Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([N:38]([CH3:42])[C:39](Cl)=[O:40])[CH:7]=[C:8]([CH3:37])[C:9]=1/[CH:10]=[CH:11]/[S:12]([N:15]1[CH2:36][CH2:35][C:18]2([N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)[NH:20][C:19]2=[O:34])[CH2:17][CH2:16]1)(=[O:14])=[O:13].[C:43]([Si:47]([CH3:53])([CH3:52])[O:48][CH2:49][CH2:50][OH:51])([CH3:46])([CH3:45])[CH3:44]>O1CCCC1>[C:43]([Si:47]([CH3:53])([CH3:52])[O:48][CH2:49][CH2:50][O:51][C:39](=[O:40])[N:38]([C:6]1[CH:5]=[C:4]([CH3:3])[C:9](/[CH:10]=[CH:11]/[S:12]([N:15]2[CH2:36][CH2:35][C:18]3([N:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:31])([F:33])[F:32])[CH:24]=4)[NH:20][C:19]3=[O:34])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[C:8]([CH3:37])[CH:7]=1)[CH3:42])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: Cc1cc(N(C)C(=O)Cl)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C(=O)OCCO[Si](C)(C)C(C)(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
Sodium hydride (60% oil suspension, 5.6 mg, 0.14 mmol) was added to a solution of N-(3,5-dimethyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-N-methyl-chloroformamide (30 mg, 50.1 μmol) in tetrahydrofuran (1.0 ml) at 0° C., and the mixture was stirred for 15 minutes. 2-(tert-Butyl-dimethyl-silanyloxy)-ethanol (30 μL, 0.14 mmol) was then added and the mixture was stirred at 40° C. for two hours. The mixture was cooled, and then quenched with water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give (3,5-dimethyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-methyl-carbamic acid 2-(tert-butyl-dimethyl-silanyloxy)-ethyl ester (29 mg, 78%).
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.F[C:26]1[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccn1-c1ncc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cn1
Temperature: 200 °C

Procedure:
A mixture of 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide (44 mg), 2,3-difluoro-5-(trifluoromethyl)pyridine (22 mg), and ethyldiisopropylamine (35 μL) in N-methyl-2-pyrrolidinone (1 mL) is heated to 200° C. for 0.5 h in a microwave oven. The reaction mixture is concentrated and the crude product is purified by preparative HPLC (MeOH/H2O/ammonia). LC (method 16): tR=1.29 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:53]>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([C:22](=[O:24])[NH:50][CH2:51][C:52]([C:54]2[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=2)=[O:53])[CH2:18]1)=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(Br)cc2)C1

Procedure:
N,N-diisopropylethylamine (5.3 mL, 30.6 mmol) was added dropwise to a mixture of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (2.2 g, 10.1 mmol), HATU (4.0 g, 10.5 mmol), the HCl salt of 2-amino-1-(4-bromophenyl)ethanone (2.4 g, 9.6 mmol), and DMF (40 mL), and stirred at ambient condition for 1 hour. Most of the volatile component was removed in vacuo, and the resulting residue was dissolved in ethyl acetate (150 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product as a white foam-like solid (3.5 g, 90%). m/z 432.9, 434.9 (M+Na)+.
Reaction SMILES: [CH2:1]([C:4]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=1[NH:12]2)[CH:2]=[CH2:3].Cl.Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C:4]1[C:16]([O:17][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:15][CH:14]=[C:13]2[C:5]=1[C:6]1[CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=1[NH:12]2)[CH:2]=[CH2:3]
Reactant: ClCc1ccc2ccccc2n1
Reactant: C=CCc1c(O)ccc2[nH]c3c(c12)CCCC3CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1c(OCc2ccc3ccccc3n2)ccc2[nH]c3c(c12)CCCC3CC(=O)OCC
Reaction time: 48 h

