Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:9]=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[CH:4]12[O:37][CH:3]1[CH2:2][N:1]([C:6]1[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:9]=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=1)[CH2:5]2
Reactant: NC(=O)c1cc(N2CC=CC2)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: NC(=O)c1cc(N2CC3OC3C2)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 2 h
Yield: 14.7 %

Procedure:
To a suspension of the 6-(2,5-dihydro-1H-pyrrol-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide (0.333 g, 0.885 mmol) in DCM (25 mL) was added mCPBA (0.201 g, 0.897 mmol, 77% solid). After 2 h, more mCPBA was added (0.198 g, 0.883 mmol, 77% solid). After stirring overnight, more mCPBA was added (0.202 g, 0.901 mmol, 77% solid) and the reaction was heated to reflux. After 5 h, more mCPBA was added (0.200 g, 0.892 mmol, 77% solid). After 2 h, more mCPBA was added (0.202 g, 0.901 mmol, 77% solid) and refluxing was continued overnight. When cooled, the reaction mixture was diluted with 100 mL DCM, washed twice with 25 mL saturated aqueous NaHCO3 solution, and once with 25 mL brine. The organic layers were dried over MgSO4, filtered, and evaporated to a residue. The residue was chromatographed over silica gel with 25-75% acetone in hexanes. The product fractions were evaporated in vacuo and the resulting solid triturated with 1 mL acetone, filtered, rinsed once with 0.5 mL acetone and dried under vacuum at 40° C. to give 6-(6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as an off-white powder (0.052 g, 0.13 mmol, 15% yield). LC/MS: m/z=393.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][CH2:17][S:18][CH2:19][CH3:20])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1C=CC(S(O)(=O)=O)=C[CH:23]=1>COC(OC)(C)C.C(OCC)(=O)C>[CH2:19]([S:18][CH2:17][CH2:16][C@@H:9]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[O:15][C:22]([CH3:23])([CH3:21])[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:20]
Reactant: CCSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: CCSCC[C@@H]1C(C(=O)OC)OC(C)(C)N1C(=O)OC(C)(C)C

Procedure:
A mixture of Example 21A (1.12 g, 3.65 mmol) and catalytic 4-methylbenzenesulfonic acid (15 mg) in 2,2-dimethoxypropane (35 mL) at ambient temperature was stirred for 36 hours, diluted with ethyl acetate, washed sequentially with aqueous NaHCO3 and pH 7 buffer, dried (MgSO4), filtered, and concentrated. Flash column chromatography (silica gel, 10% acetone/hexanes) provided the desired product. MS (ESI) m/e 348 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[C:14](C(O)=O)=[N:13]2)=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[CH:14]=[N:13]2)=[CH:4][CH:3]=1
Reactant: CC1Cc2c(-n3nc(C(=O)O)c(=O)[nH]c3=O)ccc(Cl)c2O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC1Cc2c(-n3ncc(=O)[nH]c3=O)ccc(Cl)c2O1
Temperature: 25 °C

Procedure:
A mixture of 8.0 g of 32D and 80 mL of Dowtherm® was heated at 200°-250° C. for 2 hours, cooled to room temperature, diluted with petroleum ether and filtered. The collected solid phase was dried under reduced pressure, and recrystallized from ethyl acetate/petroleum ether to give 2-(7-chloro-2,3-dihydro-2-methyl-4-benzofuranyl)-1,2,4-triazine-3,5(2H,4H)-dione, (32E) as a tan solid, m.p.: 184°-186° C.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:9]2[C:8]3[C:13](=[CH:14][C:15]([Cl:16])=[C:6]([NH:5][CH2:4][C:3]4[C:2]([CH3:1])=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:32])[CH:7]=3)[N:12]=[C:11]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:10]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: Cc1cccc(C)c1CNc1cc2c(NC3CC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C24H23ClN6O2, 462.9
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[C:18]([NH:20][CH3:21])=[O:19])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[C:18]([NH:20][CH3:21])=[O:19]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNC(=O)c1c(O)c(=O)cc(C)n1C
Yield: 100.4 %

