Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:21][O:22][CH2:23][O:24][CH3:25])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][C@H:12]([CH2:21][O:22][CH2:23][O:24][CH3:25])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15]
Reactant: [H][H]
Reactant: COCOC[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCOC[C@@H](N)CC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
To a solution of tert-butyl(3S)-3-{[(benzyloxy)carbonyl]amino}-4-(methoxymethoxy)butanoate (16.3 g, 53 mmol) in methanol (150 ml) was added 10% Pd—C (3.3 g) and the mixture was stirred for 6 hours at a hydrogen atmosphere. Additional 10% Pd—C (0.75 g) was added thereto and the mixture was stirred for 1.5 hours. After removal of catalyst by filtration, the solvent was removed in vacuo to give tert-butyl(3S)-3-amino-4-(methoxymethoxy)butanoate (9.7 g, 84%).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[C:6]([N:34]([CH3:36])[CH3:35])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].[OH-].[Na+]>O1CCCC1.CO>[CH3:36][N:34]([CH3:35])[C:6]1[C:5]([CH2:4][C:3]([OH:37])=[O:2])=[C:10]([N:11]([CH3:12])[CH3:13])[N:9]=[C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:33])[C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=3)=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc(N(C)C)c1CC(=O)O

Procedure:
A solution of methyl[4,6-bis(dimethylamino)-2-(4-{[4-(trifluoromethyl)benzoyl]amino}-benzyl)pyrimidin-5-yl]acetate (4.34 g, 8.42 mmol) in 20% tetrahydrofuran in methanol (100 mL) was treated with 1N sodium hydroxide solution (25 mL). The resulting mixture was heated at refluxing temperature for 5 hours and then the volatiles were removed by rotary evaporation under vacuum. The remaining aqueous solution was washed with diethyl ether and then neutralized with 1N hydrochloric acid at 0° C. The separated precipitate was collected by suction and rinsed with cold water. Recrystallization from methanol then gave [4,6-bis(dimethylamino)-2-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)pyrimidin-5-yl]acetic acid (3.86 g, 81%) as colorless needles.
Reaction SMILES: [NH2:1][C:2]1([CH2:18][CH2:19][OH:20])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.[C:21]([N:29]=[C:30]=S)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1.O>C1COCC1>[Br:16][C:13]1[CH:14]=[C:15]2[C:2]3([CH2:18][CH2:19][O:20][C:30]([NH:29][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:1]3)[C:3]3[C:8](=[CH:7][CH:6]=[C:5]([I:17])[CH:4]=3)[O:9][C:10]2=[N:11][CH:12]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC1(CCO)c2cc(I)ccc2Oc2ncc(Br)cc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1=NC2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a 250-mL flask, the 2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol (2.24 g, 5.01 mmol) was dissolved in THF (30 mL). Benzoyl isothiocyanate (0.607 mL, 4.51 mmol) was added. After 1 h, the mixture was concentrated. The residue was taken up in ACN (30 mL), and catalytic TEA (0.069 mL, 0.501 mmol) was added, followed by DCC (1.137 g, 5.51 mmol). A water-cooled condenser was affixed, and the solution was stirred in an 80° C. oil bath for 2 h. The reaction was then concentrated. The residue was used directly in the next step without further purification or purified by column chromatography (silica gel, 10-50% EtOAc/hexanes) to obtain N-(3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)benzamide as a yellow solid. MS (m/z) 575.8/577.7 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][NH2:25]>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:25][CH3:24])[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: CN
Solvent: COCCOC
Product: CNc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and methylamine in DME. ES-MS m/e(%): 236 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4](I)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:16][C:17]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([CH:16]=[CH2:17])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1c(F)c(Cl)cc(C(C)=O)c1OCC
Temperature: 80 °C

Procedure:
A mixture of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (13.3 g, 38.8 mmol) (from Example 139, Step 1), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.9 mL, 46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (1.0 g, 1.0 mmol) and potassium carbonate (16 g, 120 mmol) in 1,4-dioxane (200 mL) and water (100 mL) was heated at 80° C. for 2 hours. The mixture was cooled to rt and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification on silica gel using ethyl acetate in hexanes (0-30%) gave the desired compound, 7.0 g, 74%. LCMS calculated for C12H13ClFO2 (M+H)+: m/z=243.0; found: 243.1.