Procedure:
The compound from Step 4 (400 mg) is dissolved in 3.0 ml of DMF and 400 mg of 2-(chloromethyl)quinoline hydrochloride is added, followed by 275 mg of K2CO3. The reaction is stirred for 48 hours, 3.0 ml of H2O is added and the product extracted into Et2O. After washing with brine, the organic phase is dried and evaporated to yield ethyl 5-allyl-6-(quinolin-2-ylmethoxy)-1,2,3,4-tetrahydrocarbazol-1-ylacetate.
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH2:9][C:8]=1[CH2:20][S:21][C:22]1[N:26]([CH3:27])[N:25]=[N:24][N:23]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[Br:28][CH:9]1[C:8]([CH2:20][S:21][C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)=[C:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10]1(=[O:19])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)CS(=O)(=O)[C@H]12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)C(Br)S(=O)(=O)[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-tert-butylcarbonyl-7α-methoxy-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem 1,1 dioxide (350 mg) in dichloromethane (30 ml), N-bromosuccinimide (200 mg) and triethylamine (0.13 ml) were added sequentially. The mixture was stirred for 15 min at room temperature. Following dilution with dichloromethane, the organic phase was sequentially washed with 4% aqueous NaHSO3, saturated NaHCO3 and water. After drying over Na2SO4 and removal of the solvent, the residue was purified by flash chromatography (eluting with hexane-EtOAc mixtures) affording 2-bromo-4-tert-butylcarbonyl-7α-methoxy-3-(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl-3-cephem 1,1-dioxide as a waxy solid (200 mg), IR (KBr) νmax 1800, 1700 cm-1. A portion of this material (180 mg) was dissolved in acetonitrile (10 ml) and treated with silver benzoate (95 mg). The mixture was stirred for 30 min at room temperature, then filtered and rotoevaporated. Following flash chromatography (eluting with gradient of EtOAc in hexane) the title product was obtained as a light yellow solid (80 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1([CH:17]=[O:18])[CH2:15][CH2:16]1
Reactant: O=C1c2ccccc2C(=O)N1CCC1(CO)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=CC1(CCN2C(=O)c3ccccc3C2=O)CC1
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropane-methanol (0.31 g, 1.26 mmol) in CH2Cl2 (6 mL) was added sequentially 3 Å molecular sieves (0.644 g), N-methylmorpholine N-oxide (0.223 g, 1.90 mmol), and tetrapropylammonium perruthenate (88 mg, 0.25 mmol). After 30 minutes, the mixture was filtered through silica gel and the cake was washed with ether. The solvent was removed from the filtrate under reduced pressure and provided 0.25 g (82%) of 1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropanecarboxaldehyde as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Br:22]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[Br:22][C:9]1[C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:6]2=[N:7][C:8]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCCCCCCCCCc1cc(C)c2c(n1)N(C)CC2
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCc1nc2c(c(C)c1Br)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 286 mg (0.99 mmol) of 1,4-dimethyl-6-decyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 4 mL of chloroform was added 143 mg (0.50 mmol) of 1,3-dibromo-5,5-dimethylhydantoin in portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction was quenched by the addition of 5 mL of sat aq NaHCO3. The mixture was extracted with chloroform and the combined organic layer was washed with brine and dried over MgSO4. The concentrated residue was purified by flash chromatography on a silica gel column (20 1.7 cm). Elution with 100:1 hexanes/ethyl acetate gave the product as a yellow oil: yield 342 mg (94%); silica gel TLC Rf 0.7 (8:1:1 hexanes/ethyl acetate/methanol); 1H NMR (CDCl3) δ 0.87 (t, 3H, J=6.8 Hz), 1.25-1.39 (m, 16H), 1.66 (quint, 2H, J=7.2 Hz), 2.17 (s, 3H), 2.77 (t, 2H, J=8.0 Hz), 2.83-2.87 (m, 5H) and 3.40 (t, 2H, J=8.0 Hz); 13C NMR (CDCl3) δ 14.1, 19.5, 22.7, 25.2, 28.7, 29.4, 29.54, 29.59, 29.64, 29.64, 31.9, 33.0, 38.1, 52.4, 110.9, 120.4, 141.1, 156.8 and 161.8; mass spectrum, m/z 366.2 and 268.2 (M)+ (theoretical 366.2 and 368.2); mass spectrum (APCI), m/z 367.1747 and 369.1673 (M+H)+ (C19H32N2Br requires 367.1749 and 369.1728).
Reaction SMILES: C(OC([N:8]1[C:12]([NH:13][C:14](=[O:32])/[C:15](/[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([Cl:31])[CH:22]=2)=[N:16]/[O:17][CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:31][C:23]1[CH:22]=[C:21](/[C:15](=[N:16]\[O:17][CH:18]([CH3:20])[CH3:19])/[C:14]([NH:13][C:12]2[CH:11]=[CH:10][NH:9][N:8]=2)=[O:32])[CH:26]=[CH:25][C:24]=1[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CC(C)O/N=C(/C(=O)Nc1ccnn1C(=O)OC(C)(C)C)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)O/N=C(/C(=O)Nc1cc[nH]n1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
(E)-5-[2-(3-Chloro-4-methanesulfonyl-phenyl)-2-isopropoxyimino-acetylamino]-pyrazole-1-carboxylic acid tert-butyl ester (30 mg, 0.06 mmol) was dissolved in dioxane (1 mL). A 4.0 M solution of hydrochloric acid in dioxane (1 mL, 4 mmol) was added. After stirring 1 h, the volatiles were evaporated in vacuo and the residue was diluted with chloroform (3 mL) and washed with 10% aqueous potassium carbonate solution (1 mL). The aqueous phase was extracted with chloroform (2 mL) and the combined organic phases were filtered through sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 2% methanol/chloroform) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isopropoxyimino-N-(1H-pyrazol-3-yl)-acetamide (14 mg, 59%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C15H17ClN4O4S [M+] 384.07, found 385 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.35 (d, J=6.3 Hz, 6 H, 2×CH3), 3.32 (s, 3 H, SO2CH3), 4.60 (m, J=6.3 Hz, 1 H, OCH), 6.77 (brs, 1H, Ar), 7.53 (d, J=2.3 Hz, 1 H, Ar), 7.58 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.68 (d, Jm=1.5 Hz, 1 H, Ar), 8.20 (d, Jo=8.2 Hz, 1 H, Ar), 9.25 (s, 1 H, NH).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[O:11][CH2:10][C:9](=[O:13])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:12]=2[O:11][CH2:10][C:9]1=[O:13]
Reactant: ClCCCI
Reactant: CCc1cccc2c1OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1cccc2c1OCC(=O)N2CCCCl
Yield: 74.9 %

