Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.CCOCC>C(O)C>[C:2]1([CH2:1][CH2:8][CH:9]([OH:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC(O)CCc1ccccc1
Temperature: 0 °C
Yield: 91.3 %

Procedure:
Benzylacetone (7.5 mL, 50 mmol) was dissolved in ethanol (50 mL) and cooled to 0° C. Sodium borohydride (1.89 g, 50 mmol, 1 equiv.) was added. The mixture was stirred and allowed to warm to room temperature overnight. All of the starting material was gone by tlc analysis, so the mixture was poured into water (50 mL) and ether (50 mL). The layers were separated and the aqueous layer was extracted with ether (2×25 mL). The organic layers were combined and concentrated. The resulting aqueous residue was poured into ether (50 mL). The organic layer was removed, dried (MgSO4), and concentrated to provide 1c (6.86 g; 91%). 1H nmr (300 MHz, CDCl3): 7.38-7.15 (5H, m); 3.85 (1H, m(6), J=6.17 Hz); 2.82-2.61 (2H, m); 1.79 (2H, q, J=7.12 Hz); 1.421 (1H, s); 1.236 (3H, d, J=6.09 Hz). IR (neat film, cm-1): 3250 (b); 2900 (b). EIMS (m/e): 150 (M+).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][O:60][CH:61]1[CH2:66][CH2:65][CH2:64][N:63]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([CH2:74][NH:75][CH3:76])=[CH:70][CH:69]=2)[CH2:62]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:75]([CH2:74][C:71]3[CH:70]=[CH:69][C:68]([CH2:67][N:63]4[CH2:64][CH2:65][CH2:66][CH:61]([O:60][CH3:59])[CH2:62]4)=[CH:73][CH:72]=3)[CH3:76])=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CCCC(OC)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCCC(OC)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (36 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:30][N:31](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.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>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([C:26]([F:29])([F:28])[F:27])=[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH:24]=1
Reactant: CN(C)C=O
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(Cl)ccc2C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4cc(Cl)ccc4C(F)(F)F)CC3)n2c1
Temperature: 130 °C
Yield: 63 %

Procedure:
A mixture of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-chloro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (0.205 g, 0.42 mmol), zinc cyanide (0.099 g, 0.840 mmol), tetrakis(triphenylphosphine)palladium (0.048 g, 0.042 mmol), and DMF (4 mL) was heated under microwave irradiation at 130° C. for 30 min. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2×80 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-60% EtOAc in hexanes) to give 3-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (0.115 g, 63%): 1H NMR (300 MHz, CDCl3) δ 9.72 (s, 1H), 7.98 (dd, J=9.5, 1.1 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.51 (dd, J=9.5, 1.6 Hz, 1H), 7.41 (s, 1H), 7.31 (dd, J=8.5, 1.3 Hz, 1H), 5.77-5.72 (m, 1H), 5.02-4.96 (m, 1H), 3.40 (m, 2H), 3.04-2.94 (m, 1H), 2.06-1.80 (m, 4H); MS (ESI+) m/z 434 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: COCc1nc(-c2ccc(OC(F)(F)F)cc2)ncc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2COC)cc1C

