %

Procedure:
Crude L-fuculose-1-phosphate 4 (0.50 g) was powdered, dispersed in H2O (9 mL) and treated with Dowex 50W-X8 resin (H+ form, 400 mesh) until pH 2.8 for 30 min. The resin was filtered off, washed with water (2×2 mL) and the filtrate was adjusted to pH 4.7 with 6N HC1. Acid phosphatase (250 units) was added, the mixture was heated at 37° C. for 21 h, the pH was adjusted to 7.0 with saturated Ba(OH)2 soln. and methanol (2 vol) was added. The precipitate was filtered off through Celite and the solvent removed under reduced pressure. The residue was chromatographed on silica gel with CHCl3/Methanol (3:1). Compound 5 (123 mg, 46% from DHAP) was obtained as a slightly yellowish oil: [α]=0° (c 1, water), [α]D=0° (c 1.9, water)]. NMR (1H and 13C) data were in accordance with literature values reported in Liu, K. K.-C.; Xajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong, C.-H. J. Org. Chem. 1991, 56, 6280, A sample was taken and converted to the 2-nitrophenylhydrazone derivative: m. p. 158-160° C. (Lit. Green, M.; Cohen, S. S. J. Biol. Chem. 1956, 219, 557 which reports m.p. as 162-163° C.).
Reaction SMILES: [CH3:1][N:2]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:3][CH2:4][NH:5][CH3:6].N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[CH3:6][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)[C:25](=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CNCCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(C)CCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Yield: 100 %

Procedure:
Dissolve N,N′-dimethyl-N-(6-nitro-benzothiazol-2-yl)-ethane-1,2-diamine (0.255 g, 0.957 mmol) in CH2Cl2 (10 mL) and add pyridine (0.1 mL, 1.2 mmol). Add acetyl chloride (0.102 mL, 1.43 mmol) and shake the mixture overnight at room temperature. Concentrate the reaction mixture in vacuo (adsorbing onto silica gel) and subject the mixture to silica gel flash column chromatography (40 g column, eluting with 1-10% MeOH/CH2Cl2) to yield the desired product (0.295 g, 100%). mass spectrum (m/e): 309.2 (M+1).
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].CO>C(O)C>[C:1]([NH:9][C@@H:10]([C:11]([OH:13])=[O:12])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=Cc1ccccc1)NC(=O)c1ccccc1
Reactant: [H][H]
Solvent: CCO
Solvent: CO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1ccccc1
Yield: 97.7 %

Procedure:
3.2 grams of α-benzamido-cinnamic acid were dissolved in 40 ml of absolute ethanol and treated with 0.3 ml of the catalyst solution produced in Example 19. The reaction mixture was sucked into a 100 ml autoclave. It was pressurized with 6 bars of hydrogen pressure. After taking up the theoretical amount of hydrogen it was worked up as customary (e.g. see Example 6). There were isolated 3.15 grams of N-benzoyl-(R)-phenylalanine having the rotary value of [α]D27 =+38.6° (c=1/CH3OH), corresponding to an optical yield of 95.8%.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][NH:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]([C:21]3[S:22][C:23]([CH3:30])=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:25]=3)=[N:19][N:20]=2)=[CH:11][C:10]=1[CH3:31]>C1COCC1.CO.[Li+].[OH-]>[CH2:26]([C:24]1[CH:25]=[C:21]([C:18]2[O:17][C:16]([C:12]3[CH:13]=[C:14]([CH3:15])[C:9]([CH2:8][CH2:7][C:6]([NH:5][CH2:4][C:3]([OH:33])=[O:2])=[O:32])=[C:10]([CH3:31])[CH:11]=3)=[N:20][N:19]=2)[S:22][C:23]=1[CH3:30])[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)CNC(=O)CCc1c(C)cc(-c2nnc(-c3cc(CC(C)C)c(C)s3)o2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2nnc(-c3cc(CC(C)C)c(C)s3)o2)cc(C)c1CCC(=O)NCC(=O)O

Procedure:
A solution of (3-{4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenyl}-propionylamino)-acetic acid methyl ester in THF (1 mL), MeOH (1 mL) and 2 N aq. LiOH solution (0.25 mL) is stirred at rt for 4 h. The precipitate that formes is collected, washed with water and dried under HV to give (3-{4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenyl}-propionylamino)-acetic acid (9 mg) as a white powder; LC-MS: tR=0.99 min, [M+1]=456.17.