Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C@:8]2([C@H:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:11][N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)[C:7](=[O:28])[N:6]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=2)[C:5]1=[O:37])(=O)C.N1CCCC1>C1COCC1>[CH2:21]([N:10]1[CH2:11][C@@H:12]([C:13]2[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=2)[C@:8]2([NH:4][C:5](=[O:37])[N:6]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=3)[C:7]2=[O:28])[CH2:9]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)N1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1ccccc1)C[C@H]2c1ccc(C#N)cc1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: N#Cc1ccc([C@@H]2CN(Cc3ccccc3)C[C@@]23NC(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Yield: 113.3 %

Procedure:
A mixture of Example 11 (8.9 g, 16.7 mmol), TEA (3.8 ml) and pyrrolidine (2.2 ml) in THF (270 ml) was refluxed for 2 h 30 min. The mixture was concentrated in vacuo and taken into DCM, then washed with water. The organic layer was dried over MgSO4 and concentrated. The resulting solid was chromatographed over silica gel (eluent: DCM/MeOH 95/5) to yield the above-titled compound (9.3 g) as a white solid (mp=200° C.). 1H NMR (DMSO-d6): 9.32 (1H, br s), 7.84 (2H, d, J=8.2 Hz), 7.60 (1H, m), 7.25–7.45 (7H, m), 6.74 (2H, d, J=1.9 Hz), 3.65–3.9 (3H, m), 3–3.3 (4H, m).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([OH:13])=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:18]>CN(C)C=O>[CH2:1]([N:8]1[C:12]([O:13][CH3:18])=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1cnn(Cc2ccccc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C)cnn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.3 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 1-benzyl-4-methyl-1H-pyrazol-5-ol (compound 249.2, 2.0 g, 10.6 mmol) in N,N-dimethylformamide (15 mL). The solution was cooled to 0° C., then sodium hydride (600 mg, 15.00 mmol, 60% dispersion in mineral oil) was added in portions and the resulting mixture was stirred for 10 min at 0° C. Iodomethane (878 μL, 14.1 mmol) was added and the resulting mixture was stirred for 3 h at room temperature, then carefully quenched by drop-wise addition of water (10 mL). The mixture was extracted ethyl acetate (3×40 mL) and the combined organic extracts were washed with brine (3×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:8) as eluent to obtain the title compound as a yellow oil (500 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:17](=[O:18])[N:9]([CH2:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1NCC1CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=c1[nH]c2ccc(Cl)cc2n1CC1CCCCC1
Yield: 70.1 %

Procedure:
A mixture of 7.2 g of the compound obtained in step B) and 6.7 g of 1,1'-carbonyldiimidazole in 100 ml of acetonitrile is refluxed for 5 minutes. The solvent is evaporated off under vacuum, the residue is taken up with water, extracted with DCM, washed with a saturated solution of NaHCO3 and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (95/5; v/v) as the eluent to give 5.6 g of the expected product. M.p.=173° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[CH3:33][C:34]1[NH:35][C:36]([C:39](O)=[O:40])=[CH:37][N:38]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([C:19]([NH:18][C:14]2[CH:13]=[C:12]([N:11]([CH3:32])[C:6]3[N:7]=[CH:8][C:9]4[N:10]=[C:2]([NH:1][C:39]([C:36]5[NH:35][C:34]([CH3:33])=[N:38][CH:37]=5)=[O:40])[S:3][C:4]=4[N:5]=3)[CH:17]=[CH:16][CH:15]=2)=[O:31])[CH:25]=[CH:24][CH:23]=1)([CH3:27])[CH3:28])#[N:30]
Reactant: Cc1ncc(C(=O)O)[nH]1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: Cc1ncc(C(=O)Nc2nc3cnc(N(C)c4cccc(NC(=O)c5cccc(C(C)(C)C#N)c5)c4)nc3s2)[nH]1
Temperature: 90 °C
Reaction time: 20 h
Yield: 65.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 338 μmol) produced in Example D5(i) in pyridine (4 mL) were added 2-methyl-1H-imidazole-5-carboxylic acid (146 mg, 1.01 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (770 mg, 2.03 mmol), and the mixture was stirred at 90° C. for 20 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→90/10), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and methanol to give the title compound (122 mg, 65%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[OH-].[Na+].I[CH3:15]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:15])=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1nc2cc(Cl)ccc2s1
Yield: 98.1 %