Procedure:
Pd(OH)2 on charcoal (0.2 g) was added to a solution of 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide (1.25 g, 4.366 mmol) in ethanol (120 ml) under nitrogen. The mixture was hydrogenated at 50 psi hydrogen for 4 hrs. The Pd(OH)2 was removed by filtration through Celite and the Celite cake was washed with ethanol (3×25 ml). The Celite cake was further stirred with ethanol (100 ml) and then filtered through Celite. The combined ethanol filtrate was evaporated to give a solid (0.86 g, quantitative yield). Melting point: >250° C. H-NMR (COCl3:DMSO-d6 [2:1]) δ:1.81 (s, 3H, Me), 2.34 (d, 3H, NHMe), 3.01 (s, 3H, NMe), 5.67 (s, 1H, CH), 7.88 (s, 1H, NH). Elemental Analysis: Calc. C 55.09; H 6.6; N 14.28. Found. C 54.67; H 6.31; N 14.12.
Reaction SMILES: O[CH:2]1[CH2:7][N:6]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:9]([O:11][CH3:12])=[O:10])[CH2:5][C:4]2[CH:20]=[CH:21][S:22][C:3]1=2.Cl>C(O)(=O)C>[CH3:12][O:11][C:9]([C@@H:8]([N:6]1[CH2:5][C:4]2[CH:20]=[CH:21][S:22][C:3]=2[CH2:2][CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[O:10]
Reactant: COC(=O)C(c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Reaction time: 8 h

Procedure:
(±) Methyl α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate (23) (0.21 g, 0.622 mmol) was dissolved in acetic acid (4 mL) and treated sequentially with conc. HCl and SnCl2 dihydrate (0.28 g, 1.243 mmol). The reaction was allowed to stir overnight and the solvent was evaporated under vacuum. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate and the ethyl acetate layer was concentrated to provide clopidogrel free base as an oily product (0.16 g). 1H-NMR (CDCl3, ppm) 7.7 (1H, dd), 7.35 (1H, m), 7.2-7.35 (2H, m), 7.2 (1H, d), 6.68 (1H, dd), 4.95 (1H, s), 4.68 (1H, bs), 3.5-4.0 (2H, m), 3.75 (3H, s), 2.9 (4 H, s).
Reaction SMILES: C1(CO[C:6]([S:8][CH:9]2[N:12]([C:13](=C(N3CCOCC3)CBr)[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:36])[CH:10]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=O)CC1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:52][OH:53].Cl>C(Cl)Cl>[OH:53][C:52]1[CH2:6][S:8][C@@H:9]2[CH:10]([NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:11](=[O:36])[N:12]2[C:13]=1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(CBr)N2CCOCC2)C1SC(=O)OCC1CC1
Reactant: CO
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 63 %

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate (151 mg) in methylene chloride (1.5 ml) is added aluminum chloride (0.42 mg), and the mixture is stirred for 50 minutes under ice cooling. The mixture is diluted with ice water (2 ml), stirred for 5 minutes, and stirred with a mixture (15 ml) of methanol and methylene chloride (5:1) after addition of 10% hydrochloric acid (3 ml) at room temperature for 80 minutes. The reaction mixture is diluted with ice water, and is extracted with chloroform. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (63 mg). Yield: 63%. This product is identical with the product of Example 4.-III(3) produced by hydrolysis of the 4-morpholino group to be replaced with the corresponding hydroxy group.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:15]=1.[Cu][C:17]#[N:18]>N1C=CC=CC=1>[C:17]([C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:15]=1)#[N:18]
Reactant: N#C[Cu]
Reactant: CN1CC(=O)Nc2ccc(Br)cc2C1=O
Solvent: c1ccncc1
Product: CN1CC(=O)Nc2ccc(C#N)cc2C1=O

