Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])=[CH:20][CH:19]=1.C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:25](=[O:26])[CH:24]([C:21]3[CH:20]=[CH:19][C:18]([OH:17])=[CH:23][CH:22]=3)[CH:28]([CH3:30])[CH3:29])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)C(C(=O)O)c1ccc(O)cc1
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccc(O)cc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 2-(4-hydroxyphenyl)-3-methylbutanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.53-8.46 (m, 1H), 7.56 (d, J=2.8, 1H), 7.43 (d, J=7.2, 1H), 7.36 (dt, J=7.5, 18.2, 4H), 7.26 (q, J=7.1, 1H), 7.16 (dd, J=3.0, 8.6, 2H), 4.44-4.32 (m, 1H), 3.60 (d, J=13.1, 0.5H), 3.53 (d, J=13.1, 0.5H), 3.44 (d, J=13.2, 0.5H), 3.33 (d, J=13.1, 0.5H), 3.18 (d, J=10.4, 1H), 2.90 (dd, J=3.0, 9.1, 0.5H), 2.66 (s, 1H), 2.58 (d, J=8.8, 1H), 2.49 (t, J=10.5, 1H), 2.44-2.35 (m, J=10.0, 1H), 2.33-2.11 (m, 2H), 1.99-1.89 (m, 0.5H), 1.88-1.63 (m, 1.5H), 1.53-1.42 (m, 0.5H), 1.41-1.24 (m, 2H), 1.22 (dd, J=4.4, 6.3, 3H), 0.97-0.82 (m, J=21.9, 35.1, 1H), 0.79 (d, J=6.7, 3H); MS (ESI+) m/z 393 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH3:2].[C:12]([O:16][C:17](=[O:28])[NH:18][CH:19]([C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)[CH3:20])([CH3:15])([CH3:14])[CH3:13]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C(#N)C>[C:12]([O:16][C:17](=[O:28])[NH:18][CH:19]([C:21]1[CH:22]=[CH:23][C:24]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)=[CH:25][CH:26]=1)[CH3:20])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: C#Cc1ccc(OCC)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOc1ccc(C#Cc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 65 °C

Procedure:
24.6 g (168 mmol) 1-ethoxy-4-ethynyl-benzene, 52.8 g (176 mmol) [1-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (50.2) and 42.6 mL (307 mmol) TEA are added to 400 mL ACN. The mixture is warmed to 65° C. 8.84 g (7.65 mmol) Pd(PPh3)4 and 2.91 g (15.3 mmol) CuI are added and the reaction mixture is stirred at reflux for 2 h. The mixture is cooled to r.t. and the solvent is removed in vacuo. The crude product is purified by column chromatography (hexane/EtOAC 9:1→3:1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[C:12]([C:25]([OH:27])=O)=[CH:11]2.C(N(CC)CC)C.[CH3:35][C:36]([CH3:52])([CH3:51])[C:37]([O:39][CH2:40][C:41]1[S:42][C:43]2[C:48]([N:49]=1)=[CH:47][C:46]([NH2:50])=[CH:45][N:44]=2)=[O:38]>ClCCl.CN(C)C=O.O1CCCC1>[CH3:35][C:36]([CH3:52])([CH3:51])[C:37]([O:39][CH2:40][C:41]1[S:42][C:43]2[C:48]([N:49]=1)=[CH:47][C:46]([NH:50][C:25]([C:12]1[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:14]3[C:10]([CH:11]=1)=[CH:9][C:8]([F:7])=[CH:16][CH:15]=3)=[O:27])=[CH:45][N:44]=2)=[O:38]
Reactant: CC(C)(C)C(=O)OCc1nc2cc(N)cnc2s1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCc1nc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 20.2 %

