Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[CH:25]=[C:24](Cl)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:11]1)=[O:9].C(OC([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=O)(C)(C)C.C(N(CC)CC)C.C(O)(C)C>C(Cl)(Cl)Cl.O>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[CH:25]=[C:24]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:11]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cc1ccccc1-c1ccccc1)N1CC[C@H](Nc2cc(Cl)c3ccccc3n2)C1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccccc1-c1ccccc1)N1CC[C@H](Nc2cc(N3CCNCC3)c3ccccc3n2)C1
Temperature: 180 °C
Yield: 4.6 %

Procedure:
A mixture of 2-biphenyl-2-yl-1-((S)-3-(4-chloroquinolin-2-ylamino)pyrrolidin-1-yl)ethanone (0.43 g), 1-(t-butoxycarbonyl)piperazine (0.18 g), triethylamine (0.17 g), and isopropanol (1.3 mL) was heated at 180° C. in a microwave reaction apparatus for 5 h. The reaction mixture was diluted with chloroform and water, and then the aqueous layer was extracted with chloroform and dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/a solution of 2 M ammonia in methanol=9:1) and then solidified in diethyl ether to obtain the title compound (22 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:45])[CH2:10][C:11]1[CH:44]=[CH:43][CH:42]=[CH:41][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:40]=[CH:39][C:29]([CH2:30][NH:31]C(=O)OC(C)(C)C)=[CH:28][CH:27]=2)[N:16]=1>C(Cl)Cl>[NH2:31][CH2:30][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]3[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=3[CH2:10][C:9]([NH2:8])=[O:45])[C:20]([C:21]([F:23])([F:24])[F:22])=[CH:19][N:18]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.8 %

Procedure:
TFA (954 μL, 12.5 mmol) was added to a solution of tert-butyl 4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzylcarbamate (A16) (220 mg, 0.415 mmol) in DCM (10 mL) and the resulting mixture stirred for 20 hours at room temperature. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc (100 mL) and 2 M aqueous NaOH (100 mL). The layers were separated and the organic layer washed with water (100 mL), brine (50 mL), dried (MgSO4) then evaporated in vacuo to yield a white solid. The solid was taken up in DCM (10 mL) and sonicated for 2 minutes then petroleum benzine 40-60° C. (100 mL) was added and sonication continued for a further 10 minutes. The resulting suspension was filtered and the filter cake dried to give the title compound 3 as a white solid (135 mg, 76%); 1H NMR (400 MHz, d4-MeOH) δ 8.57 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 7.31-7.17 (m, 4H), 3.81 (s, 2H), 3.69 (s, 2H), 3.22-3.06 (m, 4H). LCMS-A: rt 4.722 min; m/z 428 [M−1]−.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])[CH2:2][CH3:3].[OH-].[Na+]>>[CH2:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:34])[C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:26][CH:27]=2)=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH3:3]
Reactant: CCCN[C@@H](Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CCCN[C@@H](Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Yield: 87.9 %