Procedure:
15.0 g of 7-bromo-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5 (1H)-dione and 7.5 g of copper (I) cyanide (freshly prepared) are mixed well in a mortar and heated from 165° to 195° with 7.2 ml of dry pyridine (freshly distilled over potassium hydroxide) under argon over a period of 3 hours. After cooling to 150°, the solid mass is dissolved in about 250 ml of boiling dimethylformamide. The mixture is left to cool, poured into 800 ml of ice-water and extracted three times with 500 ml of chloroform each time. The organic extracts are washed with 250 ml of 2N hydrochloric acid and three times with 500 ml of water each time, dried in the presence of active carbon and evaporated. The residue is dissolved in about 1 l of methanol. The solution is concentrated to a volume of 250 ml, treated with active carbon and cooled to 5°. The precipitated material is filtered off under suction and dried, there being obtained 7-cyano-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione as white crystals of melting point 256-258°.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][CH:8]([CH3:27])[C:9]([O:11][C:12]1[C:13]([CH3:26])=[C:14]([CH3:25])[C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=O)[C:16]=2[C:23]=1[CH3:24])=[O:10].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:17]1[C:16]2[C:23]([CH3:24])=[C:12]([O:11][C:9](=[O:10])[CH:8]([CH3:27])[CH3:7])[C:13]([CH3:26])=[C:14]([CH3:25])[C:15]=2[O:19][C:18]1([CH3:20])[CH3:21]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)C(C)C)C(=O)C(C)(C)O2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1c2c(C)c(OC(=O)C(C)C)c(C)c(C)c2OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Potassium tert-butoxide (1.53 g, 13.68 mmol) is added portionwise at 0° C. and under nitrogen to a suspension of methyltriphenylphosphonium bromide (4.9 g, 13.68 mmol) in dry tetrahydrofuran (57 mL) and the reaction mixture is stirred for 1 hr at room temperature. The 5-(2-methyl-propionoxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one (3.31 g, 11.4 mmol) in dry tetrahydrofuran (20 mL) is dropwise added at 0° C. to the yellow suspension and the reaction is stirred overnight at room temperature. Water is added and most of tetrahydrofuran is evaporated under reduced pressure. The residue is taken up in ethyl acetate, washed with brine, dried (magnesium sulfate) and the solvent is evaporated to dryness. Purification by flash chromatography eluting with heptane/ethyl acetate 95:5 and then 90:10 gave 2.8 g (85%) of 3-methylene-5-(2-methylpropionoxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran as a yellow oil. Rf=0.79 (heptane/ethyl acetate 70:30)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:14])[CH2:5][C:6]#[CH:7].[C:28]([O:32][C:33](=[O:42])[NH:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1I)([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)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)I.CN(C=O)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]#[C:7][C:40]1[CH:39]=[N:38][CH:37]=[CH:36][C:35]=1[NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:42]
Reactant: C#CCC(C(=O)OC)C1CCCN1C(=O)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC#Cc1cnccc1NC(=O)OC(C)(C)C)C1CCCN1C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 90 °C

Procedure:
A flask is charged with 2-[1-(Biphenyl-4-carbonyl)-pyrrolidin-2-yl]-pent-4-ynoic acid methyl ester (0.58 g, 1.62 mmol), (3-iodopyridin-4-yl)-carbamic acid tert-butyl ester (0.52 g, 1.62 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.057 g, 0.081 mmol), copper iodide (0.0104 g, 0.055 mmol), triethylamine (0.90 mL, 6.5 mmol) and DMF (7.3 mL) and heated at 90° C. for 2 h. The reaction is cooled to RT and partitioned between EtOAc (200 mL) and saturated sodium bicarbonate (75 mL). The organic layer is washed with saturated sodium bicarbonate (2×75 mL), brine (50 mL), dried over MgSO4 and concentrated. The residue is subjected to flash chromatography (1:1/EtOAc:hexanes) to give 2-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-yl]-5-(4-tert-butoxycarbonylamino-pyridin-3-yl)-pent-4-ynoic acid methyl ester as an impure mixture (0.35 g, three components) which is used without further purification. This material (0.35 g, 0.63 mmol estimated), DBU (0.19 g, 1.26 mmol) and acetonitrile (7 mL) is stirred at 50° C. for 6 h. The reaction mixture is concentrated and purified by flash chromatography (0.5% MeOH/CH2Cl2) to (2.0% MeOH/CH2Cl2) to give the title compound (0.18 g, 0.325 mmol). 1H NMR (CDCl3, 300 MHz) 8.83(s, 1H), 8.41(m, 1H), 8.25(d, 1H), 7.65-7.53(m, 6H), 7.52-7.32(m, 3H), 6.80(s, 1H), 4.84-4.68(m, 1H), 3.73, 3.68(two s, 3H), 3.67-3.35(m, 6H), 2.21-1.91(m, 4H), 1.67(s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]([S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(=[O:8])=[O:7])([CH3:5])[CH3:4].[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].S(=O)(=O)(O)O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:28][O:29][CH2:30][C:31]([O:1][CH2:2][C:3]([S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])(=[O:8])=[O:7])([CH3:5])[CH3:4])=[O:32]
Reactant: CC(C)(CO)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: COCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: COCC(=O)OCC(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 36 %