Procedure:
240 microliters (2.78 mmol) of oxalyl chloride are added, dropwise at 0° C., to a solution of 0.4 g (1.39 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in step 1.1, in 10 mL of dichloromethane and 0.5 mL of dimethylformamide. The mixture is stirred for 15 minutes at 0° C. and then for 1 hour at 20° C. After this time, a further 120 microliters (1.39 mmol) of oxalyl chloride are added and stirring is continued for 30 minutes at 20° C. The reaction mixture is then concentrated under reduced pressure and taken up in 5 mL of tetrahydrofuran. 219 microliters of triethylamine and then a solution of 0.44 g (1.67 mmol) of (6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl 2,2-dimethylpropanoate, prepared in step 4.2, in 10 mL of tetrahydrofuran are added, under an inert atmosphere. The reaction mixture is stirred for 15 hours at 20° C. and for 1 hour at 40° C., and then concentrated under reduced pressure and taken up in 100 mL of water. The aqueous phase is extracted three times with 50 mL of ethyl acetate. The organic phases are combined, washed successively with 50 mL of saturated sodium hydrogen carbonate solution and with 50 mL of saturated sodium chloride solution, and then dried over sodium sulfate and concentrated under reduced pressure. The product thus obtained is purified on a column of alumina, eluting with dichloromethane. 0.15 g of the expected product is thus isolated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])([CH3:4])([CH3:3])[CH3:2].O=C1CCC(=O)N1[O:29][C:30](=O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:50]([O:49][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30](=[O:29])[N:9]([CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)CCNCC(=O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Reaction time: 42 h
Yield: 85 %

Procedure:
3-(Benzyloxycarbonylmethylamino)propionic acid tert-butyl ester (0,030 g, 0.1 mmol) and octadecanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0,050 mg, 0.1 mmol) was suspended in dry DMF (1 ml). HOAt (0.014 g, 0.1 mmol) and DIPEA (0.21 ml, 1.2 mmol) was added. The yellow reaction mixture was stirred under nitrogen for 42 h. The reaction mixture was concentrated. The residue was redissolved in EtOAc and washed with 0.1 N HCl (2×), water (1×), dried (Na2SO4) and concentrated to give 17-[Benzyloxycarbonylmethyl-(2-tert-butoxycarbonyl-ethyl)-carbamoyl]-heptadecanoic acid tert-butyl ester in 85% yield (55 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: CN(C)c1ccc(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 78 %

Procedure:
Example 36 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 4-isocyanato-N,N-dimethylaniline (0.0221 g) to give the title compound (0.031 g). LC-MS (System A): Rt 1.68 mins, Mass Spectrum m/z 437 [MH+].
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1.[H-].[Na+].O>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:18][CH:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[CH3:17])[N:3]=1
Reactant: CC(O)c1cccc(F)c1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(Oc1cncc(Cl)n1)c1cccc(F)c1
Yield: 108.8 %

Procedure:
To a solution of 2,6-dichloropyrazine (298 mg, 2.00 mmol) and 1-(3-fluorophenyl)ethanol (308 mg, 2.2 mmol) in dioxane (5 mL) was added NaH (55% in oil, 96 mg, 2.2 mmol) at room temperature. The reaction mixture was stirred over night. Water (0.5 mL) was added and the mixture was stirred for 15 min. Drying (K2CO3), filtration, and concentration in vacuo gave the title compound as an oil (0.55 g) that was used directly in the next step. MS m/z 254 (M+H)+.
Reaction SMILES: [Al](C)(C)C.C(O[C:8]([C:10]1[C:15]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:13]=[C:12]([C:24](C)(C)[O:25][SiH2]C(C)(C)C)[N:11]=1)=[O:9])C.[NH2:33][C:34]1[S:35][CH:36]=[C:37]([CH3:39])[N:38]=1>>[C:20]([O:19][C:17](=[O:18])[NH:16][C:15]1[C:10]([C:8](=[O:9])[NH:33][C:34]2[S:35][CH:36]=[C:37]([CH3:39])[N:38]=2)=[N:11][C:12]([CH2:24][OH:25])=[CH:13][CH:14]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)c1nc(C(C)(C)O[SiH2]C(C)(C)C)ccc1NC(=O)OC(C)(C)C
Agent: C[Al](C)C
Product: Cc1csc(NC(=O)c2nc(CO)ccc2NC(=O)OC(C)(C)C)n1