Procedure:
8-Ethyl-4H-benzo[1,4]oxazin-3-one (0.35 g, 2.0 mmol), Cs2CO3 (0.96 g, 2.9 mmol), and 1-chloro-3-iodopropane (0.45 g, 2.2 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.38 g, 74%). Rf=0.64 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 7.01-6.89 (m, 2H), 4.58 (s, 2H), 4.12-4.07 (m, 2H), 3.62 (t, J=6.4 Hz, 2H), 2.65 (q, J=7.6 Hz, 2H), 2.21-2.12 (m, 2H), 1.20 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3) d 1.64.9, 143.3, 133.4, 128.4, 124.3, 122.6, 112.6, 67.2, 42.5, 39.2, 30.3, 23.0, 14.5.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:19]
Reactant: O=C(O)CCCc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCc1ccccc1
Temperature: 0 °C
Yield: 97 %

Procedure:
A solution of 4-phenylbutyric acid (50.0 g, 0.3 mol) in ethanol (140 mL) with concentrated sulfuric acid (0.53 mL) was stirred at reflux over 5 hours. The cooled solution was poured into ice water and extracted with ethyl acetate. The combined organic layers were backwashed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give 4-phenylbutyric acid ethyl ester (56.07 g, 0.29 mol, 97%) as a yellow liquid. 1H NMR (CDCl3) d 7.3-7.1 (m, 5H), 4.1 (q, 2H, J=7.1 Hz), 2.7 (t, 2H, J=7.7 Hz), 2.3 (t, 2H, J=7.5 Hz), 1.95 (quintet, 2H, J=7.5 Hz), 1.25 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCCC1.[BH4-].[Na+]>C(OCC)(=O)C.CO>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][CH:17]([OH:18])[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.34 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) was stirred at 40° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methanol (10 mL), sodium borohydride (0.047 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.31 g, 100%).
Reaction SMILES: [P:1]([O-:8])([O:5]CC)[O:2][CH2:3][CH3:4].[I-].[CH3:10][S+:11]([CH3:13])[CH3:12].C1OC1C>O>[CH2:3]([O:2][P:1]([O-:8])[O-:5])[CH3:4].[CH3:10][S+:11]([CH3:13])[CH3:12].[CH3:10][S+:11]([CH3:13])[CH3:12]
Reactant: CCOP([O-])OCC
Agent: CC1CO1
Agent: C[S+](C)C
Agent: [I-]
Solvent: O
Product: CCOP([O-])[O-]
Temperature: 35 °C
Yield: 149.9 %

Procedure:
Diethyl phosphite (5.5 g) and trimethylsulfonium iodide (8.2 g) are dissolved in water (80 ml). Propylene oxide (20 ml) is added and the mixture is then heated for 6 hours at 35° C. Concentration of the medium under reduced pressure gives a colorless oil (7.9 g) which crystallizes at ambient temperature. The crude product is dissolved in acetonitrile (25 ml) at ambient temperature. The solution is cooled by means of an acetone ice bath. The precipitated product is filtered off and then dried in a vacuum desiccator.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12](Br)[S:11][C:10]=1[NH:15][C:16](=[O:18])[CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:9]1[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][C:10]=1[NH:15][C:16](=[O:18])[CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1sc(Br)cc1C(=O)c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1sc(-c2ccccc2)cc1C(=O)c1ccccc1
Temperature: 90 °C
Yield: 88.6 %