Procedure:
A mixture of 422 mg (1.08 mmol) of benzyl rac-α-[[(2-hydroxyl-1,1-dimethylethyl)sulfonyl]methyl]hydrocinnamate, 2 ml (2.2 mmol) of methoxyacetyl chloride and 100 mg (0.8 mmol) of 4-dimethylaminopyridine in 2 ml of pyridine was stirred at 900 for 15 hours. Subsequently, the mixture was poured on to ice and 150 ml of 3N sulphuric acid and extracted three times with 300 ml of ether each time. The organic extracts were then washed with in each case 150 ml of ice-cold 3N sulphuric acid, water, 1M sodium hydrogen carbonate solution and saturated sodium chloride solution, then dried over magnesium sulphate and evaporated under reduced pressure. For purification, the crude product (540 mg of brown oil) was chromatographed on 50 g of silica gel with a 4:1 mixture of toluene and ethyl acetate. There were obtained 180 mg of benzyl rac-α-[[[2-(methoxyacetoxy)-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 463 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[N:6]([C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[C:7](=[O:10])[CH2:8][Cl:9])C.[OH-].[K+]>C(O)C.O>[Cl:19][CH2:18][C:17]([NH:16][CH:5]([C:4]([OH:21])=[O:3])[N:6]([C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[C:7](=[O:10])[CH2:8][Cl:9])=[O:20]
Reactant: CCOC(=O)C(NC(=O)CCl)N(C(=O)CCl)c1cscn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(CCl)NC(C(=O)O)N(C(=O)CCl)c1cscn1
Yield: 73 %

Procedure:
To a solution of 3.54 g of 2-chloroacetamidothiazol-4-yl N-chloroacetylglycine ethyl ester in 30 ml of ethanol is added dropwise a solution of 1.68 g of potassium hydroxide in 15 ml of water under ice-cooling, followed by the stirring for 15 minutes. Ethanol is distilled under reduced pressure and the residue is made acidic with 10% hydrochloric acid, followed by the extraction with ethyl acetate. The ethyl acetate layer is washed with water and dried. The distillation of ethyl acetate gives 2.38 g of 2-chloroacetamidothiazol-4-yl N-chloroacetylglycine as colorless crystals. Melting point: 184°-186° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].Cl>N1C=CC=CC=1.C(Cl)Cl>[OH:1][C@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5]
Reactant: N#CC[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CC#N)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
(3S)-3,4-Dihydroxybutyronitrile (161.8 g, 1.6 mol) was dissolved in pyridine (260 ml). To the resulting solution, a solution of tosyl chloride (396.6 g) in methylene chloride (1.6 liters) was added at 0° C. and stirred at 0° C. for 5 hours. Then, the pH of the mixture was adjusted at 2 with 6N hydrochloric acid, and the mixture was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated off. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain (3S)-3-hydroxy-4-p-toluenesulfonyloxybutyronitrile (85.9 g). Yield, 70 %.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.[NH:17]([C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[NH2:18]>N1C=CC=CC=1.CO>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:16])[CH2:9][C:10]([CH2:11][CH2:12][CH2:13][OH:14])=[N:18]1
Reactant: NNc1nc2ccccc2s1
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Solvent: CO
Solvent: c1ccncc1
Product: OCCCC1=NN(c2nc3ccccc3s2)C(O)(c2ccc(Cl)cc2)C1
Reaction time: 48 h

Procedure:
6-(4-Chlorophenyl)-4,6-diketohexanol (7.2 g, 30 mM) was treated with 2-hydrazinobenzothiazole (4.96 g, 30 mM) in pyridine (5 ml) and MeOH (150 ml) at reflux for 2 hr and then allowed to stand at RT for 48 hr. The solvents were removed in vacuo and the crude residue purified by flash chromatography on silica with Et2O:Et3N (2.5%) as eluent. The title compound (1) was obtained as a pale yellow solid, (3.15 g, mp=132°-134° C.) upon recrystallization from Et2O:hexane. NMR(CDCl3) δ 3.2 (2H, C4 -H); MS, m/e 387 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 99.9 %

