Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:15][S@@:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])([CH2:12][CH2:13][OH:14])[CH:9]([F:11])[F:10])[C:5]([F:22])=[CH:4][CH:3]=1.BrC1N=C([C@@](N[S@@](C(C)(C)C)=O)(CCO)C(F)F)C(F)=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.BrC1N=C([C@](N[S@@](C(C)(C)C)=O)(CC=O)C(F)F)C(F)=CC=1>C(Cl)Cl.O>[Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:15][S@@:16]([C:18]([CH3:20])([CH3:19])[CH3:21])=[O:17])([CH2:12][CH:13]=[O:14])[CH:9]([F:11])[F:10])[C:5]([F:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](=O)N[C@](CCO)(c1nc(Br)ccc1F)C(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)[S@@](=O)N[C@@](CCO)(c1nc(Br)ccc1F)C(F)F
Agent: CC(C)(C)[S@@](=O)N[C@](CC=O)(c1nc(Br)ccc1F)C(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[S@@](=O)N[C@@](CC=O)(c1nc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of the mixture of (R)-N-((R)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1-difluoro-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide and (R)-N-((S)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1-difluoro-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (0.17 g, 0.422 mmol) in DCM (2.1 ml) was added Dess-Martin periodinane (0.215 g, 0.506 mmol). The reaction mixture was stirred at RT. After 1 h, the mixture was diluted with water and extracted with DCM three times. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude was purified by silica gel chromatography: 40 g Grace column, 0-50% EtOAc-hexane in 20 min to give a 3:1 mixture of (R)-N-((R)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1-difluoro-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide and (R)-N-((S)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1-difluoro-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (0.12 g, 0.299 mmol, 70.9% yield) was obtained as a colorless oil. MS m/z=401, 403 M+, Calculated for C13H16BrF3N2O2S: 401.24. Used directly in the following step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1.Br[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[O:21][CH3:22].CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.BrC1N=C(N(CC2C=CC(OC)=CC=2)S(C2C=CC3N(C4C=CC(C(F)(F)F)=CC=4Cl)CCOC=3C=2)(=O)=O)SN=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[O:21][CH3:22])[C:6]=2[CH:11]=1
Reactant: Fc1ccc2c(c1)NCCO2
Reactant: COc1cc(C#N)ccc1Br
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: COc1ccc(CN(c2nc(Br)ns2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2Cl)cc1
Solvent: Cc1ccccc1
Product: COc1cc(C#N)ccc1N1CCOc2ccc(F)cc21
Yield: 91.6 %

Procedure:
To a 10-20 ml microwave vial charged with 6-fluoro-3,4-dihydro-2h-benzo[1,4]oxazine (Ark Pharm) (0.150 g, 0.979 mmol), 4-bromo-3-methoxybenzonitrile (Combi-Blocks) (0.312 g, 1.469 mmol), and sodium t-butoxide (0.240 ml, 1.959 mmol) was added Toluene (9.79 ml). The mixture was purged with argon prior to the additions of xantphos (0.113 g, 0.196 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.090 g, 0.098 mmol). The mixture was irradiated at 110° C. for 30 min. The resulting dark suspension was filtered through celite and the filtrate dried under reduced pressure and purified with a 50 g SNAP column ramping EtOAc in heptane (0-40%, 10% DCM throughout) providing product as a light brown foam 4-(6-fluoro-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-3-methoxybenzonitrile (0.255 g, 0.897 mmol, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.58-3.65 (m, 2 H) 4.19-4.26 (m, 2 H) 6.07 (dd, J=10.95, 2.93 Hz, 1 H) 6.47 (td, J=8.51, 2.93 Hz, 1 H) 6.79 (dd, J=8.80, 5.58 Hz, 1 H) 7.41-7.45 (m, 1 H) 7.45-7.51 (m, 1 H) 7.62 (d, J=1.66 Hz, 1 H). m/z (ESI) 285.2 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[CH:9][C:10]=1Br)([CH3:3])[CH3:2].O1CCCC1.C([Li])CCC.[B:23](OCC)([O:27]CC)[O:24]CC>CCCCCC>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[CH:9][C:10]=1[B:23]([OH:27])[OH:24])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Br)c(OC(C)C)c1
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(B(O)O)c(OC(C)C)c1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
To a 125 mL 3N round-bottomed flask equipped with N2 inlet and septum were added 3.59 g (15.7 mmol) 3-isopropoxy-4-bromotoluene and 30 mL dry tetrahydrofuran. The solution was cooled to −70° C. and 7.5 mL (18.8 mmol) of a 2.5 M solution of butyl lithium in hexane was added over 5 minutes, and the solution stirred 5 minutes at −70° C. Then 3.2 mL (18.8 mmol) triethyl borate was added, followed by stirring for 5 minutes at −70° C. and then stirring at room temperature for 24 hours. The reaction was quenched with 1 N aqueous hydrochloric acid and extracted into ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to a white solid, 1.7 g (56%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:18][CH2:19][CH2:20][NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCc1ccccc1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Product: O=C1Cc2cc(NCCCc3ccccc3)ccc2N1