Procedure:
A stirred solution of 0.448 g (1.38 mmol) of N-(3-benzoyl-5-bromo-thiophen-2-yl) acetamide in 20 ml toluene and 10 ml EtOH was degassed with argon. Tetrakis-(triphenylphosphine) palladium (0) (0.320 g, 0.27 mmol), phenyl boronic acid (0.194 g, 1.59 mmol) and 20 ml of an aqueous solution of Na2CO3 1N were added. The mixture was heated at 90° C. for 1 hour before cooling down to RT, filtered through Celite and concentrated. The mixture was extracted with ethyl acetate and aq. NaHCO3. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 0.393 g (88%) N-(3-benzoyl-5-phenyl-thiophen-2-yl)-acetamide as a light yellow solid. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][C:9](OC)=O)[O:7][CH2:6][CH2:5][O:4]1)C.C(=O)([O-])[O-:14].[K+].[K+].O1CCCC1>O>[CH2:8]([C:3]1([CH2:1][OH:14])[O:4][CH2:5][CH2:6][O:7]1)[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CCC1(CC(=O)OC)OCCO1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CO)OCCO1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 71.5 %

Procedure:
A mixture of methyl (2-ethyl-1,3-dioxolan-2-yl)acetate (1.39 g, 7.94 mmol), potassium carbonate (2.19 g, 15.9 mmol), tetrahydrofuran (20 ml) and water (10 ml) was stirred at room temperature for 6 hours and 50 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, which was subjected to NH silica gel pad filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (0.75 g, 71.5%) as colorless oil.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20]C=1C(C1C=CC(C)=CC=1)=O.P([O-])([O-])(O)=O.[Na+].[Na+].NC(N)=O.OO.C(=O)([O-])O.[Na+]>ClCCl>[Cl:8][C:9]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[C:5]([OH:4])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2Cl)cc1
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Solvent: ClCCl
Product: O=C(O)c1ccc(F)cc1Cl
Reaction time: 12 h
Yield: 71.3 %

Procedure:
2.1 g (20 mmol) of acetic anhydride were added dropwise at 0° C. to a mixture of 2.0 g (8 mmol) of 2-chloro-4-fluoro-4'-methylbenzophenone, 9.9 g (0.07 mol) of disodium hydrogenphosphate and 3.8 g (40 mmol) of urea/hydrogen peroxide adduct in 50 ml of dichloromethane. The resulting mixture was then allowed to warmup to room temperature. After 12 h at 20° C., it was neutralized with sodium hydrogencarbonate solution and the aqueous phase was subsequently extracted with dichloromethane. The solvent was then distilled off from the organic phase under vacuum. 50 g of 70% sulfuric acid were added to the residue (2.5 g, containing ca. 80% of phenyl 2-chloro-4-fluorobenzoate) and the mixture was heated for 6 h at the boiling point. Dilution of the cooled mixture, extraction with methyl tert-butyl ether, drying, removal of the solvent and recrystallization of the crude product from water gives 1.0 g (5.7 mmol, 72%) of 2-chloro-4-fluorobenzoic acid in the form of a colorless powder (m.p. 182°-186° C.).
Reaction SMILES: [C:1]([CH:11]1[O:17][CH:16]2[CH:13]([C:14](=[O:26])[N:15]2[C:18](=[C:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[NH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>O1CCCC1>[C:1]([CH:11]1[O:17][CH:16]2[C:13]([C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:14](=[O:26])[N:15]2[C:18](=[C:23]([CH3:24])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[NH:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)C(=C(C)C)N1C(=O)C2NC(C(=O)OCc3ccccc3)OC21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)OCc3ccccc3)OC12
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 4.90 g of methyl α-(3ξ-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 50 ml of tetrahydrofuran are added 2.4 ml of triethylamine and then 2.5 ml of phenylacetyl chloride under ice-cooling, and the mixture stirred for 30 minutes, poured into water and extracted with ethyl acetate. The extract is washed with water dried on magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on 150 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 4.37 g of methyl α-(3ξ-carbobenzoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 67.2% yield.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1)[CH:7]([CH3:9])[CH3:8])C.[H][H]>C1COCC1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.O=[V]>[Cl:19][C:12]1[N:13]=[CH:14][C:15]2[NH:16][C:4](=[O:3])[CH2:5][N:6]([CH:7]([CH3:9])[CH3:8])[C:10]=2[N:11]=1
Reactant: [H][H]
Reactant: CCOC(=O)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Agent: O=[V]
Agent: CC(=O)/C=C(/C)O
Solvent: C1CCOC1
Product: CC(C)N1CC(=O)Nc2cnc(Cl)nc21
Yield: 87 %

Procedure:
A suspension of [(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]-acetic acid ethyl ester (40 g; 0.132 mol), Pt/C5% (2 g) and vanadylacetylacetonate (2 g; 0.754 mmol) in THF (50 ml) was treated with hydrogen (5 bar) overnight. The reaction mixture was warmed (in order to solubilize the precipitate formed) and filtered on a celite pad, then concentrated in vacuo. The crude was diluted in ethyl acetate and the organic phase was washed with NaOH 10% solution, dried with MgSO4 and concentrated in vacuo. 28 g (0.115 mol; 87% yield) of solid material were obtained.