Reaction SMILES: C(O)(C(F)(F)F)C(F)(F)F.[O:11]=[C:12]1[O:18][C@H:17]([C@H:19]([CH2:21][OH:22])[OH:20])[C:15]([OH:16])=[C:13]1[OH:14].[CH2:23]1[O:31][CH:24]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[OH:31][CH2:23][CH:24]([O:16][C:15]1[C@@H:17]([C@H:19]([CH2:21][OH:22])[OH:20])[O:18][C:12](=[O:11])[C:13]=1[OH:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CC#N
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: O=C1O[C@H]([C@@H](O)CO)C(OC(CO)c2ccccc2)=C1O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
Under an argon atmosphere, 4 ml of 1,1,1,3,3,3-hexafluoro isopropanol and 10 ml of acetonitrile were added to L-ascorbic acid (1.00 g), and further, styrene oxide (1.37 g) was added. The mixture was heated up to 70° C. and stirred for 48 hours, then, concentrated under reduced pressure, and 2.73 g of the resultant residue was subjected to silica gel column chromatography. Thereafter, it was eluted with chloroform/methanol/water(volume ratio:20/3/0.3) to obtain two elution fractions (first eluted fraction: 225 mg, later eluted fraction: 228 mg). Based on the measurement results of high resolution mass analysis, infrared absorption spectrum, 1H-NMR, 13C-NMR and specific optical rotation on the resultant elution fractions, it was confirmed that these are two 3-O-(2-hydroxy-1-phenylethyl) ascorbic acids which are in mutual stereoisomerism and both of them are represented by the following structural formula.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10](=[CH:13][C:33]2[C:28]([NH2:27])=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:9][C:8]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)C1=C(c2ccccc2)CC(=Cc2cccnc2N)C=C1

Procedure:
A mixture of the resultant aldehyde from Example 16E (1.0 equivalent), 2-aminopyridine (1.0 equivalent) and NaCNBH3 (1.5 equivalents) in methanol/acetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured into aqueous NaHCO3 and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ClC(OCC(C)C)=O.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:25]=1[CH2:26][NH2:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:27][CH2:26][C:25]1[C:28]([O:32][CH3:33])=[CH:29][CH:30]=[CH:31][C:24]=1[O:23][CH3:22])=[O:9]
Reactant: COc1cccc(OC)c1CN
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1CNC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
5-Chloro-2-nitrobenzoic acid (25.0 g, 201.6 mmol) was placed in 250 mL dichloromethane and stirred for 5 minutes. After 17.0 mL triethylamine had been added at 25° C., the yellow suspension dissolved gradually. After storing for 10 minutes, the mixture was cooled to 5° C. Isobutyl chloroformate (16.25 mL, 122.8 mmol) was added by drops without dilution within 15 minutes. The reaction mixture was allowed to reach room temperature while stirring and stirring was continued for 1.5 hours. A light yellow precipitate was formed. The mixture was again cooled to 5° C. and 2,6-dimethoxybenzylamine (20.5 g, 122.8 mmol) was added by portions over a period of 20 minutes. For dilution, another 250 mL dichloromethane was added and the mixture was stirred for 15 minutes at 5° C. and then for 65 hours at room temperature. The reaction was monitored by thin layer chromatography, revealing traces of the starting materials. The batch was mixed with 5% citric acid, whereupon a precipitate formed and was filtered out. Product was still detected in the organic phase, so the organic phase was extracted again with 5% citric acid (1×), washed until neutral with sodium bicarbonate solution (1×) and extracted with sodium chloride solution. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo. The solid yellow residue was suspended in diethyl ether/pentane as solvents, then filtered out and washed with diethyl ether. The two crystal products were combined and a pure 5-chloro-N-(2,6-dimethoxybenzyl)-2-nitrobenzamide was isolated. Yield: 31.3 g (89.2 mmol, 73%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl:9][C:10]([Cl:16])=[CH:11][CH:12]=[C:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[Ca+2].[Cl-].[Ca+2].[Cl-].[Br-].[K+].Cl[O-].[Na+].BrBr.ClCl.Cl>O.[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[Cl-].C[N+](CC)(CC)CC.C(OCCCC)(=O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]([CH:11]=[C:10]([Cl:16])[Cl:9])[C:13]1([CH3:15])[CH3:14])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)=CC=C(Cl)Cl
Agent: BrBr
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: CC[N+](C)(CC)CC
Solvent: O
Solvent: CCCCOC(C)=O
