Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59]>>[C:58]([NH:57][CH2:56][CH2:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[O:48][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:60])[CH3:59]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1ccccc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.30 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate and 0.16 g of N-[2-(2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a colourless oil. Rf=0.17 (3:1 EtOAc-heptane); Rt=5.65.
Reaction SMILES: ClC1C=C(NC(C)C(O)=O)C=CC=1F.COC(OC)CNCCCN1CCC2(CC2)[C@H](O)C1.[Cl:34][C:35]1[CH:36]=[C:37]([NH:42][CH:43]([CH3:65])[C:44]([N:46]([CH2:59][CH:60](OC)OC)[CH2:47][CH2:48][CH2:49][N:50]2[CH2:57][CH2:56][C:53]3([CH2:55][CH2:54]3)[C@H:52]([OH:58])[CH2:51]2)=[O:45])[CH:38]=[CH:39][C:40]=1[F:41]>>[Cl:34][C:35]1[CH:36]=[C:37]([N:42]2[CH2:60][CH2:59][N:46]([CH2:47][CH2:48][CH2:49][N:50]3[CH2:57][CH2:56][C:53]4([CH2:54][CH2:55]4)[C@H:52]([OH:58])[CH2:51]3)[C:44](=[O:45])[C@@H:43]2[CH3:65])[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: COC(CN(CCCN1CCC2(CC2)[C@H](O)C1)C(=O)C(C)Nc1ccc(F)c(Cl)c1)OC
Agent: CC(Nc1ccc(F)c(Cl)c1)C(=O)O
Agent: COC(CNCCCN1CCC2(CC2)[C@H](O)C1)OC
Product: C[C@H]1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(F)c(Cl)c1

Procedure:
The title compound was produced in analogy with examples 74 and 75, steps D-F. Thus, coupling of 2-(3-chloro-4-fluoro-phenylamino)-propionic acid (intermediate 14) with (S)-6-[3-(2,2-dimethoxy-ethylamino)-propyl]-6-aza-spiro[2.5]octan-4-ol (examples 74/75C) in step D led to 2-(3-chloro-4-fluoro-phenylamino)-N-(2,2-dimethoxy-ethyl)-N-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-propionamide, which was cyclized in step E. Finally, HPLC purification of the epimeric mixture, 4-(3-chloro-4-fluoro-phenyl)-1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one, in step F afforded the title compound. Light yellow gum, MS: 410.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=S)[CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[OH:24]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]2[O:24][C:14]3[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH:7]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Reactant: Cc1ccc(F)cc1N=C=S
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3cc(F)ccc3C)oc2c1
Temperature: 25 °C
Reaction time: 27 h
Yield: 45.9 %

Procedure:
In methanol (50 ml), 5-fluoro-2-methylphenyl isothiocyanate (2.00 g, 12.0 mmol) was added to methyl 4-amino-3-hydroxyphenylacetate (2.17 g, 12.0 mmol) and the resulting mixture was stirred at room temperature for 27 hours. Mercuric oxide (yellow) (3.12 g, 14.4 mmol) was added to the reaction mixture, followed by stirring at 70° C. for 4 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, followed by washing with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (10/1) eluate fractions, methyl (2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl)acetate (1.73 g, 46%) was obtained as a brown oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=3)=[CH:27][CH:26]=2)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)CCNC(=O)c1ccc(C(Oc2ccc(Br)cc2)C2CCCCC2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(OC(c3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[(4-bromo-phenoxy)-cyclohexyl-methyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 512.3 [M−H].
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.O>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([N:62]2[CH2:61][CH2:60][N:59]([C:42](=[O:41])[CH2:43][NH:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:49][CH:48]=3)=[O:46])[CH2:64][CH2:63]2)=[O:19])=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(Cl)nc2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 33.9 %

Procedure:
DIPEA (179.7 mg, 0.24 mL, 1.39 mmol) was added to a stirred solution of 6-chloro-pyridine-3-carboxylic acid (48.6 mg, 0.37 mmol) in DMF (3 mL). HOBT (45.9 mg, 0.34 mmol) and EDCI (148.1 mg, 0.77 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 90% EtOAc in Hexane as eluent) to afford 58 mg (40.8% yield) of biphenyl-4-carboxylic acid {2-[4-(6-chloro-pyridine-3-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 95.92, 1H NMR (DMSO-d6): δ 8.7-8.6 (t, 1H), 8.5 (d, 1H), 8.0-7.9 (m, 3H), 7.84-7.7 (q, 4H), 7.68-7.6 (d, 1H), 7.54-7.46 (t, 2H), 7.46-7.36 (m, 1H), 4.2 (bs, 2H), 3.8-3.4 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:19])[CH2:13][C:14](=O)[CH2:15][CH2:16][CH3:17])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.OS(O)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]2[C:4]=1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12](=[O:19])[NH:11]2
Reactant: CCCC(=O)CC(=O)Nc1cc(OC)cc(OC)c1
Agent: O=S(=O)(O)O
Product: CCCc1cc(=O)[nH]c2cc(OC)cc(OC)c12
Yield: 90 %