Procedure:
The Al(Me)3-catalyzed reaction of 0.53 g (1.29 mmol) of 3-tert-Butoxycarbonylamino-6-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine-2-carboxylic acid ethyl ester and 2-amino-4-methyl thiazole in accordance with the general method of Example 78, step 2 yielded 0.58 g of crude [6-Hydroxymethyl-2-(4-methyl-thiazol-2-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (which also contains 2-amino-4-methyl thiazole) as a dark brown oil, MS (ISP): m/e=365.1 (M+H+). This crude material was dissolved in 4 ml of methylene chloride and 2.4 ml of trifluoroacetic acid. The solution was stirred overnight at room temperature. The pH of the solution was adjusted to 8 by addition of saturated sodium carbonate solution and extracted three times with methylene chloride. The combined organic phases were dried over magnesium sulfate and concentrated to yield 0.47 g of 3-Amino-6-hydroxymethyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide as a dark brown oil (containing 2-amino-4-methyl thiazole), MS (ISP): m/e=265.3 (M+H+). The crude material was reprotected with tert-butyldimethylchlorosilane/imidazole according to the general procedure described in step 4 to yield, after extraction and purification, 88 mg (0.23 mmol, 13%) of the pure title compound as a light yellow solid, MS (ISP): m/e=379.3 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:31][CH2:32][CH3:33]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:31][CH2:32][CH3:33]
Reactant: CCCBr
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: CCCOc1ccc(-c2nc(CNC(=O)c3ccccc3OCC)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 373 and 1-bromopropane, white powdery N-[2-(3-difluoromethoxy-4-propoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 98.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[CH:11][C:10]=2[NH2:16])[C:5](F)=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[NH:16][C:10]3[CH:11]=[N:12][C:13]([Cl:15])=[CH:14][C:9]=3[C:4]=2[CH:3]=1
Reactant: Nc1cnc(Cl)cc1-c1cc(Br)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
A solution of 5-bromo-6′-chloro-2-fluoro-[3,4]bipyridinyl-3′-ylamine (2.21 g, 7.32 mmol) in THF (124 mL) was added dropwise over 10 minutes to sodium bis-(trimethylsilyl)amide (1N solution in THF, 14.6 mL, 14.6 mmol). The reaction mixture was stirred for 1 h at ambient temperature and then quenched by the addition of water (2 mL). The resultant brown solution was partitioned between ethyl acetate (75 mL) and brine (50 mL). An off-white solid precipitated and was collected by filtration to afford the title compound as a grey solid (1.01 g, 49%). 1H NMR (DMSO-D5, 300 MHz): 9.01 (d, J=2.3 Hz, 1H), 8.73 (s, 1H), 8.70 (d, J=2.3 Hz, 1H), 8.35 (s, 1H). LCMS (Method B): RT=3.33 min, M+H+=284.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]([CH3:9])[CH2:7][NH2:8].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH:8][CH2:7][CH:6]([O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[CH3:9]
Reactant: COc1ccccc1OC(C)CN
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccc(F)cc23)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccccc1OC(C)CNCCCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A solution of 2-(2-methoxy-phenoxy)propylamine (0.26 g, 1.2 mmol), 5-fluoro-3-(3-p-toluenesulfonyloxypropyl)indole (0.26 g, 0.81 mol) and triethylamine (0.13 g, 1.2 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 8 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.1 g (36%) of product of product as a yellow oil.
Reaction SMILES: C(OC(=O)CC)(=O)CC.[C:10]([OH:14])(=O)[CH2:11][CH3:12].[OH:15][C:16]1[CH2:21][CH:20]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([O:30][CH3:31])[C:23]=2[CH3:32])[CH2:19][C:18](=[O:33])[CH:17]=1.[OH-].[Na+].Cl>FC(F)(F)S(O)(=O)=O.O>[OH:33][C:18]1[CH2:19][CH:20]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([O:30][CH3:31])[C:23]=2[CH3:32])[CH2:21][C:16](=[O:15])[C:17]=1[C:10](=[O:14])[CH2:11][CH3:12]
Reactant: COc1c(C)cc(C)c(C2CC(=O)C=C(O)C2)c1C
Reactant: CCC(=O)O
Agent: CCC(=O)OC(=O)CC
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(OC)c2C)CC1=O
Temperature: 115 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of propionic anhydride (4.0 ml) and propionic acid (4.0 ml) was added to 3-hydroxy-5-(3-methoxy-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (2.0 g) and the mixture was heated at 115° C. with stirring until a clear solution was obtained. Trifluoromethanesulfonic acid (10 drops) was then added and the heating and stirring was continued for a further 2 hours. The mixture was cooled, poured into water, basified with sodium hydroxide and stirred at room temperature for 30 minutes. The aqueous mixture was then acidified to pH 6.0 with dilute hydrochloric acid and extracted with diethyl ether. The ether phase was washed successively with water, dilute aqueous sodium bicarbonate and water, then dried over anhydrous sodium sulfate and evaporated to give a crude red oil (2.3 g). Purification by column chromatography over silica gel (eluant dichloromethane) gave 3-hydroxy-5-(3-methoxy-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one (1.35 g; 55.0%) as a pale yellow oil. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.15 (3H, t); 2.23 (3H, s); 2.33 (6H, s); 2.35-4.00 (7H, m); 3.66 (3H, s); 6.84 (1H, s); 18.24 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].Br[CH2:12][CH2:13][O:14][CH3:15]>C(O)C>[CH3:15][O:14][CH2:13][CH2:12][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccccc1S
Reactant: COCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCSc1ccccc1N
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 2-aminothiophenol (93%, 123 g, 0.910 mole) and sodium hydroxide (40.2 g, 1.00 mol) in 90% aqueous ethanol (637 ml) was added dropwise 2-bromoethylmethylether (127 g, 0.910 mol) at room temperature. When the addition was complete, the reaction mixture was refluxed for 2 hours, cooled to room temperature, and then concentrated in vacuo. The resulting residue was diluted with water (1400 ml) and extracted with methylene chloride (3×500 ml). The extracts were washed with water (2×500 ml) and brine (500 ml), dried with (MgSO4), filtered and concentrated to give a dark oil. Distillation of the crude product gave 2-(2-methoxyethylthio)benzenamine (148 g, 89%) as a light yellow oil: bp 90°-103° (0.1 mm).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].C(=O)(O)[O-].[Na+].[C:17](Cl)([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18]>O1CCOCC1.O>[N:2]1([C:17]([O:19][CH2:20][CH:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28]3[C:33]2=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:18])[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1COCCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl morpholine-3-carboxylate hydrochloride (2.0 g, 11.01 mmol) in a mixture of 1,4-dioxane (10 mL) and water (20 mL) was added sodium bicarbonate (2.79 g, 33.2 mmol). The suspension was cooled in an ice-water bath and a solution of Fmoc chloride (2.93 g, 11.33 mmol) in 1,4-dioxane (30 mL) was added. The mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate (150 mL) and water (150 mL). The phases were separated and the organic extract washed with 1 M aqueous HCl (150 mL) and brine (50 mL). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to leave a colourless gum, 4.2 g. LCMS [LCMS4] Rt 3.10 min, m/z (ES+) 368 (M+H).
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=[O:8].OC1C(=O)[NH:15][S:16](=[O:25])(=[O:24])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:11][C:6]1[C:7](=[O:8])[NH:15][S:16](=[O:24])(=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1NS(=O)(=O)C(c2ccccc2)=C1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1NS(=O)(=O)C(c2ccccc2)=C1Cl
Temperature: 25 °C
Yield: 49.6 %