Procedure:
By reaction of 5-amino-2-oxindole (1.48 g) with 3-phenylpropanal using the procedure of Example 1, the title compound (1.20 g) was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[CH:18].C(NCC)C>CN(C)C=O.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:18]#[C:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1I
Reactant: C#Cc1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Temperature: 50 °C
Yield: 62 %

Procedure:
To a stirred solution of 4-chloro-2-iodo-phenylamine (500 mg, 1.97 mmol) in dimethylformamide (4 ml) was added PdCl2(PPh3)2 (7 mg, 0.02 mmol) followed by copper(I)iodide (3.7 mg, 0.02 mmol), 1-chloro-2-ethynyl-benzene (0.28 ml, 2.36 mmol) and diethylamine (1.65 ml, 15.78 mmol) under nitrogen at RT. The resulting reaction mixture was purged with nitrogen and then heated to 50° C. for 5 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (elution with 4% EtOAc in hexane) to yield 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (320 mg, 62% yield) as an off white solid. LC-MS: 262 (M+H)+.
Reaction SMILES: [I-].[Na+].Cl[Si](CC)(CC)CC.S(=O)(=O)(O)O.[CH3:16][O:17][C:18](=[O:37])[C@H:19]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[N:20]1[CH2:25][CH:24](O)[C:23]2[S:27][CH:28]=[CH:29][C:22]=2[CH2:21]1.C(=O)(O)[O-].[Na+]>C(#N)C.CC(C)=O>[CH3:16][O:17][C:18]([C@@H:19]([N:20]1[CH2:21][C:22]2[CH:29]=[CH:28][S:27][C:23]=2[CH2:24][CH2:25]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])=[O:37]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: CC[Si](Cl)(CC)CC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC#N
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium iodide in acetonitrile, and acetone is added chlorotriethylsilane. The mixture is stirred at room temperature under nitrogen for 1 hour. (αS,7RS)-methyl-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate bisulfate salt 25.0 g, 66.8 mmol) is added to the mixture at 0–5° C. After the addition is complete the mixture is warmed to room temperature and stirred for 12 hours. The reaction mixture is then basified with aqueous sodium bicarbonate solution. The organic layer is then washed with aqueous sodium thiosulfate solution, followed by water, then brine. The organic layer is then dried, filtered and concentrated to provide clopidogrel free base as an oily product (20.6 g). The product obtained was found to be identical to the product obtained in Example 1 by 1H-NMR.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
4-Hydroxycinnamic acid (700 mg, 4.26 mmol) was dissolved in EtOAc (15 mL) and 10% Pd/C (51 mg, 0.479 mmol) was added. The reaction mixture was stirred under an atmosphere of H2 overnight at room temperature before it was filtered through diatomaceous earth and concentrated in vacuo. No further purification was needed to yield 3-(4-hydroxyphenyl)propanoic acid (700 mg, 99%). A solution of 3-(4-hydroxyphenyl)propanoic acid (700 mg, 4.21 mmol) in anhydrous DMF (16 mL) at 0° C. was treated with a solution of 60% NaH (450 mg, 18.75 mmol) in DMF dropwise. The reaction mixture was stirred for 10 min before benzyl bromide (0.675 mL, 5.68 mmol) was added. The reaction mixture was stirred overnight at room temperature, quenched with aqueous 1 N HCl and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl, saturated aqueous NaCl and dried over Na2SO4. Column chromatography (SiO2, 4×9 cm, 20-40% EtOAc-hexanes gradient) afforded 3-(4-(benzyloxy)phenyl)propanoic acid (780 mg, 72%) as a white solid: 1H NMR (CDCl3, 500 MHz) 7.44 (d, 2H, J=7.4 Hz), 7.40 (t, 2H, J=7.4 Hz), 7.35-7.32 (m, 1H), 7.14 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.4 Hz), 5.06 (s, 2H), 2.92 (t, 2H, J=7.7 Hz), 2.66 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 125 MHz) 179.0, 157.3, 137.0, 132.5, 129.2, 128.5, 127.9, 127.4, 114.9, 70.0, 35.8, 29.7. (See: Xue, C.-B.; He, X.; et al. J. Med. Chem. 2001, 44, 3351-3354)
Reaction SMILES: O[C:2]1([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:29])[CH3:28]>C(O)C>[CH3:28][C:3]1([CH3:29])[CH:2]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3cccs3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3cccs3)C(C)(C)O4)CC2)cc1
Yield: 78 %