Procedure:
Compound 10 (19 g, 71.69 mmol) was treated with Conc. H2SO4 (48 mL, 901 mmol) for 30 min. as described for II after usual work up afforded 5,7-dimethoxy-4-propyl-1,2-dihydro-2-quinolinone (12,159) in 90% yield as a white solid. M.P. 193-196° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH3:2].[OH-].[Na+].C(O)C>O>[CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH3:2]
Reactant: CCc1c(CCNC(=O)CCCCC(=O)OC)ccc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1c(CCNC(=O)CCCCC(=O)O)ccc(OC)c1OC
Yield: 79.5 %

Procedure:
A mixture of the product from Stage (i) (11 g), 2N sodium hydroxide solution (200 ml) and ethanol (300 ml) was heated under reflux for 1 h. The solution was cooled and poured into water (1000 ml). The mixture was washed with ether, acidified with 2N hydrochloric acid and then extracted with ether. The extracts were washed with water, dried and evaporated to give the title compound (8.4 g) as a white solid, m.p. 92°-94°.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:34])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:23]=[C:22]([CH3:34])[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1CCl
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(F)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
36 mg (0.89 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 185 mg (0.85 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.85 mmol) 3-chloromethyl-6-(4-fluoro-phenyl)-2-methyl-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. The residue was dried at 40° C. in vacuum to give 295 mg (83%) of the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:10]C(=O)[O:8][C:7](=O)[C:6]=2[CH:13]=1.C(O)(=O)C.[CH3:19][NH2:20].O>C(#N)C>[NH2:10][C:5]1[C:4]([CH3:14])=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:20][CH3:19])=[O:8]
Reactant: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Reactant: CN
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1cc(Cl)cc(C)c1N
Temperature: 5 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a suspension of 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (211.6 g, 1000 mmol) in acetonitrile (700 mL) was added acetic acid (7.3 g, 122 mmol). Then 40% aqueous methylamine (104 mL) was added dropwise over 30 minutes at 25-30° C. Stirring was continued for 2 h, and then water (700 mL) was added slowly. The resulting suspension was cooled to 5° C., and stirred for 30 minutes at this temperature. The suspension was then filtered, and the solids were washed with water (3×200 mL) and dried under nitrogen to afford the title compound as off-white needles, 172.8 g (87.0% yield), m.p. 141-143° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[O:13]1[CH2:17][CH2:16][CH:15]([C:18]2([CH:22]=[O:23])[CH2:21][CH2:20][CH2:19]2)[CH2:14]1.CC#N>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:22]([C:18]1([CH:15]2[CH2:16][CH2:17][O:13][CH2:14]2)[CH2:19][CH2:20][CH2:21]1)[OH:23]
Reactant: O=CC1(C2CCOC2)CCC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: OC(c1ccccn1)C1(C2CCOC2)CCC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 11.4 %