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl cyanoacetate (24.88 parts), 1,1-dichloro-4-methylpenta-1,3-diene (30.2 parts) cupric chloride (2.68 parts), calcium carbonate (40 parts), calcium chloride and potassium bromide as indicated in the table below, is heated in water in the presence of a phase transfer catalyst (either cetyl trimethyl ammonium bromide (CTMAB) or methyl triethyl ammonium chloride (MTEAC)]]. Sodium hypochlorite solution, bromine or chlorine are then added at a uniform rate to the mixture at an elevated temperature. Heating is continued for a further period. After cooling the reaction mixture, the suspension is diluted with butyl acetate (100 parts by volume). Concentrated hydrochloric acid (50 parts by volume) diluted with water (100 parts) is slowly added, the mixture is stirred for about 30 minutes and then filtered to remove extraneous matter. The butyl acetate layer is separated and washed with water (4×50 parts). The butyl acetate is removed by distillation under reduced pressure to yield crude ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane -1-carboxylate. Details of the reaction conditions are given in the table below, together with the yield, strength and composition of the product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[N:14]1[CH2:17][C:16]2([CH2:20]N(C(OC(C)(C)C)=O)[CH2:18]2)[CH2:15]1>>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[N:10]1[CH:11]=[CH:12][CH:13]=[N:8][C:9]=1[N:14]1[CH2:15][C:16]2([CH2:18][CH2:2][CH2:20]2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ncccn1)C2
Solvent: O=C(O)C(F)(F)F
Product: c1cnc(N2CC3(CCC3)C2)nc1
Temperature: 2.5 °C

Procedure:
A 1 L round-bottom flask was charged with trifluoroacetic acid (153.0 mL) and the mixture cooled to 0-5° C. Tert-butyl 2-pyrimidin-2-yl-2,6-diazaspiro[3,3]heptane-6-carboxylate (51.0 g, 0.19 mol) was added and the reaction mixture was stirred at 0-5° C. until dissolution occurred. Then the reaction mixture warmed to 20-25° C. and stirred for 60 min. The reaction mixture was concentrated, azeotroped with DCM (2×50.0 mL), and diluted with DCM (150.0 mL). This solution was slowly added to a well-stirred solution of MTBE (600.0 mL). The resultant slurry was heated to 35-40° C. to give a free-flowing off-white solid. The slurry was cooled to <15° C. and filtered to afford the title compound. 1H NMR (300 MHz, CD3OD) δ: 8.39 (d, J=5.03 Hz, 2H), 6.77 (t, J=5.03 Hz, 1H), 4.35 (s, 4H), 4.32 (s, 4H); 13C NMR (75 MHz, DMSO-d6) δ: 162.5, 158.2, 111.2, 60.0, 55.3, 36.0; LC/MS: m/z=177 [M]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33]N>>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1ccc(F)cc1F
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(F)cc3F)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 2,4-difluoro-phenylhydrazine according to the method described for example 43. MS: M=429.1 (M+H)+
Reaction SMILES: Cl.FC1C=C(CCN)C=C(C(F)(F)F)C=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27].C1COCC1>>[ClH:16].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: N#CCc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: NCCc1cc(F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: NCCc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was synthesized in analogy to 2-(3-fluoro-5-trifluoromethyl-phenyl)-ethylamine hydrochloride (described in example S1-B) from 3.188 g of crude (4-chloro-3-trifluoromethyl-phenyl)-acetonitrile (14.5 mmol) and 76 ml of a 1M borane-THF complex solution in THF (76 mmol). The product was obtained as a white solid (1.52 g, 40%). MS (ISP) 224.1 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)[C:5]=2[CH:4]=[CH:3]1.BrC1C2C=COC=2C=CC=1.CC1(C)C(C)(C)OB(C2CCN(C(OC(C)(C)C)=O)CC=2)O1.C([O-])=O.[NH4+]>[Pd].CO>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:5]=2[CH:4]=[CH:3]1
Reactant: C1=C(c2cccc3occc23)CCNC1
Agent: [Pd]
Agent: Brc1cccc2occc12
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Solvent: CO
Product: c1cc(C2CCNCC2)c2ccoc2c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A stirred mixture of 4-(4-benzofuranyl)-1,2,3,6-tetrahydro-pyridine hydrochloride [CAS-No. 158984-66-8] (2.05 g, 8.7 mmol), prepared from commercially available 4-bromo-benzofurane [CAS-No. 128868-60-0] and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, palladium on carbon (10%, 0.46 g, 0.44 mmol), ammonium formate (2.74 g, 43.5 mmol) and MeOH (79 ml) was heated at reflux conditions for 1 h, cooled to RT, filtrated and evaporated. Saturated sodium bicarbonate solution (50 ml) was added to the residue, and the inorganic layer was extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (40 ml), dried (MgSO4) and evaporated to yield 4-(4-benzofuranyl)-piperidine as a colorless oil (1.65 g, 94%), MS (ISP) m/z=202.3 [(M+H)+].