Procedure:
Using 1-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(2-thienyl)-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine obtained in Example 41, the title compound was synthesized in the same manner as in Example 46. Yield 78%. mp. 139–141° C. (ethanol).
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[C:13]2[N:12]3[C@H:14]([CH3:18])[CH2:15][NH:16][CH2:17][C@H:11]3[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH3:4].C([O-])(=O)C.[Na+]>C(O)(=O)C.ClCCl>[Br:1][C:7]1[CH:6]=[C:5]([CH2:3][CH3:4])[C:13]2[N:12]3[C@H:14]([CH3:18])[CH2:15][NH:16][CH2:17][C@H:11]3[CH2:10][C:9]=2[CH:8]=1
Reactant: BrBr
Reactant: CCc1cccc2c1N1[C@@H](CNC[C@H]1C)C2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1cc(Br)cc2c1N1[C@@H](CNC[C@H]1C)C2
Yield: 31.8 %

Procedure:
Bromine (0.2 M solution in acetic acid, 0.48 mL, 96 μmol) was added dropwise at room temperature to a solution of (4R,10aR)-6-ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (21 mg, 97 μmol) and sodium acetate (8.0 mg, 97 μmol) in acetic acid (0.5 mL). After 30 min the reaction mixture was diluted with dichloromethane and extracted with 2 M aq. potassium hydroxide solution, dried (MgSO4), and evaporated. Chromatography on SiO2 (CH2Cl2/MeOH/NH4OH 95:5:0.1) yielded the title compound (9 mg, 31%). Yellow oil. ISP-MS: m/e=295.3, 297.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:13][NH:14][C:15](=[O:16])[C:11]=2[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[H-].[Na+].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:12]2[CH2:13][N:14]([CH2:35][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=3)[C:15](=[O:16])[C:11]=2[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COc1ccc(COc2c3c(c(OC)c4cccnc24)CNC3=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c3c(c(OC)c4cccnc24)CN(Cc2ccc(C(F)(F)F)cc2)C3=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.6 %

Procedure:
5-Methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 304 (25.4 mg, 0.073 mmol,) was dissolved in dimethylformamide (0.4 ml) and cooled to 0° C. Sodium hydride (3.6 mg, 0.095 mmol) was added, followed by stirring at 0° C. for 5 minutes. 4-trifluoromethyl-benzylbromide (21.0 mg, 0.088 mmol) was added and the reaction mixture was allowed to warm to room temperature and kept at room temperature with stirring for 5 minutes. It was cooled to 0° C., quenched with acetic acid (0.030 ml), and concentrated in vacuo. The mixture was diluted with ethyl acetate, washed twice with water, once with brine, dried over magnesium sulfate, and concentrate in vacuo. The residue was purified by silica gel chromatography (99/1—ethyl acetate/acetic acid) to afford 5-Methoxy-9-(4-methoxy-benzyloxy)-7-(4-trifluoromethyl-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 305 (13 mg, 0.026 mmol, 35%). 1H NMR δ 9.15 (dd, 1H), 8.60 (dd, 1H), 7.60 (m, 4H), 7.40 (d, 2H), 6.80 (d, 2H), 5.85 (s, 2H), 4.80 (s, 2H), 4.42 (s, 2H), 3.98 (s, 3H), 3.86 (s, 3H). MS: 509.2 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=O)[NH:9][N:8]=1.O=P(Cl)(Cl)[Cl:22]>C(#N)C>[Cl:22][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=1
Reactant: COc1ccc2c(Cc3ccco3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2c(Cc3ccco3)nnc(Cl)c2c1
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
A suspension under N2 of 4-furan-2-ylmethyl-7-methoxy-2H-phthalazin-1-one (1.8 g, 7.02 mmoles), prepared as described in example 126, in acetonitrile (40 ml) was added under stirring with POCl3 (3.27 ml, 35.1 mmoles), and refluxed for 1 hour, then dried. The residue was suspended in water (50 ml), added with NaHCO3 up to alkalinity, and stirred for 30 minutes, then extracted in CH2Cl2. The organic phase was anhydrified over Na2SO4 and dried to give a residue which was taken up in petrolatum and filtered. The resultant solid was dried under vacuum at 40° C. to give 1.72 g of the title compound (yield: 89%).
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:10](OC)(=[O:15])[CH2:11][C:12]([CH3:14])=O>C(O)(=O)C>[CH:2]1([N:8]2[C:10](=[O:15])[CH2:11][C:12]([CH3:14])=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NNC1CCCCC1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC1=NN(C2CCCCC2)C(=O)C1
Temperature: 100 °C
Yield: 102.6 %