Procedure:
With stirring under ice cooling, 2.00 g (9.92 mmols) of 5-chloro-2-mercaptobenzothiazole was added gradually to 10 ml of a solution of 0.24 g (10.00 mmols) of sodium hydroxide in dimethylformamide (DMF). The mixture was dropwise added to 20 ml of a solution of 0.62 ml (9.96 mmols) of iodomethane in 20 ml of DMF with stirring under ice cooling and the mixture was stirred for further 30 minutes under ice cooling. The mixture was concentrated under reduced pressure, and to the residue was added an aqueous saturated sodium bicarbonate followed by extraction of the solution with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =100/1) to afford 2.10 g (yield: 98%) of 5-chloro-2-methylthiobenzothiazole.
Reaction SMILES: CC1C=C(OCCN2CCN(C)CC2)N([CH2:17][C:18]2[CH:23]=CC=C[CH:19]=2)N=1.[OH2:24]>>[C:18]([O:24][O:24][C:18]([CH3:17])([CH3:19])[CH3:23])([CH3:17])([CH3:19])[CH3:23]
Reactant: O
Reactant: Cc1cc(OCCN2CCN(C)CC2)n(Cc2ccccc2)n1
Product: CC(C)(C)OOC(C)(C)C
Yield: 0.5 %

Procedure:
As an example it can be mentioned that, with an apparatus including four infrared sources forming an infrared zone having a length of only 300 mm and having a peak value of the wave lengths around 1.2 μm, it has proved possible to produce tubes having a diameter of 15 mm and a wall thickness of 2.5 mm at a speed of 16.5 kg/h. The atmosphere in the oven was nitrogen mixed with air, that is, not an entirely inert atmosphere. The power of the infrared source furthermore was relatively limited. In spite of this the quality of these tubes with regard to dimensional stability, termal stability, surface finish and cross-linking approaches the quality of the tubes obtained with the slow process according to SE-B-324 450, whilst the speed of manufacture approaches the speed of manufacture for the "PEXEP"-method mentioned introductorily. In another example, tubes intended for tap water were manufactured with the same dimensions as the preceding ones with a dispensed mass of 35 kg/h at a melting temperature of about 175° C. and a total applied effect in two IR-zones having each four IR-lamps or 14-15 kW. With an admixture of 0.5% ditert.butylperoxide, cross-linking degrees of between 76 and 78% were obtained, which is well within the range of the desirable degree of cross-linking, 70-90%. The tubes at the same time displayed a very high surface finish both on the inside and on the outside.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[C:11]([CH3:25])=[C:12]([NH:17][C:18]([NH:20][C:21](=[NH:24])[NH:22][CH3:23])=[O:19])[C:13]([CH3:16])=[CH:14][CH:15]=1)C1C=CC=CC=1.Cl.CO>C(O)C.[Pd]>[ClH:1].[CH3:25][C:11]1[C:10]([OH:9])=[CH:15][CH:14]=[C:13]([CH3:16])[C:12]=1[NH:17][C:18]([NH:20][C:21](=[NH:24])[NH:22][CH3:23])=[O:19]
Reactant: CNC(=N)NC(=O)Nc1c(C)ccc(OCc2ccccc2)c1C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CNC(=N)NC(=O)Nc1c(C)ccc(O)c1C
Reaction time: 0.75 h

Procedure:
1-(3-benzyloxy-2,6-dimethylphenyl)-3-methylamidinourea hydrochloride (18.2 g) and 5% Pd/C (1.0 g) in absolute ethanol (200 ml) containing HCl/methanol (50 ml) are shaken under an atmosphere of H2 (50 psi) for 45 minutes. The reaction mixture is filtered through Celite and the filtrate is concentrated. in vacuo. The resulting solid is crystallized from methanol/acetonitrile to give after drying 12.3 grams of the desired amidinourea hydrochloride salt as a white powder, M.P. 224°-5° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[C:12](=[O:20])[CH2:13][CH2:14][O:15][C:16]=3[C:17]([I:19])=[CH:18][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:23]([Mg]Br)[CH3:24]>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[C:12]([CH2:23][CH3:24])([OH:20])[CH2:13][CH2:14][O:15][C:16]=3[C:17]([I:19])=[CH:18][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(=O)CCO3
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(O)(CC)CCO3
Temperature: 25 °C
Yield: 108.2 %

Procedure:
Into a glass vial containing the product from step (f) (170 mg, 0.409 mmol) dissolved in diethyl ether (4 ml), ethylmagnesium bromide (3M diethyl ether, 1.3 ml, 4.09 mmol) was added at reflux. The reaction mixture was stirred at reflux for 20 minutes. The reaction mixture was allowed to cool to room temperature and was then quenched with saturated aqueous NH4Cl (30 ml). The aqueous mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give a yellow oil (197 mg) that was used without further purification. MS: ESI (positive): 446 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1.[CH3:26][NH:27][C:28](=O)[O:29]C1C=CC=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[NH2:25][C:21]1[CH:20]=[C:19]([O:18][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[O:8][CH2:7][CH2:6][CH2:5][O:4][CH3:3])[N:15]([C:28]([NH:27][CH3:26])=[O:29])[CH:14]=[CH:13]3)[CH:24]=[CH:23][N:22]=1
Reactant: CNC(=O)Oc1ccccc1
Reactant: COCCCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)c(OCCCOC)cc21
Reaction time: 0.17 h
Yield: 93 %