Procedure:
In a similar manner to that described in Example 2, methyl (S)-2-propylamino-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (169 mg), which is the product of Example 169, was reacted with aqueous sodium hydroxide solution (1N, 0.73 ml) and the reaction mixture was treated to give the title compound (144 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CO
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of 4-bromophenylacetic acid (50 g) in methanol (250 mL) thionyl chloride (34.2 mL) is added dropwise while the temperature of the reaction mixture is kept at 0-5° C. Upon complete addition, the cooling is removed and the mixture is allowed to warm to rt. Stirring is continued for 75 min before the solvent is removed in vacuo. The yellow oil is dissolved in benzene and evaporated. The residue is dissolved in EA, washed with water, brine, 2 N aq. Na2CO3, and brine. The organic phase is dried over MgSO4 and evaporated and dried under high vacuum at 85° C. for 30 min to give 4-bromophenylacetic acid methyl ester (52.4 g) as a yellow oil. 1H-NMR(D6-DMSO): 3.60 (s, 3H), 3.67 (s, 2H), 7.22 (d, 8.5, 2H), 7.50 (d, 8.5, 2H).
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:3]1[CH:4]=[C:5]([C:16](O)=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:3]1[CH:4]=[C:5]([C:16]([NH:36][C@@H:34]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)[CH3:35])=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3ccccn3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(C(O)c3ccccn3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(hydroxy-pyridin-2-yl-methyl)-4′-methyl-biphenyl-3-carboxylic acid (25 mg, 0.078 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (35 mg, 0.17 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (50 mg, 0.13 mmol), and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2N11]) to afford a light color solid.
Reaction SMILES: Br[C:2]1[C:11](Br)=[C:10]([N+:13]([O-])=O)[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:16]([OH:18])=[O:17].[H][H]>[Pd].O>[NH2:13][C:10]1[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]([C:16]([OH:18])=[O:17])=[CH:2][CH:11]=1
Reactant: O=C(O)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: Nc1ccc(C(=O)O)c2c1OCCO2
Temperature: 50 °C
Yield: 83.7 %

Procedure:
400 ml of water, 98.5 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid, 100 ml of soda and 10 g of Pd/c were introduced into an autoclave and then hydrogen under a pressure of 40 kg/cm2 was introduced while heating to 50° C. The mixture was filtered and then treated with 95 ml of hydrochloric acid. The precipitate was dried off, washed and dried. 42 g of 8-amino-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 186° C.; yield: 83.7%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7](Cl)(=[O:9])=[O:8].[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)(=[O:9])=[O:8]
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1sccc1Br
Product: O=S(=O)(c1sccc1Br)n1cccc1

Procedure:
N-(3-Bromothiophene-2-sulfonyl)pyrrole was prepared in the same manner as described in Example 14A by reacting 3-bromothiophene-2-sulfonyl chloride with pyrrole (for 16 hr.). N-(3-Bromothiophene-2-sulfonyl)pyrrole was obtained in 54% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.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.[C:69]([O:73][C:74](=[O:79])[NH:75][CH2:76][CH2:77][SH:78])([CH3:72])([CH3:71])[CH3:70].C(N(C(C)C)CC)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[C:69]([O:73][C:74](=[O:79])[NH:75][CH2:76][CH2:77][S:78][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:11]=3[N:10]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH:3]=1)([CH3:72])([CH3:70])[CH3:71]
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3cc(F)ccc3[nH]2)CC1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC(OC(c2cccc(SCCNC(=O)OC(C)(C)C)c2)c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A screw-capped tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole (example 437D, 418 mg), palladium bis(dibenzylideneacetone) (30 mg), Xantphos (30 mg), (2-mercaptoethyl)carbamic acid tert-butyl ester (1 equivalent), diisopropylethylamine (180 μL) and 1,4-dioxane (6 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. overnight, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol from 98/2 to 95/5) to afford (2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)carbamic acid tert-butyl ester. 1H NMR: 11.07 (sl, 1H), 7.69-7.59 (m, 1H), 7.39-7.36 (m, 1H), 7.30-7.15 (m, 2H), 7.04-6.91 (m, 2H), 5.83 (s, 1H), 5.30 (sl, 1H), 4.20 (s, 2H), 3.65-3.40 (m, 3H), 3.30-3.05 (m, 2H), 2.80-2.65 (m, 2H), 2.27 (s, 3H), 2.25-1.75 (m, 6H), 1.55 (s, 9H).
Reaction SMILES: [N:1]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1.CN1C(=O)N(C)CCC1>[CH3:22][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Temperature: -60 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (2.107 g, 7.23 mmol) in dry THF (22 mL) and DMPU (1.4 mL, 1160 mmol) cooled at −78° C. was added dropwise lithium bis(trimethylsilyl)amide (1.271 g, 7.59 mmol, 7.60 mL of 1M solution in THF). After addition, the reaction mixture was stirred at −60° C. for 1 h. Then iodomethane (0.520 mL, 8.32 mmol) in DMPU (0.344 mL, 2.86 mmol was added dropwise. After addition, the reaction was stirred at −60° C. for 1.5 h, then slowly warmed up to −20° C. over approximately 1 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction solution was extracted with EtOAc (2×). The combined organics were washed with saturated aqueous NH4Cl and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex. The desired fractions were concentrated to give product, benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (1.66 gm, 5.44 mmol, 75.2% yield) as a light brown oil. Anal. Calcd. for C17H23NO4 m/z 305.3, found: 306.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.44-7.27 (m, 5 H), 5.20-5.09 (m, 2 H), 4.24-4.04 (m, 2 H), 3.99 (d, J=13.19 Hz, 1 H), 3.59 (br. s., 1 H), 3.27 (d, J=7.15 Hz, 1 H), 3.13 (d, J=12.64 Hz, 1 H), 2.16-1.95 (m, 1 H), 1.74-1.52 (m, 2 H), 1.51-1.39 (m, 1 H), 1.25-1.07 (m, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]Cl.[C-]#N.[Na+].[CH3:18][N:19](C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:18]#[N:19])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1cc(CC#N)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
3,4,5-trimethoxy benzyl chloride 7.0 g and sodium cyanide 6.3 g were dissolved into 50 ml of N,N-dimethylformamide and they were then stirred at 80° C. for 45 minutes. The temperature of the reactive liquid was then lowered down to the room temperature, 200 ml of water was added thereto and then extraction was made thrice by means of 100 of ethyl acetate.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:20](=[O:21])([O:22][CH2:23][CH3:24])[O:17][C:1](=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OC(=O)OCC