Procedure:
Dry DMF (1.2 ml) was added dropwise to a mixture of oxalyl chloride (4.96 g, 39.1 mmol) and 4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (2.2 g, 9.77 mmol) in DCM. The resulting solution was heated under reflux until it turned orange. The mixture was then cooled to room temperature and filtered affording the title compound (1.18 g, 50%) as white solid. 1H NMR (400 MHz, d6-DMSO): δ 7.41-7.54 (m, 3H), 7.77-7.80 (m, 2H), 12.70 (br.s, 1H); 13C-NMR (100 MHz, d6-DMSO): δ 126.1, 127.1, 128.3, 129.9, 130.6, 144.9, 162.2.
Reaction SMILES: Cl.[CH2:2]([O:5][N:6]=[C:7]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37]C=O)[N:32]=1)[C:8]([NH:10][CH:11]1[C:29](=[O:30])[N:13]2[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH:18]([S:20][C:21]3[NH:25][N:24]=[N:23][N:22]=3)[CH3:19])[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]>CO>[CH2:2]([O:5][N:6]=[C:7]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[N:32]=1)[C:8]([NH:10][CH:11]1[C:29](=[O:30])[N:13]2[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH:18]([S:20][C:21]3[NH:25][N:24]=[N:23][N:22]=3)[CH3:19])[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cccc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Conc. hydrochloric acid (0.31 ml.) was added to a solution of 7-[2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.75 g.) in methanol (7 ml.), and the mixture was stirred at ambient temperature for 30 minutes. The methanol was removed by distillation from the reaction mixture, and the remaining aqueous solution was diluted with water (80 ml.) and then adjusted to pH 2-3 with an aqueous solution of sodium bicarbonate. The aqueous solution was subjected to column chromatography on a macroporous, non-ionic adsorption resin "Diaion HP-20" (Trade Mark, manufactured by Mitsubishi Chemical Industries Ltd.) (50 ml.). After the column was washed with water (1 l.), elution was carried out with 50% aqueous methanol (1 l.) and fractions containing the desired compound were collected. The methanol was removed by distillation from the combined fractions under reduced pressure and the resultant aqueous solution was lyophilized to give 7-[2-allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.13 g.), mp. 149°-151° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[C:6]([CH:14]=1)[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([OH:13])=[N:9]1.[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Br)[CH3:23].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][O:13][C:10]1[CH:11]=[CH:12][N:8]([CH2:7][C:6]2[CH:14]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:9]=1)[CH3:23]
Reactant: CCC(CC)COc1ccc(Br)cc1Cn1ccc(O)n1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccn(Cc2cc(Br)ccc2OCC(CC)CC)n1
Temperature: 120 °C