Procedure:
50-72% Oily sodium hydride (308 mg) was added to a solution of 4-((6-(3-methoxypropoxy)-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 32-7 (2.23 g, 7.12 mmol) in N,N-dimethylformamide (30 mL) under nitrogen atmosphere at 0° C. The reaction liquid was stirred for 10 minutes, then phenyl methylcarbamate described in Production Example 1-7 (1.40 g, 9.25 mmol) was added, and the resultant was further stirred at the same temperature for 30 minutes. Water and ethyl acetate were added to the reaction liquid. The organic layer was washed serially with water and a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=9:1-0:1) to obtain the title compound (2.44 g, 93%).
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H:2]([C:12](O)=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.F[C:30]1[CH:35]=[CH:34][C:33]([N:36]2C3C(=CC(I)=CC=3)C=N2)=[CH:32][CH:31]=1>>[C:6]1([CH2:5][O:4][CH2:3][C:2]2[CH:12]=[CH:34][CH:35]=[CH:30][C:31]=2[CH2:32][CH2:33][NH2:36])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: NCCc1ccccc1COCc1ccccc1

Procedure:
(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-[[(phenylmethoxy)methyl]benzeneethanamine is synthesized in analogy to the sequence previously described in example 1: commercially available Boc-Ser(Bn)-OH is transformed into its Weinreb-amide. Reduction to the aldehyde with LiAlH4, reaction with 3-fluorophenylgrignard, cleavage of the tert.-butyloxycarbonyl protecting group, liberation of the amine from the hydrochloride and etherification with 1-(4-fluorophenyl)-5-iodo-1H-indazole gives the desired amine. This amine (123.3 mg, 0.25 mmol) is dissolved in 10 mL of dichloromethane. Triethylamine (0.084 mL, 0.61 mmol) and 0.028 mL (0.3 mmol) 2-methoxyacetylchloride are added. The reaction mixture is stirred overnight at r.t., then diluted with dichloromethane, washed with water and brine and dried over Na2SO4. After filtration the solvent is evaporated and the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane). 79.1 mg (55.9%) of the title compound as a mixture of stereoisomers are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.C1N=CN([C:21](N2C=NC=C2)=[O:22])C=1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:7][C:21](=[O:22])[NH:9][N:8]=2)=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(Cl)ncc1-c1n[nH]c(=O)o1

Procedure:
6-chloro-4-(isopropylamino)nicotinohydrazide (10) (800 mg, 3.5 mmol) was taken in DMF (4 mL). Added CDI (3.8 mmol, 1.1 equiv.) and stirred at room temperature for overnight. The reaction mass was concentrated under reduced pressure to remove excess of DMF. The residue was diluted using EtOAc, washed the EtOAc layer with water followed by brine solution. Collected the EtOAc layer, dried over Na2SO4, filtered and concentrated. The crude material obtained was taken to next step as such, without purification. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.76 min; LCMS (ES-API), m/z 255.6 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=1)[CH:5]=2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[C:3](=[O:16])[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([O:15][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=1)[CH:5]=2)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1C(O)=CC=C2C1=Cc1cc(O)ccc12
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC1=CC=C2C(=Cc3cc(OC(=O)C(C)(C)C)ccc32)C1=O
Reaction time: 2 h

