Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C@@H:3]1([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@@H:6]2[CH2:7][O:8][C@H:5]2[CH2:4]1>C(O)(C)C>[C@@H:3]1([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[CH:5]=[CH:4]1
Reactant: Cc1cn([C@H]2C[C@@H]3OC[C@H]3O2)c(=O)[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 50 °C
Yield: 39.2 %

Procedure:
A five liter, three-necked flask was equipped with an overhead stirrer and paddle, a reflux condenser, a temperature probe, and a heating mantle. Isopropanol (1.25 L) and potassium hydroxide (198 g, 3.0 moles) were added to the flask and heated to 50° C. stirring. Then, 3', 5'-anhydrothymidine (168.2 g, 0.75 mole) was added portion-wise. The resulting solution was then heated at 78°-80° C. for 3.5 hours. The solution was cooled to 20°-25° C., diluted with isopropanol (1.75 L), then taken to pH 4-6 with concentrated HCI and cooled to 0° C. The precipitated KCl was filtered off and washed with isopropanol (200 mL). The combined filtrate and wash was divided into three equal portions. Each portion was mixed with N-methylpyrrolidinone (54 mL) and concentrated to a thick oil at 50° C./15-20 mm Hg, then diluted with acetone (120 mL) and warmed at 50° C. for 15 minutes. The mixture was then cooled to 15° C., forming a thick slurry. The solids were collected by filtration to give a total of 65.96 g (81.6%) of the title compound which assays 68.5% (by weight) d4T.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([C:29]#[N:30])=[N:15][C:16]=2[NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N.[H][H]>C(O)C.[Pd]>[NH2:30][CH2:29][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@H:3]2[C@H:2]([OH:1])[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4]2)=[C:16]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:15]=1
Reactant: [H][H]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(C#N)nc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Agent: N
Solvent: CCO
Product: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
A solution of 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-(phenethylamino)-9H-purine-2-carbonitrile (2.9 g, 7.07 mmol) (preparation 47) in ethanol (300 ml), saturated with ammonia gas, was treated with 5% palladium on charcoal (1.0 g), pressurised to 1034 kPa (150 psi) with hydrogen gas in a sealed vessel and stirred at room temperature for 48 hr. The reaction mixture was filtered through Arbocel (trade mark) and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane and the solvent removed under reduced pressure to give a product that was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (92:8:0.4) to give the title compound (1.7 g) as a foam. MS: 416 (MH+)
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[SH:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][S:21][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: OCCS
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccccc2)OC(CC(SCCO)c2ccsc2)=CC1=O

Procedure:
Following the procedure of Method C, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 2-mercapto-1-ethanol to provide 5-[2-[(2-hydroxyethyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (DMSO-d6) δ1.54 and 1.57 (singlets, 3H), 3.35-3.60 (m ovelapped with DMSO, ˜4H), 4.58 (m, 1H), 5.55 and 5.56 (overlapped singlets, 1H), 7.18-7.37 (m, 6H), 7.40-7.57 (m, 2H); MS(LR-ESI) m/z 361 (M+H calcd. for C19H21O3S2 361).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:26](O)=[O:27])[CH2:3][C:4]1[N:8]=[CH:7][N:6](C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH:5]=1.[NH2:46][C@@H:47]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C@@H:48]([OH:54])[C@H:49]([CH:51]1[CH2:53][CH2:52]1)[OH:50].N1CCCCC1>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)[C:26]([NH:46][C@@H:47]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C@@H:48]([OH:54])[C@H:49]([CH:51]1[CH2:52][CH2:53]1)[OH:50])=[O:27]
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)[C@@H](O)C1CC1
Reactant: O=C(N[C@@H](Cc1cn(C(=O)OCC2c3ccccc3-c3ccccc32)cn1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described in Example 1, paragraph (c), by the condensation of Fmoc-His(Fmoc)-OH and (1S,2R,3S)-3-amino-1-cyclopropyl-4-phenyl-1,2-butanediol followed by cleavage of the protecting groups using piperidine in methylene chloride there was obtained (S)-α-amino-N-[(1S,2R,3S)-1-benzyl-3-cyclopropyl-2,3-dihydroxypropyl]-imidazole-4-propionamide as a colourless foam, MS: 359 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].C1(O)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:26])[CH:23](Br)[CH3:24]>>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH:3]=1)[O:1][CH:23]([CH3:24])[C:22]([O:21][CH3:20])=[O:26])=[O:6]
Reactant: COC(=O)C(C)Br
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1cc(C=O)ccc1[N+](=O)[O-]