Procedure:
Cyclohexylhydrazine hydrochloride (2.00 g, 13.3 mmol) and methyl acetoacetate (2.37 g, 20.4 mmol) were combined in glacial acetic acid (55 mL). The reaction was heated to 100° C. for 18 h. After allowing the reaction to cool to RT, the solvent was removed under reduced pressure to give 2.46 g of the desired product as a pale orange solid. This material was used without further purification. MS (ES+) m/z 181.2 (M+H+).
Reaction SMILES: C([N:11]1[CH2:18][C@H:17]([O:19][C:20]([NH:22][CH3:23])=[O:21])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[H][H]>[C].[Pd].CO.O>[CH3:23][NH:22][C:20]([O:19][C@H:17]1[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1)=[O:21]
Reactant: CNC(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CNC(=O)O[C@H]1CN[C@H](C(=O)O)C1

Procedure:
A solution of 2.7 g. (0.0084 mole) of trans-N-carbobenzyloxy-4-[[(methylamino)carbonyl]oxy]-L-proline in 100 ml. of methanol-water (2:1) is treated with 1 g. of 5% palladium-carbon and 45 lb. of hydrogen and shaken on a Parr hydrogenator for 6 hours. The catalyst is filtered off under nitrogen, washed with methanol and the combined filtrates are evaporated, finally at 0.1-0.2 mm, to give 1.5 g. (96%) of a residue which gradually crystallizes to give trans-4-[[(methylamino)carbonyl]oxy]-L-proline as a greyish solid; m.p. 213°-215° (dec.), preceded by gradual darkening and sintering. [α]D26 -12° (c, 0.25% in 1:3 ethanol-methanol).
Reaction SMILES: [NH2:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][NH:4][C:3]1=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20](S(C)(=O)=O)[N:19]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>[NH2:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]([C:20]2[N:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]([O:17][CH3:16])[N:19]=2)[C:3]1=[O:9]
Reactant: CSc1n[nH]c(=O)n1N
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)nc(-n2nc(SC)n(N)c2=O)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A mixture of 3.0 g (0.02 mol) of 4-amino-5-methylthio-2,4-dihydro-3H-1,2,4-triazol-3-one and 200 ml of acetone is refluxed for 4 hours after 0.1 g of p-toluenesulphonic acid has been added. The mixture is concentrated, the residue is taken up in 100 ml of acetonitrile, and the reaction mixture is refluxed for 12 hours after 8.3 g (0.06 mol) of potassium carbonate and 4.4 g (0.02 mol) of 4,6-dimethoxy-2-methylsulphonyl-pyrimidine have been added. The cooled mixture is filtered, the filtrate is concentrated, the residue is taken up in 100 ml of ethanol/water (vol. 1:1) and stirred for 3 hours at 60° C. after 2 ml of concentrated hydrochloric acid have been added. The mixture is concentrated, the residue is stirred with saturated sodium hydrogen carbonate solution, and the crystalline product is isolated by filtering off with suction. 4.9 g (86% of theory) of 4-amino-5-methylthio-2 -(4,6-dimethoxy-pyrimidin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 198° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.CS(O[CH2:16][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH2:16][C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)=[C:4]([Cl:10])[CH:3]=1
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Reactant: CS(=O)(=O)OCC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1cc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)cc1Br
Temperature: 125 °C
Reaction time: 48 h

