Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:29])([C:16]([S:19]CC1C=CC(OC)=CC=1)([CH3:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:29])([C:16]([SH:19])([CH3:17])[CH3:18])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: COc1ccc(CSC(C)(C)C(O)(Cn2cncn2)c2ccc(F)cc2F)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(S)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 85.7 %

Procedure:
To 72.0 g (172 mmol) of (+)-2-(2,4-difluoro-phenyl)-3-((4-methoxyphenyl)methylthio)-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol were added 18.6 g (172 mmol) of anisole and 1010 ml of trifluoroacetic acid in this order, followed by stirring at 70° C. for 1.5 hours. After allowing the mixture to cool, the solvent was removed by distillation under reduced pressure, and the residue was neutralized with a saturated sodium hydrogencarbonate aqueous solution, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution and dried. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography using chloroform as an eluent. The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from a mixed solvent of isopropyl ether and hexane to obtain 44.1 g (86%) of (-)-2-(2,4-difluoro-phenyl)-3-mercapto-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol as a colorless crystal.
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[Fe:18](Cl)Cl>C(OCC)(=O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:5]=[C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[NH:10]1.[Fe+2:18]
Reactant: Nc1ccccn1
Reactant: Cl[Fe]Cl
Reactant: N#Cc1ccccc1C#N
Solvent: CCOC(C)=O
Product: [Fe+2]
Product: c1ccc(N=C2NC(=Nc3ccccn3)c3ccccc32)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL round-bottom flask equipped with a nitrogen inlet and an internal fritted-glass filter is charged with phthalonitrile (2.56 g, 20.0 mmol) and ethyl acetate (50 mL). 2-Aminopyridine (3.77 g, 40.0 mmol, 2.1 eq.) and iron(II) chloride (2.54 g, 20.0 mmol) are added to the flask, and the mixture is stirred under nitrogen at room temperature for 1 h. The mixture is stirred at room temperature for 120 h, yielding a white precipitate.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[P:19](Cl)(Cl)(Cl)=[O:20]>BrCCBr.O1CCCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([P:19](=[O:20])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)=[CH:12][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(P(=O)(c2ccc(C)cc2)c2ccc(OC)cc2)cc1
Temperature: 67 °C
Reaction time: 5 h
Yield: 82.7 %

Procedure:
Magnesium (1430 g, 58.8 mol), tetrahydrofuran (12 L), and 1,2-dibromoethane (2.2 g, 0.012 mol) were stirred under nitrogen for 1 h. The mixture was then heated to reflux and the heating stopped. A mixture of 4-bromotoluene (3268 g, 19.1 mol) and 4-bromoanisole (7150 g, 38.2 mol) was added at a rate to maintain a slow reflux (67° C.) over a period of 4 h. The reaction mixture was then held for a further 5 h at 70° C. Phosphorus oxychloride (2930 g, 19.1 mol) was added at a rate to maintain a temperature of 70° C. (5 h). The reaction was then held at 70° C. for a further 5h. The reaction mixture was then worked up to give the product mixture (5563.8 g, 83%) as an amber colored oil upon concentration. 31P NMR: (d6-DMSO) δ 27.3 (s), 27.1 (s), 26.9 (s), 26.9 (s), 26.7 (s). GC(area %): tris(4-methylphenyl)phosphine oxide 3.8%, bis(4-methylphenyl)(4-methoxyphenyl)phosphine oxide 21.0%, bis(4-methoxyphenyl)(4-methylphenyl)phosphine oxide 39.4%, and tris(4-methoxyphenyl) phosphine oxide 25.1%.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:20])=[O:19])[C:12]3([CH2:14][CH2:13]3)[CH2:11]2)=[N:3][CH:2]=1.[CH3:29][S:30]([CH2:33][CH2:34][CH2:35]O)(=[O:32])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(/N=N\C(=O)OC(C)C)=O)(C)C>C1COCC1.O>[CH3:29][S:30]([CH2:33][CH2:34][CH2:35][N:21]([S:18]([N:15]1[C:12]2([CH2:14][CH2:13]2)[CH2:11][N:10]([C:4]2[C:5]3[CH:9]=[CH:8][NH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH2:17][CH2:16]1)(=[O:19])=[O:20])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)CCCO