Procedure:
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-methoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine (example 155E]) to give the title compound as brown oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[C:18]([C:33](OC)=[O:34])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH2:11][CH2:10]1)=[O:8])[CH3:5].CO>C1COCC1>[OH:34][CH2:33][C:18]1[C:17]([O:16][CH2:15][CH:12]2[CH2:11][CH2:10][N:9]([C:7]([O:6][CH:4]([CH3:5])[CH3:3])=[O:8])[CH2:14][CH2:13]2)=[CH:22][CH:21]=[C:20]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[N:19]=1
Reactant: COC(=O)c1nc(-c2ccc(S(C)(=O)=O)cc2)ccc1OCC1CCN(C(=O)OC(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2CO)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
NaBH4 (32 mg, 0.82 mmol) was added to a stirred solution of methyl 3-{[(1-{[(1-methylethyl)oxy]carbonyl}-4-piperidinyl)methyl]oxy}-6-[4-(methylsulfonyl)phenyl]-2-pyridinecarboxylate (Example 135, 0.20 g, 0.41 mmol) in THF (4 mL) at 0° C. MeOH (2 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h, then allowed to warm to ambient temperature and stirred overnight. The mixture was heated at 70° C. for 2 h, more NaBH4 (100 mg, 2.56 mmol) was added. Heating was continued at 70° C. for 2 h, then more NaBH4 (100 mg, 2.56 mmol) was added. The mixture was heated at 70° C. for 2 h, cooled to ambient temperature, quenched with saturated aqueous NH4Cl and extracted with EtOAc (70 mL×2). The combined organic extracts were washed with brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a light brown oil. The crude material was purified by flash chromatography on a silica gel column eluted with 1:8 acetone/CH2Cl2 to give 0.153 g (81%) of 1-methylethyl 4-[({2-(hydroxymethyl)-6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.5 Hz), 7.71 (d, 1H, J=8.6 Hz), 7.24 (d, 1H, J=8.6 Hz), 4.93 (septet, 1H, J=6.2 Hz), 4.82 (s, 2H), 4.22 (bs, 2H), 3.91 (d, 2H, J=6.1 Hz), 3.09 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.90_1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 463 (M+H).
Reaction SMILES: [CH:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:15]([C:20]1[N:21]=[CH:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])=[CH:8]2)=[CH2:2]>CO.C1COCC1.[C].[Pd]>[CH2:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:15]([C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])=[CH:8]2)[CH3:2]
Reactant: C=Cc1c(OC)ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(OC)ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
1-(5-Ethenyl-6-methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.28 g) was dissolved in a mixture of methanol and THF (1:1, 50 ml). To the solution was added 10% palladium carbon (0.3 g), and the mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated. The residue was dissolved in a mixed solution of methanol and THF (3:1, 40 ml). To the solution was added pyridine hydrochloride (0.65 g), and the mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated to dryness, and to the residue were added ethyl acetate and 1N-hydrochloric acid (20 ml). The organic layer was extracted four times with 1N-hydrochloric acid. The aqueous layer was neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried and concentrated. The residue was purified by silica gel chromatography (eluent, dichloromethane-methanol=10:1) followed by crystallization from dichloromethane-diisopropyl ether-hexane to give the titled compound (0.49 g) as a colorless powder.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:42]2[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][CH2:51][OH:52])=[C:44]([O:53][CH3:54])[N:43]=2)=[CH:24]\[C@@H:25]2[N:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH3:40])[C:28](=[O:41])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].O>C(Cl)(Cl)Cl>[CH3:8][S:9]([O:52][CH2:51][CH2:50][CH2:49][CH2:48][C:45]1[C:44]([O:53][CH3:54])=[N:43][C:42](/[C:23](/[C:20]2[CH:21]=[CH:22][C:17]([C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:18][CH:19]=2)=[CH:24]/[C@H:25]2[CH2:26][CH2:27][C:28](=[O:41])[N:29]2[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=2[O:39][CH3:40])=[CH:47][CH:46]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCO)c(OC)n2)c(OC)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCOS(C)(=O)=O)c(OC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (50 μL) and methanesulfonyl chloride (25 μL) were added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(4-hydroxybutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (144 mg) in chloroform (2 mL), and the mixture was stirred at room temperature for three hours. Triethylamine (50 μL) and methanesulfonyl chloride (25 μL) were further added thereto and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)butyl methanesulfonate as a crude product. 2 M dimethylamine (solution in methanol) (3 mL) was added to 4-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)butyl methanesulfonate, and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated from the reaction solution and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0→4:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-[4-(dimethylamino)butyl]-6-methoxypyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][O:5][C:3]1=[O:4].[OH-:9].[K+:10]>O>[K+:10].[OH:5][CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[C:3]([O-:9])=[O:4]
Reactant: [OH-]
Reactant: CC1(C)CCOC1=O
Agent: [K+]
Solvent: O
Product: CC(C)(CCO)C(=O)[O-]
Yield: 86.8 %