Procedure:
Palmitic acid and ethyl chloroformate are reacted with methylene chloride in a molar ratio of 1:1 in the presence of dry sodium carbonate. Inorganic material is filtered off, and the resulting filtrate is used directly in the reaction.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Fc1ccc(CBr)cc1
Reactant: N#Cc1ccc(O)cc1F
Product: N#Cc1ccc(OCc2ccc(F)cc2)cc1F
Yield: 100 %

Procedure:
As described for example 1a, 2-fluoro-4-hydroxy-benzonitrile (5.0 g, 36 mmol) [using 4-fluorobenzyl bromide instead of 3-fluorobenzyl bromide] was converted to the title compound (8.9 g, 100%) which was obtained as a white solid. MS: m/e=245.0 (M+).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].CO.O1CCCC1.C(O)(=O)C>[C].[Pd].O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CC(C)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 38.8 %

Procedure:
4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-isobutoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 14.2 g.), 10% palladium carbon (5.7 g.), methanol (57 ml.), tetrahydrofuran (142 ml.), acetic acid (1 ml.) and water (10 ml.) were treated in a similar manner to that of Example 15-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-isobutoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 4.25 g.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH:6]([CH2:12][CH2:13][CH3:14])[C:7]([O:9]CC)=O)[CH3:2].Cl.[C:18]([NH2:21])(=[NH:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH2:12][CH2:13][CH3:14])=[C:7]([OH:9])[N:21]=[C:18]([CH3:19])[N:20]=1)=[O:16])[CH3:2]
Reactant: CCCC(C(=O)OCC)C(=O)C(=O)OCC
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCc1c(O)nc(C)nc1C(=O)OCC
Temperature: 70 °C