Procedure:
A mixture of 4-bromo-2,5-dichlorophenol (1.35 g, 5.58 mmol), adamantan-1-ylmethyl methanesulfonate (Fr. Demande, 2909090, 30 May 2008) (1.5 g, 6.14 mmol), and potassium carbonate (0.85 g, 6.14 mmol) in N,N-dilmethylformamide (10 mL) was stirred at 65° C. for 16 h and at 125° C. for 48 h. The reaction mixture was cooled down to ambient temperature, diluted with water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 5% to 10% gradient of ethyl acetate in hexanes to afford 1-((4-bromo-2,5-dichlorophenoxy)methyl)adamantine as a colorless solid (1.7 g, 71%): MS (ES+) m/z 391.3 (M+1);
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:17]1[CH:24]2[NH:25][CH:19]([CH2:20][C:21]([CH2:23]2)=[O:22])[CH2:18]1.Cl.C(N(CC)CC)C.C(O)C>C1COCC1.ClCCl.O>[C:11]1([C:10]2[C:3]3[C:2]([N:25]4[CH:19]5[CH2:18][CH2:17][CH:24]4[CH2:23][C:21](=[O:22])[CH2:20]5)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Reactant: O=C1CC2CCC(C1)N2
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: O=C1CC2CCC(C1)N2c1ncnc2scc(-c3ccccc3)c12
Temperature: 70 °C
Yield: 72.9 %

Procedure:
A mixture of 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (1.00 g, 4.05 mmol), nortropinone hydrochloride (0.983 g, 6.08 mmol) and triethylamine (1.71 mL, 12.2 mmol) in THF (20 mL) was heated to 70° C. overnight. Ethanol (20 mL) was added and the mixture was heated to 70° C. for 3 hr. Further batches of nortropinone hydrochloride (0.983 g, 6.08 mmol) and triethylamine (1.71 mL, 12.2 mmol) were added and the mixture was heated to 70° C. overnight. Further batches of nortropinone hydrochloride (0.983 g, 6.08 mmol) and triethylamine (1.71 mL, 12.2 mmol) were added and the mixture was heated to 70° C. over 3 nights. It was cooled to room temperature and diluted with dichloromethane (40 mL) and water (40 mL). The layers were separated and the aqueous was extracted with dichloromethane (2×40 mL). The combined organic layers were washed with brine (1×40 mL), filtered through a hydrophobic frit and evaporated to give a brown oil. Mass: 3.21 g. This was purified by silica chromatography (100 g cartridge; eluent petrol/ethyl acetate 0 to 40%). Fractions corresponding to the main peak were combined and evaporated to give 8-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one as a white solid (0.99 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:23](=[O:24])[N:5]2[C:6]([C:20]([O-:22])=[O:21])=[C:7]([CH2:10][N+:11]3[N:12]([CH2:17][CH2:18][OH:19])[C:13]([NH2:16])=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12.C(=O)(O)[O-].[Na+].[NH2:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:40][O:41][CH2:42][CH3:43])[C:37](O)=[O:38])[N:35]=1.ON1C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1.C(OCC)(=O)C>[NH2:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:40][O:41][CH2:42][CH3:43])[C:37]([NH:2][C@@H:3]2[C:23](=[O:24])[N:5]3[C:6]([C:20]([O-:22])=[O:21])=[C:7]([CH2:10][N+:11]4[N:12]([CH2:17][CH2:18][OH:19])[C:13]([NH2:16])=[CH:14][CH:15]=4)[CH2:8][S:9][C@H:4]23)=[O:38])[N:35]=1
Reactant: Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCO
Reactant: CCON=C(C(=O)O)c1csc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(N)n3CCO)CS[C@H]12)c1csc(N)n1
Temperature: 30 °C
Reaction time: 5 h

Procedure:
A solution of 7β-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate hydrochloride. dihydrate (1.5 g) in a mixture of water (15 ml) and tetrahydrofuran (30 ml) was adjusted to pH 7 with saturated sodium bicarbonate aqueous solution and 2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer) activated by 1-hydroxy-1H-benzotriazole (2.22 g) was added thereto at room temperature. The mixture was stirred for 5 hours at 30° C. maintaining pH 7 with addition of 20% potassium carbonate aqueous solution. To the reaction mixture was added ethyl acetate (30 ml) and the separated aqueous layer was washed with ethyl acetate (20 ml×2). The aqueous solution was adjusted to pH 4 with 1N-hydrochloric acid and washed with ethyl acetate (20 ml×3). The aqueous solution was adjusted to pH 2 with addition of 1N hydrochloric acid and subjected to column chromatography on "Diaion HP-20" (60 ml) using aqueous isopropyl alcohol, as an eluent. Fractions containing the object compound were combined and evaporated and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido ]-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (1.30 g).