Procedure:
A mixture of 2,2-dimethylbutyrolactone (8.17 g, 71.7 mmol) and KOH (4.02 g,71.7 mmol) in 72 ml of water was refluxed overnight and then the mixture was concentrated in vacuo (50° C.). The crude residual oil was crystallized in ethanol/ether and the resulting white solid product was filtered and dried (100° C./0.1 mm) to afford 10.6 g (87%) of 4-hydroxy-2.2-dimethylbutyric acid monopotassium salt.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:16][O:15][C:14]([CH2:18]I)([CH3:17])[CH2:13][N:12]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([CH:11]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[CH2:13][N:12]1[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CI)CN(Cc2ccccc2)C(C(=O)OCc2ccccc2)CO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(C)CN(Cc2ccccc2)C(C(=O)OCc2ccccc2)CO1
Yield: 85 %

Procedure:
To a solution of 4-benzyl-6-iodomethyl-6-methyl-morpholine-3-carboxylic acid benzyl ester (Intermediate 17, 1.23 g) and tributyltin hydride (1.8 ml, 2.5 eq.) in 11 ml of toluene under gentle reflux was added over 1.5 hr a solution of AIBN in toluene (25 mg/1 ml). The mixture was allowed to cool down and was concentrated to dryness. The residue was partitioned into 15% 1M HCl in acetonitrile and hexane. The separated hexane phase was extracted two times with the acetonitrile solution. The combined acetonitrile solutions were washed with hexane two times and concentrated. The residue was partitioned into ether and 1M K2CO3. The separated ether phase was washed successively with 0.4M Na2S2O3 and brine, dried over MgSO4 and concentrated. The residue was purified on silica (7.5% EtOAc/hexane) to give 760 mg (oil, 85% yield) of compound 4-benzyl-6,6-dimethyl-morpholine-3-carboxylic acid benzyl ester.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(O[CH2:9][C:10]1[CH2:17][S:16][CH:15]2[N:12]([C:13](=[O:28])[CH:14]2[NH:18][C:19](=[O:27])[CH2:20][C:21]2[S:22][C:23](=[O:26])[S:24][CH:25]=2)[C:11]=1[C:29]([OH:31])=[O:30])(=O)C>O.C(=O)(O)[O-].[Na+]>[N:1]([CH2:9][C:10]1[CH2:17][S:16][CH:15]2[N:12]([C:13](=[O:28])[CH:14]2[NH:18][C:19](=[O:27])[CH2:20][C:21]2[S:22][C:23](=[O:26])[S:24][CH:25]=2)[C:11]=1[C:29]([OH:31])=[O:30])=[N+:2]=[N-:3]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Temperature: 50 °C
Yield: 44.8 %

Procedure:
Sodium azide (0.871 g.) is added to a solution of 3-acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3 g.) in water (60 cc.) and sodium bicarbonate (0.588 g.), and the mixture is heated to 50° C. for 16 hours. It is allowed to cool and sodium bicarbonate (0.4 g.) is added. The mixture is extracted twice with ethyl acetate (40 cc.). The aqueous phase is treated with decolourising charcoal and brought to pH 2 by adding 6 N hydrochloric acid. A product precipitates, and is extracted with ethyl acetate (240 cc.). The organic extracts are dried over sodium sulphate and then concentrated to dryness under reduced pressure (20 mm.Hg). A residue (1.9 g.) is obtained, which is recrystallised from acetonitrile (18 cc.) to give 3-azidomethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (1.29 g.), m.p. 160° C., after a further recrystallisation from acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCC(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(OCC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from [2-amino-4-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example J30) (230 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (298 mg, 75%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][O:7][CH2:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][NH:11][C:12]([CH2:14][CH2:15][NH:16]C(=O)[O-])=[O:13].[ClH:35].O1CCOCC1>O1CCOCC1>[ClH:35].[NH2:16][CH2:15][CH2:14][C:12]([NH:11][CH2:10][CH:9]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:8][O:7][CH2:6][C:5]1[CH:26]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:28]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=1)=[O:13]
Reactant: O=C([O-])NCCC(=O)NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCCC(=O)NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reaction time: 20 h