Procedure:
A mixture of 120 (20 mmol), acetamidine hydrochloride (40 mmol) and K2CO3 (6.9 g, 50 mmol) in EtOH (50 ml) is heated at 70° C. overnight. The solid is filtered and the residue is dissolved in water (30 ml). Acetic acid is added to adjust the pH to 4. The mixture is then extracted with CH2Cl2 (4×50 ml) and the combined extracts are washed with brine (100 ml). The solution is dried (Na2SO4) and evaporated in vacuo to give a light yellow solid (121), which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([C@@H:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[C:33]([O:35]CCCC)=[O:34])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([C@@H:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[C:33]([OH:35])=[O:34])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CCCCOC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC)cc4s3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3F)sc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of butyl (1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)-amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate in methanol (8 mL) was added 1 N aqueous sodium hydroxide (6.15 mL), and the mixture was stirred at 50° C. overnight. The solvent was then removed by rotary evaporation. Water (5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The aqueous layer was then treated with 1 N aqueous HCl to adjust the acidity to pH 2, and then extracted with ethyl acetate. The organic phase was evaporated under reduced pressure, and the residue was purified by flash chromatography (Biotage Flash 40S, 6:1 EtOAc/hexane) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid (129 mg, 30%, 89% ee). LC-MS ret. time 3.56 min, m/z 491.3 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 1.58-1.84 (m, 4H), 1.96-2.01 (m, 1H), 2.14-2.17 (m, 1H), 3.22 (q, 1H), 3.77 (s, 3H), 4.02-4.10 (q, 1H), 6.94 (dd, 1H), 7.46 (d, 1H), 7.53 (d, 1H), 7.65-7.76 (m, 2H), 7.86 (d, 2H), 8.04 (d, 2H), 8.72 (t, 1H), 10.33 (br s, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5]CC[CH2:2]1.Cl.ClCCN(C)C>C(Cl)Cl.CO>[CH3:2][N:1]([CH3:5])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: CN(C)CCCl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCOc1ccc(N)cc1

Procedure:
The title compound is prepared as described in Example 1 for 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine but using 1-chloro-2-dimethylaminoethane hydrochloride. Title compound: ES-MS: 181.2 [M+H]+; Rf=0.18 (CH2Cl2/MeOH, 70/30).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[C:7]2[CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=O.[CH3:22][NH2:23]>O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[C:7]2[CH2:14][CH2:15][CH2:16][C:17]([NH:23][CH3:22])=[O:19]
Reactant: CCOC(=O)CCCc1cncc2ccc(OC)cc12
Reactant: CN
Agent: Cl
Solvent: O
Product: CNC(=O)CCCc1cncc2ccc(OC)cc12

Procedure:
The compound obtained in Step A (2.2 g; 7 mmol) is dissolved in 30 ml of methylamine (40% in water) and the mixture is heated at reflux for 3 hours with stirring. The reaction mixture is taken up in 50 ml of water and extracted with ether. The organic phase is washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oil obtained is purified by chromatography on silica gel (eluant: dichloromethane with the progressive addition of methanol). The oil obtained is evaporated under reduced pressure and the precipitate so formed is recrystallised from toluene to yield the title product in the form of a white solid.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6]([N:9]([CH2:13][CH2:14][CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:12])[CH3:11])([CH3:8])[CH3:7].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:15][CH2:14][CH2:13][N:9]([CH:6]([CH3:8])[CH3:7])[C:10](=[O:12])[CH3:11])=[S:4]
Reactant: CC(=O)N(CCCC(=O)c1ccccc1)C(C)C
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)N(CCCC(=NNC(N)=S)c1ccccc1)C(C)C
Yield: 100.2 %

Procedure:
Thiosemicarbazide (6.1901 g, 67.9 mmol) was added to a solution of N-isopropyl-N-(4-oxo-4-phenyl-butyl)-acetamide (11.20 g, 45.3 mmol), prepared in the previous step, in 160 ml of methanol plus 12.2 ml of 1 N HCl, plus 12.2 ml of water and the reaction stirred at room temperature for 22 hours (overnight). The reaction was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, washed five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 14.54 g of a yellow foam. The foam was crystallized from ethyl acetate to give 10.28 g (71%) of the title compound as a white solid, mp 141-147° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24](=[N:30]O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:16][N:30]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2nc(-c3ccccc3)oc2C)n1
Yield: 12.8 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(5-methyl-2-phenyloxazol-4-yl)acetic acid (0.411 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.076 g (13%) of ethyl 5-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.