Procedure:
Using 3-hydroxy-4-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a tan solid: 1H NMR (DMSO-d6, 400 MHz): δ ppm 10.03 (s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.62-7.79 (m, 2H), 5.43 (q, J=6.8 Hz, 1H), 3.69 (s, 3H), 1.55 (d, J=6.8 Hz, 3H). ESI-MS: m/z 254.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=C1CCC(n2cc(Br)cnc2=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(Br)cnc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-bromo-1-(4-oxo-cyclohexyl)-1H-pyrimidin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][CH2:5][CH:4]([C:7](OC)=[O:8])[CH:3]([C:11](OC)=[O:12])[CH2:2]1.[BH4-].[Na+]>CCO>[OH:12][CH2:11][CH:3]1[CH:4]([CH2:7][OH:8])[CH2:5][CH2:6][N:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CO)C(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a mixture of 1-tert-butyl 3,4-dimethyl piperidine-1,3,4-tricarboxylate (4.00 g, 13.30 mmol, 1 eq) in 50 mL of anhydrous EtOH was added NaBH4 (1.26 g, 33.20 mmol, 2.5 eq) in portions at 0° C. The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by a silica gel column chromatography (5:1 (v/v) CH2Cl2/MeOH) to afford the title compound as a white solid (3.00 g, 92.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 246.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1.[OH-].[Na+].[NH2:28]O.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:28][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
Cis-methyl 2-(4-chlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.11 g, 5.74 mmol) was dissolved in MeOH (24 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.687 mL, 5.74 mmol) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.352 mL, 5.74 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (29.5 mL, 177.26 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-chlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (923 mg, 47%) was isolated. MS m/z 337 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH2:10][CH2:9]1.[CH2:20](Br)[CH:21]([CH3:23])[CH3:22].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:11](=[O:19])[CH2:10][CH2:9]1
Reactant: CC(C)CBr
Reactant: O=C1CCC(c2ccccc2Cl)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)CCC(c2ccccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(2-chlorophenyl)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (2.8 g) and isobutyl bromide (2.24 ml) in dimethylformamide (20 ml) was added sodium hydride (0.82 g, 60% oil) at 0° C. The mixture was stirred for 4 hours at room temperature, then the solvent was distilled off, and the residue was purified by means of a silica-gel column chromatography to give 2.98 g of colorless crystals, m.p. 139°-140° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN(C=O)C>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: Clc1nc2ccccc2s1
Reactant: O=C(O)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Oc2nc3ccccc3s2)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A solution of 2-fluoro-4-hydroxy-benzoic acid (4.0 g, 25.6 mmol) in DMF (250 mL) was added Cs2CO3 (9.2 g, 28.2 mmol) and the reaction mixture was stirred at 80° C. for 1 h prior to the addition of 2-chloro-benzothiazole (3.3 mL, 25.6 mmol). The reaction mixture was stirred at 100° C. for 50 h, then cooled to rt, and the solid was filtered. The filtrate was diluted with EtOAc (200 mL) and water (100 mL), neutralized with 1 M HCl and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×200 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated to afford the title compound as a colorless solid (4.7 g, 63%). MS (ESI): mass calcd. for C14H8FNO3S, 289.0; m/z found, 290.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.21 (t, J=8.5 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.11 Hz, 1H), 7.63-7.45 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:16])[CH2:13][CH:14]=[CH2:15]>>[C:6]([C:5]1[CH:10]=[CH:11][C:2]([CH2:15][CH2:14][CH2:13][CH:12]=[O:16])=[CH:3][CH:4]=1)([O:8][CH3:9])=[O:7]
Reactant: C=CCCO
Reactant: COC(=O)c1ccc(Br)cc1
Product: COC(=O)c1ccc(CCCC=O)cc1

Procedure:
condensing methyl p-bromobenzoate with 3-buten-1-ol; extracting the reaction mixture with an organic solvent to obtain an organic extract; decolorizing the organic extract with silica gel, and then removing the organic solvent to give 4-(4-carbomethoxyphenyl) butanal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:20])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N+:8]([O-:20])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution of 3-ethoxycarbonylpyridine (25 g, 165.4 mmol, 1 eq) in DCM was slowly added mCPBA (70% wt, 198.5 mmol) and the reaction mixture was stirred at rt overnight. Reaction was cooled and diluted with DCM and then neutralized with slow addition of sat. NaHCO3. Aqueous layer was washed with DCM (3×) and the combined organic layer was dried and evaporated to give a residue, which was purified by column chromatography (EtOAc/MeOH) to give 3-ethoxycarbonylpyridine N-oxide (13.6 g). MS: exact mass calculated for C8H9NO3, 167.06; m/z found, 168 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:53])[CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH3:39])[CH:37]=2)[C:32]([Sn](CCCC)(CCCC)CCCC)=[N:31]1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[Si:17]([O:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:32]3[C:33]4[C:38](=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)[N:30]([CH2:29][CH2:28][N:27]([CH3:26])[CH3:53])[N:31]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:12])([CH3:25])[CH3:24])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCN(C)C)c2cc(C)ccc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)c4n3)nn(CCN(C)C)c2c1
Temperature: 85 °C