Procedure:
To a suspension of 4-methyl-5-nitro-2-(1,2,4-triazol-1-yl)pyridine (4.1 g, 20 mmol) in dry DMF (30 mL) was added dimethylformamide dimethyl acetal (5.9 mL, 44 mmol) and the mixture heated at 90° C. for 20 min. The solvent was evaporated in vacuo using toluene as an azeotrope to give the title compound (5.2 g, 100%) as a dark red solid. mp 225°-228° C. 1H NMR (360 MHz, CDCl3) δ 3.10 (6H, s) 6.13 (1H, d, J=13.1Hz), 7.54 (1H, d, J=13.1Hz), 7.81 (1H, s), 8.04 (1H, s), 8.92 (1H, s) and 9.17 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30]CC3C=CC=CC=3)=[CH:26][CH:25]=2)[C:21](=[O:23])[CH3:22])=[CH:5][CH:4]=1.Cl>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[N:20]([C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)[C:21](=[O:23])[CH3:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2N(C(C)=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2sc3cc(OC)ccc3c2N(C(C)=O)c2ccc(O)cc2)cc1
Reaction time: 4 h
Yield: 66 %

Procedure:
2-(4-Methoxyphenyl)-3-[N-(4-benzyloxyphenyl)acetamido]-6-methoxy-benzo[b]thiophene (2.43 g, 4.77 mmol) was dissolved in 50 mL of 1:1 EtOH/EtOAc containing 5% con. HCl. To this solution was added 1.0 g of 5% Pd/C. The resulting mixture was hydrogenated at 40 psi for 4 h. The mixture was then filtered through Celite to remove the catalyst. The filtrate was concentrated in vacuo to a semi-solid. Chromatography (SiO2, CHl3) provided 1.32 g (83%) of 2-(4-methoxyphenyl)-3-[N-(4-hydroxyphenyl)acetamido]-6-methoxy-benzo[b]thiophene as an amber foam. 1H NMR (DMSO-d6) δ (doubling due to amide rotamers) 9.53 and 9.36 (s, 1H), 7.62-6.51 (m, 11 H), 3.78 and 3.58 (s, 6H), 2.01 and 1.76 (s, 3H). FD mass spec: 419. Anal. Calcd. for C24H21NO4S.O 0.19 CHCl3 : C, 65.71; H, 4.83; N, 3.17. Found: C, 65.80; H, 4.70; N, 3.01.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH2:8][CH3:9])[CH2:3][OH:4].[N:18]#[C:19]Br>>[F:17][C:12]1[CH:11]=[C:10]([CH:7]([CH2:8][CH3:9])[CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:19]([NH2:18])=[N:1]2)[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: N#CBr
Reactant: CCC(CC[C@H](N)CO)c1cc(F)cc(F)c1
Product: CCC(CC[C@H]1COC(N)=N1)c1cc(F)cc(F)c1

Procedure:
In analogy to example 1d (S)-2-amino-5-(3,5-difluoro-phenyl)-heptan-1-ol was reacted with cyanogen bromide to give (4S)-4-[3-(3,5-difluoro-phenyl)-pentyl]-4,5-dihydro-oxazol-2-ylamine. Light yellow liquid. MS (ISP): 269.3 ([M+H]+).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.Cl[CH2:21][C:22]#[C:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C1COCC1>[CH3:3][C:2]([CH3:4])([CH2:21][C:22]#[C:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: ClCC#CCN1CCOCC1
Reactant: CCOC(=O)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CC#CCN1CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of ethyl isobutyrate (530 μl; 4.08 mmol) in THF (5 mL) was added lithium bis(trimethylsilyl)amide (7.30 mL; solution 1.00 M in THF; 7.30 mmol) at −78° C. The mixture was removed from the cooling bath and stirred for 30 min. It was then cannulated over a suspension of 4-(4-chlorobut-2-yn-1-yl)morpholine hydrochloride (prepared as described by Gomez et al., 1997 Tetrahedron, 53(50), 17201-17210; 714 mg; 3.40 mmol) in THF (5 mL) maintained at −78° C. The reaction mixture was left in the cooling bath and allowed to warm up to rt. After 3 h, it was quenched with water and extracted twice with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtrated and concentrated. Purification of the crude by flash chromatography on silica (gradient DCM:MeOH 100:0 to 90:10) gave the title compound as a colorless oil (600 mg, 70% yield). 1H NMR (DMSO-d6) δ: 4.11 (qd, J=7.1 Hz, 2H), 4.14 (m, 4H), 3.31 (t, J=2.1Hz, 0.6H), 3.25 (m, 1.4H), 2.52 (m, 4H), 2.43 (t, J=2.3 Hz, 2H), 1.25 (s, 6H), 1.23 (t, J=7.0 Hz, 3H).