Procedure:
2.1 g (0.01 mole) of 2,7-dihydroxyfluorenone and 2.5 g (0.025 mole) of pivaloyl chloride were warmed to 50° C. in 6 mls of pyridine in a drying tube attached for 2 hrs. The solvent was removed via rotary evaporator and H2O was added. The crystals were filtered and air dried. Recrystallized from ethanol; 3 g (79%); M.P.~174°-175° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38]CC3C=CC([N+]([O-])=O)=CC=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].Cl.[C:52]([O:55][C@@H:56]1[CH2:60][CH2:59][N:58]([C:61](=[NH:64])[CH2:62][SH:63])[CH2:57]1)(=[O:54])[NH2:53]>C(#N)C.CS(C)=O.O1CCCC1.P([O-])([O-])([O-])=O.[C].[Pd].CCOCC>[C:52]([O:55][C@@H:56]1[CH2:60][CH2:59][N:58]([C:61](=[NH:64])[CH2:62][S:63][C:32]2[C@H:33]([CH3:34])[C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]3[C:31]=2[C:36]([OH:38])=[O:37])[CH2:57]1)(=[O:54])[NH2:53]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: N=C(CS)N1CC[C@@H](OC(N)=O)C1
Agent: [Pd]
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CC[C@@H](OC(N)=O)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
0.28 ml of diisopropylethylamine and 0.29 ml of diphenylphosphoryl chloride were added dropwise to an ice-cooled solution of 500 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 6 ml of anhydrous acetonitrile, and then the mixture was stirred for one hour with ice-cooling. 0.20 ml of diisopropylethylamine and a solution of 458 mg of 2-[(3R)-3-carbamoyloxypyrrolidin-1-yl]-2-iminoethylmercaptan hydrochloride in 3.6 ml of dimethylsulfoxide were added to the reaction mixture, and then the whole mixture was stirred for a further 30 minutes with ice-cooling. The reaction mixture was poured into 200 ml of anhydrous ether and the solvent was decanted off from the gummy material which formed. This material was dissolved in a mixture of 40 ml of tetrahydrofuran and 46 ml of 0.1M phosphate buffer (pH 7.0), and the solution was subjected to hydrogenation for 2 hours at room temperature in the presence of 0.6 g of 10% palladium-carbon. The hydrogenation mixture was filtered over "Celite" (Trade Mark) filter aid, and the filtrate was extracted with 80 ml of ether. The aqueous layer was concentrated under reduced pressure and the concentrate was subjected to chromatography through a 160 ml column of "Dowex 50W" (Trade Mark) cation exchange resin (Na+ type), giving 132 mg of the title product from the fraction eluted with water.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O>CS(C)=O>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1nc2cc(F)ccc2nc1Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNc2nc3ccc(F)cc3nc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To 2-chloro-6-fluoro-3-methoxyquinoxaline (4.00 g, 18.8 mmol) dissolved in dimethylsulfoxide (40 ml), 2,4-dimethoxybenzylamine (7.86 g, 47.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 24 hours and then water was added thereto. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (6:1) mixture and concentration gave 4.45 g of the titled compound (yield, 92%).
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.C(O)=O>CN(C=O)C>[Cl:1][C@@H:2]([C@H:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC(=O)C(Cl)C(=O)OCC
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC[C@@H](O)[C@H](Cl)C(=O)OCC
Reaction time: 3 h

Procedure:
Ethyl 2-chloro-3-oxohexanoate (194 mg), DMF (2.4 ml), RuCl[(S,S)-MesDPEN](p-cymene) complex (1 mol %) and triethylamine (5 equivalents) were mixed, and formic acid (5 equivalents) was gradually added thereto. The reaction was carried out at 40° C. for 3 hours. The reaction mixture was analyzed. As a result, the conversion ratio was 97%, and the isomer ratio of (2S,3R):(2S,3S):(2R,3R):(2R,3S) is 94.7:1.3:0:4.0. In the above, “Mes” represents a methylenesulfonyl group.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]2)=[O:25])=[C:22]([F:36])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:38][OH:39].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][C@H:27]2[CH2:28][CH2:29][C@H:30]([OH:33])[CH2:31][CH2:32]2)=[O:25])=[C:22]([F:36])[CH:21]=1)[CH2:9]/[C:10](=[N:38]\[OH:39])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)N[C@H]3CC[C@H](O)CC3)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)N[C@H]3CC[C@H](O)CC3)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, trans-4-[1-(2-chloro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-N-(4-hydroxy-cyclohexyl)-benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam. The ratio of E/Z isomers was 87:13, MS (ESI+): m/z=526.4 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Br:21][C:22]1[S:26][C:25]([CH:27]2[S:33](=[O:35])(=[O:34])[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].[Cl-].[NH4+]>O1CCCC1>[C:48]([O:47][C:45](=[O:46])[CH2:44][C:27]1([C:25]2[S:26][C:22]([Br:21])=[CH:23][CH:24]=2)[S:33](=[O:35])(=[O:34])[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:29][CH2:28]1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)s2)S(=O)(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC1(c2ccc(Br)s2)CCN(C(=O)OC(C)(C)C)CCS1(=O)=O
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
To a solution of lithium diisopropylamide in tetrahydrofuran (10 ml) prepared from diisopropylamine (801 mg) and n-butyl lithium (5.18 ml, 1.53M in n-hexane) was added dropwise a solution of 7-(5-bromo-2-thienyl)-4-tert-butoxycarbonylperhydro-1,4-thiazepine 1,1-dioxide (2.5 g) in tetrahydrofuran (25 ml) at −50° C. under a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a solution of tert-butyl bromoacetate (1.78 g) in tetrahydrofuran (5 ml) was added dropwise therein under the same condition and the reaction mixture was stirred for 30 minutes. After addition of a saturated aqueous solution of ammonium chloride, the mixture was extracted with ethyl acetate (50 ml). The extract was washed successively with 5% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent; hexane:ethyl acetate=5:1) to afford tert-butyl-2-[7-(5-bromo-2-thienyl)-4-tert-butoxycarbonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (1.62 g) as an amorphous powder.