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: CC(C)OC(=O)/N=N\C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCS(C)(=O)=O)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Tert-butyl N—[[5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octan-8-yl]sulfonyl]carbamate (Intermediate 53)(0.12 mmol) was dissolved in dry THF (1 mL) and added 3-methylsulfonylpropan-1-ol (0.13 mmol) and triphenylphosphine (0.15 mmol). The reaction mixture was cooled to 0° C. and slowly added isopropyl (NZ)—N-isopropoxycarbonyliminocarbamate (0.15 mmol). The reaction mixture was allowed to warm up freely to rt and stirred at rt for 16 h. The crude mixture was treated with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[CH:7][C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1.[Cl-].[Na+].[O:20]1[CH2:24]C[CH2:22][CH2:21]1>CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][C:10]1[S:9][C:8]([CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3][CH2:22][CH:21]2[O:20][CH2:24]2)=[N:12][N:11]=1
Reactant: Cc1nnc(C=Cc2ccccc2O)s1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.72 g (0.085 mole) of 55% strength sodium hydride in paraffin oil are suspended in 150 ml of absolute tetrahydrofuran and 18.6 g (0.085 mole) of 2-(2-hydroxystyryl)-5-methyl-1,3,4-thiadiazole in 200 ml of absolute hexamethylphosphorotriamide are then added dropwise at 0°-3° C. in the course of 1.5 hours. Stirring is continued at room temperature for 1 hour, after which 11.7 g (0.085 mole) of dibromohydrin are added dropwise. The solution is left to stand at room temperature for 16 hours and is then poured into 1.5 liters of ice water and 0.5 liter of saturated sodium chloride solution. The solid obtained is filtered off and recrystallized from acetone. 11.8 g (51% of theory) of yellow crystals are obtained. Melting point 134°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C[N:15]([CH:17]=[O:18])[CH3:16].[C:19](Cl)(=[O:23])C(Cl)=O>C1COCC1>[CH2:9]([C@@H:16]1[CH2:19][O:23][C:17](=[O:18])[N:15]1[C:11](=[O:13])/[CH:10]=[CH:9]/[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a solution of (2E)-3-(3,4-dichlorophenyl)prop-2-enoic acid (5.0 g) and DMF (178 μL) in THF (115 mL) was added oxalyl chloride (3.98 mL) at room temperature, and the mixture was stirred for 45 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (13.8 mL). The THF solution was added dropwise to a solution of (4R)-4-benzyl-1,3-oxazolidin-2-one (4.48 g), triethylamine (15.9 mL) and LiCl (4.87 g) in THF (115 mL) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and brine and dried, and the solvent was evaporated under reduced pressure to give (4R)-4-benzyl-3-[(2E)-3-(3,4-dichlorophenyl)prop-2-enoyl]-1,3-oxazolidin-2-one (4.22 g, 49%) as a white powder.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[N:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([O:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])=[CH:15][CH:14]=1.O.NN.C(OCC)(=O)C>C(O)C>[NH2:3][CH2:12][C:13]1[N:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([O:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])=[CH:15][CH:14]=1
Reactant: CC(=O)OCCOc1ccc(CN2C(=O)c3ccccc3C2=O)nc1[N+](=O)[O-]
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(=O)OCCOc1ccc(CN)nc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To a solution of 0.35 gm (0.97 mmol) of Acetic acid 2-[6-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-nitro-pyridin-3-yloxy]-ethyl ester 97 in 5 mL of ethanol was added 0.051 mL (1.01 mmol) of hydrazine hydrate at room temperature. The reaction mixture was allowed to stir for 4 h. The mixture was then transferred with ethyl acetate and the solvent was removed at reduced pressure. The residue was taken up in CHCl3 (200 mL) and washed twice with water (100 mL), saturated brine, dried (Na2SO4), and the solvents removed under reduced pressure. This was used without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][N:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:37][C:38]([NH2:40])=[O:39]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)=[N:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cn3)ncc2Cl)n[nH]1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC(N)=O)CC4)cn3)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-methyl-5-(piperidin-4-yl)pyridin-2-yl)pyrimidine-2,4-diamine (50 mg, 0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL), was added 2-bromo-acetamide (25 mg, 0.18 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was purified by RP-HPLC to afford 2-(4-(6-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidin-1-yl)acetamide as a white solid; 1H NMR (400 MHz, MeOD-d4) δ 8.30 (s, 1H), 8.21 (s, 1H), 7.28 (s, 1H), 6.19 (s, 1H), 4.0 (s, 2H), 3.80-3.73 (m, 2H), 3.33-3.21 (m, 3H), 2.61 (s, 3H), 2.37 (s, 3H), 2.37-2.32 (m, 2H), 2.20-2.16 (m, 2H); ESMS m/z 456.2 (M+H+).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[NH:28][CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Sc1ncc[nH]1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3ncc[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2-mercaptoimidazole was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11]1)([O-])=O.CC(O)=O.O>[Fe]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:11]1