Procedure:
To a solution of 2-bromopyridine (203 mg, 1.28 mmol) in THF (5 mL) was added 2.5N n-BuLi solution (0.6 mL, 1.54 mmol) dropwise and stirred at −78° C. for 1.5 hours. Then a solution of Example 284C (0.18 g, 1.17 mmol) in THF (2 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (2×20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC(C18 column, water (0.05% TFA):CH3CN, 55:45 to 85:15) to obtain the title compound as a colorless oil (31.2 mg, yield 11.5%). LC-MS: MS (M+H)+ 234.1; 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J=4.8 Hz, 1H), 7.69-7.64 (m, 1H), 7.30 (d, J=7.6 Hz 1H), 7.26-7.22 (m, 1H), 4.71 (d, J=28.8 Hz, 1H), 4.53 (brs, 1H), 3.89-3.79 (m, 1.5H), 3.65-3.54 (m, 2H), 3.38 (t, J=8.6 Hz, 0.5H), 2.35-2.04 (m, 3H), 1.99-1.55 (m, 6H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:23](O[Na])(C)=[O:24].O>CN(C=O)C>[CH2:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=[O:24])=[CH:15][CH:14]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC(=O)O[Na]
Reactant: CCCCCCOc1cccc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc(C=O)c2ccccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
POCl3 (3.22 g, 21 mmol) was dropwise added to a solution of compound 2 (4 g, 17.5 mmol) in anh. DMF (5 ml) at room temperature and under N2. The resulting dark red solution was heated to 100° C. for 3 hours. Concentrated AcONa solution (5 ml) was then added and heating was continued for 2 hours more. After being cooled to room temperature, water (100 ml) was added. The mixture was extracted with Et2O (2×150 ml), the ethereal combined fractions were washed with 10% HCl solution (100 ml), water (100 ml), dried over MgSO4, filtered and evaporated to dryness. Recrystallisation of the brown solid from EtOH afford 2.1 g (47%) of compound 3 as brownish crystals.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:6]1)(=O)[CH3:2].O(P(OC1C[C@@H:46]2[C@@H:56]([C@H:57]([OH:59])[CH3:58])[C:55](=[O:60])[N:47]2[C:48]=1[C:49]([O:51][CH2:52][CH:53]=[CH2:54])=[O:50])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[OH-].[Na+].Cl.C(N(CC)C(C)C)(C)C>>[CH2:13]([O:12][C:10]([N:8]1[C@@H:7]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:6][C@H:5]([S:4][C:1]2[CH2:2][C@@H:46]3[C@@H:56]([C@H:57]([OH:59])[CH3:58])[C:55](=[O:60])[N:47]3[C:48]=2[C:49]([O:51][CH2:52][CH:53]=[CH2:54])=[O:50])[CH2:9]1)=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@H](Cc3cccc4ccccc34)N(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 73.5 %

Procedure:
Allyl (5R,6S)-2-[(3S,5S)-N-(allyloxycarbonyl)-5-(1-naphthylmethyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (633 mg, yield: 70.1%) was prepared as a yellow powder, from (2R,4S)-4-acetylthio-N-allyloxycarbonyl-2-(1-naphthylmethyl)pyrrolidine (610 mg, 1.53 mmol), allyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (743 mg, 1.53 mmol), 1N aqueous sodium hydroxide (1.8 ml, 1.8 mmol), 1N aqueous hydrochloric acid (1.8 ml, 1.8 mmol) and N,N-diisopropylethylamine (800 μl, 4.59 mmol), in the same manner as in Example 135-1.
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([N:5]([CH3:28])[C@H:6]([C:14]([NH:16][C@H:17]([C:25](O)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH2:39][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42].C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([N:5]([CH3:28])[C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:39][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Reactant: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 50 %