Procedure:
To a solution of 1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazol-3-ol, 3, 0.06 g (0.15 mmol) in acetone (3 mL) was added ethylbromoacetate (24 μL 0.22 mmol), K2CO3 (0.03 g, 0.22 mmol) and tetrabutylammonium iodide (0.008 g, 0.022 mmol). The resulting mixture was heated at 120° C. in an Emrys microwave reactor for 20 min. The volatiles were removed in vacuo and the crude product was purified on silica to yield to {1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazol-3-yloxy}-acetic acid ethyl ester, 4.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O.Cl.[NH:61]1[CH2:66][CH2:65][C:64](=[O:67])[CH2:63][CH2:62]1>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:61]3[CH2:66][CH2:65][C:64](=[O:67])[CH2:63][CH2:62]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)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
Solvent: O
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCC(=O)CC3)cs2)c1-c1ccc(F)cc1
Yield: 58.8 %

Procedure:
A solution of the compound (60 mg, 0.17 mmol) obtained in step 6, HATU (76 mg, 0.20 mmol), DIEA (0.035 mL, 0.20 mmol) and piperidin-4-one monohydrochloride monohydrate (30.8 mg, 0.20 mmol) in DMF (1.5 mL) was stirred at room temperature for 4 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→100% ethyl acetate/hexane) to give the title compound (44 mg, 0.100 mmol, 60%) as a white powder.