Procedure:
A mixture of 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (210 mg, 0.5 mmol) and N,N-dimethyl-2-(6-methyl-3-(tributylstannyl)-1H-indazol-1-yl)ethanamine (1.4 g, 2.85 mmol) with tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol), copper iodide (10 mg, 0.52 mmol) in 15 mL of dry DMF was heated to 85° C. overnight under N2. The reaction mixture was cooled to room temperature, diluted with 50 mL of water, extracted with dichloromethane (8×50 mL), combined organics dried with sodium sulfate and concentrated. The crude product was used into the next step without further purification. LCMS: (M+H)+=550.
Reaction SMILES: C1O[C:4]([CH2:6][N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])([CH3:5])[O:3]C1.[Br:19]Br>C(O)COCCO>[C:11]1(=[O:12])[N:7]([CH2:6][C:4](=[O:3])[CH2:5][Br:19])[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]12
Reactant: BrBr
Reactant: CC1(CN2C(=O)c3ccccc3C2=O)OCCO1
Solvent: OCCOCCO
Product: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Yield: 70.9 %

Procedure:
A solution of phthalimidoacetone ethylene ketal (2.47 g, 10 mmole) in 10 mlof diethylene glycol is heated on a steambath. To this hot solution bromine(1.6 g, 10 mmole) is added dropwise under nitrogen. The reaction mixture iscooled to room temperature and is quenched in 20 ml hexane. To this mixtureis added solid sodium carbonate followed by chloroform and ice water. The organic layer is separated and the aqueous layer is extracted 3 times withchloroform. The chloroform extracts are washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue is crystallized from ethyl acetate/hexane to afford 2 g (55%) of (3-phthalimidoacetonyl)bromide, ethylene ketal as white prisms of melting point 139°-141° C. An analytical sample has a melting point of 140°-141° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[NH:5][N:4]=1.C(O[CH:12]=[CH:13][C:14]#[N:15])C>O>[ClH:1].[CH3:8][C:6]1[CH:7]=[C:3]2[N:2]=[CH:12][CH:13]=[C:14]([NH2:15])[N:4]2[N:5]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CCOC=CC#N
Agent: Cl
Solvent: O
Product: Cc1cc2nccc(N)n2n1
Yield: 83 %

Procedure:
150 cc of 35% hydrochloric acid were introduced into a 500 cc three-necked flask equipped with a magnetic stirrer, a thermometer and a condenser, and 47.5 g of 3-amino-5-methylpyrazole dissolved in 100 cc of water were added dropwise. The temperature rose to 60° C. 47.5 g of 3-ethoxyacrylonitrile were then added and the reaction was refluxed for 1 h. The reaction medium was cooled and concentrated under reduced pressure. 50 cc of acetone were added and the precipitate obtained was filtered off. It was rinsed with diisopropyl ether. After drying under vacuum over phosphorus pentoxide, 78.7 g of 2-methylpyrazolo[1,5-a]pyrimidin-7-ylamine hydrochloride were obtained in the form of white crystals. (Yield=83%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:13]([O:16]S(C)(=O)=O)[CH2:14]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:13]1[O:16][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H](CO)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 196.7 g of the N-benzyloxycarbonyl-3(S)-amino-2(R)-methanesulfonyloxy-4-phenyl-1-butanol obtained in the above Example 3 in 2,500 ml of methanol was added 90 g of potassium carbonate. The obtained mixture was then stirred at room temperature for 5 hours. The pH value of the reaction mixture was adjusted to 7 with a 10% aqueous solution of citric acid. Then the solvent was concentrated under reduced pressure. After adding water to the residue, it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. After adding anhydrous sodium sulfate and activated carbon, the mixture was filtered. Then the filtrate was concentrated and n-hexane was added thereto for crystallization. The crystals thus precipitated were filtered and dried. Thus the target N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane was obtained in the form of white crystals. The overall yield of Referential Example 2 and Example 3 through Example 4 was 72.3%.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C:7]3[C@H:12]1[CH2:11][CH2:10][C:9](=[O:20])[CH:8]=3)[CH2:3]2>N1C=CC=CC=1.[Pd]>[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@H:12]1[CH2:11][CH2:10][C:9](=[O:20])[CH2:8]3)[CH2:3]2
Reactant: C[C@]12C[C@H]3CCC4=CC(=O)CC[C@H]4[C@@H]3C[C@@H]1CCC2=O
Agent: [Pd]
Solvent: c1ccncc1
Product: C[C@]12C[C@H]3CC[C@H]4CC(=O)CC[C@H]4[C@@H]3C[C@@H]1CCC2=O
Reaction time: 2 h