Procedure:
Condensation of BocPro-MePhe-PheOH (670 mg.) and HGly-Leu-MetNH2 (Example 7, 418 mg.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MePhe-Phe-Gly-Leu-MetNH2 in 50% yield. De-t-butoxycarbonylation of BocPro-MePhe-Phe-Gly-Leu-MetNH2 (480 mg.) using hydrogen chloride in ethyl acetate gave HPro-MePhe-Phe-Bly-Leu-MetNH2, which was isolated as the amorphous white solid hydrochloride salt monohydrate in 85% yield.
Reaction SMILES: C([Li])CCC.[I:6]I.S([O-])([O-])(=O)=S.[Na+].[Na+].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23]>C1COCC1>[I:6][C:19]1[CH:20]=[CH:21][C:16]([F:15])=[C:17]([F:23])[C:18]=1[F:22]
Reactant: Fc1cccc(F)c1F
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(I)c(F)c1F
Temperature: -60 °C
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere, 1,2,3-trifluorobenzene was dissolved into THF, and cooled to −60° C. Then, butyllithium (1.56 M hexane solution) was added dropwise for 30 minutes, and stirred for 2 hours. Then, the THF solution containing iodine was added dropwise for 1 hour, and warmed to room temperature. After the reaction solution was poured into a sodium thiosulfate aqueous solution and stirred for a while, an organic layer was separated, and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure to obtain 4-iodo-1,2,3-trifluorobenzene.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][O:7][CH2:6][C@H:5]1[NH:10]C(=O)OC(C)(C)C)=[N+:2]=[N-:3].O1CCOCC1.Cl.Cl>C(Cl)Cl>[N:1]([C@H:4]1[CH2:9][CH2:8][O:7][CH2:6][C@H:5]1[NH2:10])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@@H]1N=[N+]=[N-]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: [N-]=[N+]=N[C@H]1CCOC[C@H]1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Tert-butyl ((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)carbamate (1.5 g, 6.19 mmol) was taken up in DCM (5 ml) and 4N HCl dioxane (4.64 ml, 18.57 mmol) added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed to give (3S,4S)-4-azidotetrahydro-2H-pyran-3-amine (1.1 g, 6.16 mmol, 99% yield) as an HCl salt. MS (ES+) C5H10N4O requires: 142, found: 143 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][S:5](=[O:19])(=[O:18])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].[OH-].[Na+].Cl.CCOCC.CCCCCC>O1CCOCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][S:5]([CH2:4][C:3]([OH:20])=[O:2])(=[O:19])=[O:18])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:9]=1
Reactant: COC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
2.2 g (6.98 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-acetic acid methyl ester is dissolved in 20 ml of dioxane, and the solution is mixed with 10 ml (20 mmol) of 2N sodium hydroxide solution. A slight warming occurs and the saponification is complete after 10 minutes. The solution is neutralized with 2N hydrochloric acid with pH control and gently evaporated to dryness in a vacuum. The residue is extracted with 30 ml ethyl acetate, the solution is shaken out once with 10 ml of water, the organic phase is dried on magnesium sulfate, filtered and evaporated to dryness. 1.96 g (6.51 mmol)=93.2% of the theoretical yield is obtained. Melting point 120-121° C. (ether/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:9])[CH3:8])[S:5][CH:6]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1
Reactant: CC(O)c1cc(Br)cs1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1cc(Br)cs1
Yield: 87 %

Procedure:
A solution of raw 4-bromo-2-(1′-hydroxyethyl)thiophene (1.28 g, 6.18 mmol) and PCC (2.6 g, 13.26 mmol) in 20 ml of dichloromethane is put into a flask fitted with magnetic stirring and under an atmosphere of argon. It is agitated vigorously for 2 hours at ambient temperature, the reaction medium becoming progressively black. It is then filtered on a column of florisil (eluent ether), the solvent evaporated and the raw product produced is purified by flash chromatography on silica (eluent pure petroleum ether). 1.10 g of a white solid is obtained 4-bromo-2-acetyl-thiophene (yield=87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=S)[CH3:2].Cl.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[CH:25]([OH:38])[CH:26]([NH:29][C:30](=[O:37])[CH:31]([NH2:36])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27][CH3:28].C(N(C(C)C)CC)(C)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:1]([O:3][C:4](=[O:14])[N:5]=[C:6]([NH:36][C@H:31]([C:30](=[O:37])[NH:29][C@H:26]([C:25]([C:17]1[O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)=[O:38])[CH2:27][CH3:28])[CH2:32][CH:33]([CH3:34])[CH3:35])[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCC(NC(=O)C(N)CC(C)C)C(O)c1nc2ccccc2o1
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N=C(N[C@@H](CC(C)C)C(=O)N[C@@H](CC)C(=O)c1nc2ccccc2o1)N1CCOCC1
Temperature: 25 °C

Procedure:
(Morpholine-4-carbothioyl)carbamic acid ethyl ester (55 mg, 0.25 mmol), 2-amino-4-methylpentanoic acid [1-(benzoxazol-2-ylhydroxymethyl)propyl]amide hydrochloride (90 mg, 0.25 mmol), and diisopropylethylamine (0.13 mL, 0.76 mmol) were dissolved in dichloromethane (5 mL). 2-Chloro-1-methylpyridinium iodide (84 mg, 0.33 mmol) was added and the reaction mixture was stirred at ambient temperature over night. After dilution with ethyl acetate (100 mL), the solution was washed with sat. aq. NaHCO3, and brine, dried with MgSO4 and evaporated under vacuum. The residue was dissolved in dichloromethane (10 mL) and Dess-Martin periodinane (400 mg) was added. The reaction mixture was stirred at ambient temperature for 1 h. After dilution with ethyl acetate (100 mL), the solution was washed with a 0.26 M solution of Na2S2O3 in sat. aqu. NaHCO3, then with sat. aq. NaHCO3, and brine, dried with MgSO4 and evaporated under vacuum. After purification by flash chromatography on silica gel, the title compound was obtained as yellowish glass (10 mg, 0.020 mmol). MS: (M+H)+ 502.