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][C:24]1([CH3:62])[N:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@:27]([CH3:61])([C:36]([NH:38][NH:39][C:40](=O)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[C:43]([C:56]([F:59])([F:58])[F:57])[CH:42]=2)=O)[CH2:26][O:25]1.C([O-])(O)=O.[Na+].CCCCCCC>C1(C)C=CC=CC=1>[CH3:23][C:24]1([CH3:62])[N:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@:27]([CH3:61])([C:36]2[S:10][C:40]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[C:43]([C:56]([F:59])([F:58])[F:57])[CH:42]=3)=[N:39][N:38]=2)[CH2:26][O:25]1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2nnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Temperature: 20.5 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A 12 L, round bottom flask was inerted and charged with Lawesson's reagent (211.5 g, 0.52 mol, 1.2 equiv), a solution of (S)-tert-butyl 2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)benzoyl)-hydrazinecarbonyl)oxazolidine-3-carboxylate (D8A) (250 g—based on theoretical output, 0.43 mol) in toluene (2.5 L), and the resulting slurry was heated to 80° C. and held for 3 hours. TLC indicated the reaction was complete. The mixture was cooled to 18-23° C., charged with saturated NaHCO3 solution (2 L), which was slightly exothermic. The aqueous was extracted twice with ethyl acetate (2 L, 1.5 L), the organic phases were combined, concentrated, dissolved in dichloromethane (500 mL), charged with silica-gel (500 g), concentrated to remove dichloromethane, and purified using a silica-gel (2.5 kg) column which was eluted with 5% ethyl acetate: 95% heptane to afford the title product (185 g, 74% yield, 95% AUC by HPLC) as a yellow color oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]Cl.[CH3:11][NH:12][CH:13]=[N:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]>N1C=CC=CC=1>[CH3:11][N:12]([S:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH:13]=[N:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]
Reactant: ClSc1cc(Cl)ccc1Cl
Reactant: CNC=Nc1c(C)cccc1Cl
Solvent: c1ccncc1
Product: Cc1cccc(Cl)c1N=CN(C)Sc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
32.1 g of 2,5-dichlorophenylsulfenyl chloride is added dropwise at 5°-10° C., with continuous stirring, to a solution of 27.4 g of N-methyl-N'-(2'-chloro-6'-methylphenyl)-formamidine in 70 ml of pyridine. The mixture is stirred for 20 minutes at room temperature; the excess pyridine is then removed at 1 mm Hg pressure and 50° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:25][CH:26]1[C:46](=[O:47])[N:28]2[C:29]([C:43]([OH:45])=[O:44])=[C:30]([CH2:33][S:34][C:35]3[N:39]([CH2:40][CH:41]=[CH2:42])[N:38]=[N:37][N:36]=3)[CH2:31][S:32][C@H:27]12>>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:25][CH:26]2[C:46](=[O:47])[N:28]3[C:29]([C:43]([OH:45])=[O:44])=[C:30]([CH2:33][S:34][C:35]4[N:39]([CH2:40][CH:41]=[CH2:42])[N:38]=[N:37][N:36]=4)[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 95.4 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.) and 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2 g.) were treated in a similar manner to that of Example 20-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.7 g.).
Reaction SMILES: [ClH:1].[CH2:2]([CH:4]([CH2:33][CH3:34])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[O:19])=[CH:13][CH:12]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH3:3].[OH-].[Na+]>CCOC(C)=O>[ClH:1].[CH2:33]([CH:4]([CH2:2][CH3:3])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[O:19])=[CH:13][CH:12]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH3:34]
Reactant: CCC(CC)C(c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCC(CC)C(c1ccc(NC(=O)C2CCNCC2)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
HCl conc. (3.6 ml) was added at RT to a mixture of (±)-1,1-dimethylethyl 4-[[[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]amino]carbonyl]-1-piperidinecarboxylate (0.0032 mol) in EtOAc (30 ml). The mixture was stirred at RT for 4 hours, then basified with a concentrated NaOH solution and extracted with EtOAc and then CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (1 g) was converted into the hydrochloric acid salt (1:1) in 2-propanol. The precipitate was filtered off and dried, yielding 0.85 g (68%) (±)-N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]-phenyl]-4-piperidinecarboxamide monohydrochloride (compound 57).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16]CC)=[O:15])=[C:7]2[NH:19][CH2:20][C@@H:21]([O:23][CH3:24])[CH3:22].Cl>O.O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]2[NH:19][CH2:20][C@@H:21]([O:23][CH3:24])[CH3:22]
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1NC[C@H](C)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H](C)CNc1c(C(=O)O)cnc2ccc(Br)cc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
Add a solution of sodium hydroxide (296.7 g, 7.42 mol, 6 eq.) in water (454 mL) to a solution of ethyl 6-bromo-4-[[(2S)-2-methoxypropyl]amino]quinoline-3-carboxylate (454 g, 1.24 mol) in tetrahydrofuran (4.54 L) at room temperature. Heat the mixture at 50° C. overnight. After 18 hours, cool the reaction to 0° C., add 37% aq. HCl dropwise over 30 minutes until pH=6 (ca. 450 mL) with the temperature under 23° C. Filter the precipitate formed with filter paper and wash it with water (2 L), acetone (2 L) and methyl tert-butyl ether (2 L) subsequently. Dry the white solid to give the titled compound (359 g, 86%). MS (ESI) m/z (M+H)+338.9, 340.9.