Reactant: O=C(N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1)OCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of benzyl [(3S)-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (2.96 g, 8.30 mmol) in AcOH (36.00 mL, 633.2 mmol), iron powder (2.703 g, 48.40 mmol) was added followed by water (5.00 mL, 278 mmol). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure. EtOAc (100 mL) was added to the resulting residue. The mixture was filtered through a pad of diatomaceous earth (CELITE®). The diatomaceous earth pad was washed with a 10 wt % aq. K3PO4 (150 mL) and EtOAc (100 mL). The organic layer was washed with brine (150 mL), dried over Na2SO4 and concentrated. The resulting residue was purified by flash chromatography on silica gel (0-20% MeOH in DCM) to give the sub-title compound as an off-white solid (2.24 g, 83%). LCMS calc. for C18H23N4O2 (M+H)+: m/z=327.2. found 327.2.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH2:28][NH:29]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.BrB(Br)Br.C(Cl)[Cl:42]>>[ClH:42].[NH2:29][CH2:28][C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:4]3[C:5]4[C:6]5[CH:17]=[CH:16][S:15][C:7]=5[C:8](=[O:14])[NH:9][C:10]=4[C:11]([CH3:13])=[CH:12][C:3]=3[OH:2])=[CH:23][CH:22]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CCC2)cc1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Cc1cc(O)c(-c2ccc(C3(CN)CCC3)cc2)c2c1[nH]c(=O)c1sccc12
Product: Cl
Yield: 65 %

Procedure:
Following General Procedure F, tert-butyl (1-(4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)cyclobutyl)methylcarbamate (130 mg, 0.32 mmol was reacted with tribromoborane (1.0 M in methylene chloride, 1.9 mL, 1.9 mmol to afford the desired product (82 mg, 65%) as a white solid: 1H NMR (500 MHz, MeOD) δ 7.63 (d, J=5.4 Hz, 1H), 7.46-7.41 (m, 2H), 7.38-7.32 (m, 2H), 7.09 (d, J=0.7 Hz, 1H), 6.26 (d, J=5.4 Hz, 1H), 3.36-3.33 (m, 2H), 2.65 (dd, J=21.2, 9.3 Hz, 2H), 2.58 (s, 3H), 2.45-2.37 (m, 2H), 2.27 (ddd, J=17.7, 11.5, 8.6 Hz, 1H), 2.12-2.01 (m, 1H); ESI MS m/z 391 [C23H22N2O2S+H]+; HPLC >99% (AUC), tR=9.37 min.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:10][C:9]1([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[F:11])(C)(C)C.Cl.O>CO.C(O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2([F:11])[CH2:10][CH:8]2[NH2:7])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1CC1(F)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CO
Product: NC1CC1(F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-(4-chlorophenyl)-2-fluoro-cyclopropyl)-carbamic acid tert-butyl ester from example P5c) (1.00 g; 3.5 mmol) was dissolved in methanol (10 ml) and a saturated solution of HCl in ethanol (10 ml) added. The solution was stirred at room temperature for 2 h then evaporated leaving a white solid. Water (50 ml) then added and mixture extracted twice with ethyl acetate. The aqueous phase was made alkaline with 2M NaOH and extracted twice with ethyl acetate. The extracts were dried (MgSO4) and evaporated. 0.60 g of 2-(4-chlorophenyl)-2-fluoro-cyclopropylamine was obtained in the form of a yellow oil (92% of theory) as a 7:3 mixture of cis/trans isomers.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[SiH:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17]>O1CCCC1>[CH2:16]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:17]
Reactant: CSc1ccccc1
Reactant: CC[SiH](CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)CSc1ccccc1
Yield: 67.9 %

Procedure:
The reaction was conducted according to the General Procedure by heating thioanisole (62 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 65 hours at 65° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using hexanes (isochratic) to obtain 81 mg (68%) of the title compound as a colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.31-7.26 (m, 2H), 7.25-7.19 (m, 2H), 7.11-7.01 (m, 1H), 1.03 (t, J=7.9 Hz, 9H), 0.78-0.60 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 140.73, 128.31, 125.69, 124.19, 13.01, 6.62, 3.06. HRMS: [C13H21SSi] calculated 237.1140, measured 237.1133. The HSQC spectra of the thioanisole and its reaction product as provided in FIGS. 7A and 7B.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:51][OH:52])[C:27]([NH:29][CH:30]2[C:49](=[O:50])[N:32]3[C:33]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>[Ag]=O.CN(C)C=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:51][O:52][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:27]([NH:29][CH:30]2[C:49](=[O:50])[N:32]3[C:33]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[C:34]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
0.5 g of silver oxide were added at 20° C. to a mixture of 0.074 g of the product of Step B, 0.7 ml of dimethylformamide and 0.5 ml of tert.-butyl bromoacetate and the mixture was stirred for 30 minutes and was vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was added to 10 ml of water. The mixture was decanted and the aqueous phase was extracted with 5 ml of ethyl acetate. The combined organic phases were washed with 5 ml of aqueous sodium chloride solution, dried over magnesium sulfate and was vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was evaporated to dryness. The residue was taken up in isopropyl ether and efflorescenced. The mixture was vacuum filtered and the product was rinsed with isopropyl ether and dried to obtain 0.02 g of the syn isomer of tert.-butyl 7-[2-(2-tritylamino-4-thiazolyl)-2-(tert.-butoxycarbonylmethoxyimino)-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate with Rf=0.34 (methylene chloride containing 5% ether). The product was identical to the product of Example 3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=O)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[S:45])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6yl)phenyl)cyclobutyl)carbamate (5 g, 10.60 mmol) in toluene (380 ml) was added Lawesson's reagent (4.29 g, 10.60 mmol). The resulting mixture was heated under reflux for 5 hours. After it was cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in the minimum amount of dichloromethane (500 ml) and treated with diisopropyl ether (800 ml). A yellow solid crushed out. It was filtered and dried until constant weight (4.7 g, 91%). LCMS (Method D): RT=1.526 min, M+1=488.
Reaction SMILES: Br.[OH:2][C@@H:3]1[C:12]2[CH:11]=[CH:10][N:9]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:8]3[C:7]=2[NH:6][C@H:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:4]1[OH:23]>>[OH:2][C@H:3]1[C:12]2[CH:11]=[CH:10][N:9]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:8]3[C:7]=2[NH:6][C@H:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:4]1[OH:23]
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@@H]3O
Agent: Br
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@H]3O
Temperature: 0 °C

Procedure:
To a of 0° C. cooled and stirred solution of hydrobromic acid is added 1.00 g (3.39 mmol) (7R,8R,9R)-7,8-dihydroxy-2-methyl 9-phenyl-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine. After 0.5 h the reaction is quenched by adding ice and aqueous ammonia solution until the reaction mixture is transferred to pH 9.8. The precipitated solid is separated, washed with water and dried in vacuo at 60° C. to provide the title compound as a armorph solid. 1H-NMR (200 MHz, [D6] DMSO): δ=2.30 (s, 3 H), 3.84 (m, 1H), 4.34 (t, 1H), 4.48 (dd, 1H), 6.72 (d, 1H.), 7.25–7.45 (m, 5H), 7.56 (d, 1H), 7.73 (d, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH2:30]=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH3:30])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccn1)c1ccc2c(Cl)c[nH]c2c1
Reactant: C=O
Product: CN1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccn2)CC1

Procedure:
Using alkylation method B, 3-chloro-N-[1-(2-pyridinyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (30 mg, 0.07 mmol) and paraformaldehyde (15 mg, 0.12 mmol) afforded, after purification (SiO2: 10% isopropylamine in DCM), 20 mg (65%) of the title compound.