Procedure:
To a solution compound 12 (150 mg, 0.54 mmol) in pyridine (30 mL) was added Pd/C (50 mg) at room temperature. A hydrogenation was carried out under 7 atm H2 for 2 h at room temperature. The reaction was filtered through Celite® 545 which was washed with EtOAc (100 mL). Solvents were removed under reduced pressure and 13C NMR of the crude product (145 mg) showed the 4aS to 4aR diastereomer ratio to be 2:1: 1H NMR (CDCl3) δ 0.84 (s, 3H); 13C NMR (CDCl3) 4aS diastereomer δ 220.4, 212.2, 47.8, 45.6, 42.7, 39.9, 38.9, 38.6, 38.2, 38.1, 36.3, 35.4, 30.7, 28.5, 28.4, 27.1, 23.9, 13.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[C:6]([CH:13]3[CH2:15][O:14]3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH4+].[Cl-].[N-:18]=[N+:19]=[N-:20].[Na+]>CO>[N:18]([CH:13]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[N:11]2)[CH2:15][OH:14])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cnc2cccc(C3CO3)c2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2cccc(C(CO)N=[N+]=[N-])c2n1
Temperature: 65 °C
Yield: 78 %

Procedure:
A mixture of 2-methoxy-8-oxiranyl-quinoxaline (4.7 g, 23 mmol; prepared as in WO 2004/002490), NH4Cl (2.2 g, 1.8 eq.) and NaN3 (3.8 g, 2.5 eq.) in MeOH (60 mL) was heated at 65° C. for 5 h, filtered and concentrated in vacuo. The residue was taken up in EA and washed with sat. NaHCO3 and brine, dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 1:1) to give the desired intermediate as a beige solid (4.4 g, 77% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:17]2[CH:18]=[N+:19]([O-:23])[CH:20]=[CH:21][CH:22]=2)[C:8]2[C:15](=[O:16])[O:14][CH2:13][C:9]=2[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[CH3:24][NH2:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:17]2[CH:18]=[N+:19]([O-:23])[CH:20]=[CH:21][CH:22]=2)[C:8]([C:15]([NH:25][CH3:24])=[O:16])=[C:9]([CH2:13][OH:14])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccc[n+]([O-])c1
Reactant: CN
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)NC)C1c1ccc[n+]([O-])c1

Procedure:
A mixture of 10.0 g of 2-methyl-4-(1-oxido-3-pyridyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylic acid ethyl ester and 100 ml of a 33% solution of methylamine in ethanol is heated at 90° in a sealed tube for 16 hours. The reaction mixture is concentrated to dryness by evaporation under reduced pressure and the residue is partitioned between methylene chloride and a 2N aqueous sodium carbonate solution. The organic phase is removed, washed with water, dried and concentrated by evaporation under reduced pressure. The residue is chromatographed over silica gel and eluted with ethyl acetate. The uniform fractions ascertained by means of a thin layer chromatograph are concentrated to dryness by evaporation under reduced pressure and the residue is recrystallised from a mixture of isopropanol and petroleum ether to yield 6-hydroxymethyl-2-methyl-5-methylaminocarbonyl-4-(1-oxido-3-pyridyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester melting at 197°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:15]2[C:19](Cl)=[C:18]([S:21][CH3:22])[N:17]([CH3:23])[N:16]=2)[C:7]=1[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])#[N:2].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:15]2[CH:19]=[C:18]([S:21][CH3:22])[N:17]([CH3:23])[N:16]=2)[C:7]=1[CH:8]([O:9][CH2:10][CH3:11])[O:12][CH2:13][CH3:14])#[N:2]
Reactant: CCOC(OCC)c1c(C#N)cnn1-c1nn(C)c(SC)c1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(OCC)c1c(C#N)cnn1-c1cc(SC)n(C)n1

Procedure:
1.0 g (2.8 mmol) of 4-cyano-5-diethoxymethyl-1-(4chloro-1-methyl-5-methylthio-3-pyrazolyl)pyrazole (Example B.1) and 1.0 g (5.8 mmol) of m-chloroperbenzoic acid in 10 ml of dichloromethane are stirred at 0° C. for 3 hours and subsequently at room temperature for 12 hours. The reaction mixture is washed with sodium thiosulfate solution, sodium bicarbonate solution and water and dried (sodium sulfate), and the solvent is distilled off. Silica gel column chromatography (ethyl acetate/ hexane) gives the desired product in the form of colorless flakes.