Procedure:
Compound 73 (1.32 g, 2.4 mmol) produced in Example 95 was dissolved in dioxane (4 mL) and 4 mol/L hydrogen chloride/dioxane (4 mL) was added thereto at room temperature. After the mixture was stirred for 20 hours, the solvent was evaporated therefrom in vacuo. Ether was added to the resulting residue to crystallize whereupon Compound 74 (1.10 g, 95%) was produced.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:12]=O.C([CH2:29][C:30]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=[O:36])=[O:31])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:29]/[C:30]([NH:32][C:33]2[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=2[C:35]([OH:37])=[O:36])=[O:31])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC#CCCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCCCC#CCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 79.1 %

Procedure:
Piperidine (95 μL, 0.96 mmol) was added to a suspension of 3-methoxy-4-(oct-3-ynyloxy)benzaldehyde (0.25 g, 0.96 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.20 g, 0.90 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(3-methoxy-4-(oct-3-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.30 g, 79%) as a colourless crystalline solid; mp 169-170° C.; δH (400 MHz, DMSO-d6) 0.85 (t, J=7.2 Hz, 3H, CH3), 1.31-1.42 (m, 4H, CH3CH2CH2), 2.13 (t, J=7.2 Hz, 2H, CH2), 2.60 (t, J=7.2 Hz, 2H, CH2CH2O), 3.83 (s, 3H, OCH3), 4.05 (t, J=7.2 Hz, 2H, OCH2), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 7.00 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.37 (d, J5′,6′=1.6 Hz, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.30 (s, 1H, NH), 13.55 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 13.4, 17.7, 19.2, 21.3, 30.4, 55.7, 67.0, 76.7, 81.6, 110.9, 113.0, 116.7, 120.1, 120.3, 122.5, 122.6, 127.6, 131.1, 133.9, 141.0, 141.5, 149.1, 149.5, 164.1, 169.4; HRMS (ESI) calculated for C25H27NO5 [M+H]+ 421.1962. found 421.1962; vmax 757, 1143, 1220, 1514, 1601, 1652, 1690, 2939 cm−1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[O:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[C:40]([C:39]3[CH:38]=[CH:37][C:36]([C:34]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:23][CH2:22][O:21][CH2:26][CH2:25]5)=[CH:32][CH:31]=4)=[O:35])=[CH:43][CH:42]=3)[NH:18][C:11]=2[CH:10]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3ccc(OCc4ccccn4)cc3[nH]2)cc1

Procedure:
Compound 624 was prepared according to the procedure similar to that described in Scheme III from 1-(pyridin-2-ylmethoxy)-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C30H27N5O3: 506.21; found: 506.06.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[OH-].[K+].[CH2:27]([O:34]CCBr)[C:28]1C=CC=CC=1.C1C=CC=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCOCC)C>[C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:28][CH2:27][OH:34])(=[O:3])[CH3:2]
Reactant: BrCCOCc1ccccc1
Reactant: CC(=O)OC[C@H]1OC(O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOCOCC
Product: CC(=O)OC[C@H]1OC(OCCO)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetyl-mannopyranose, 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 82.93 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of diethoxymethane is cooled to 0° C. At 0° C., 32.26 g (150 mmol) of 2-benzyloxy-ethylbromide is added in drops over 30 minutes while being stirred vigorously. It is stirred for two hours at 0° C. 300 ml of benzene is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until hydrogen absorption is completed. Then, catalyst is suctioned out, it is rewashed with a little ethanol and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/nhexane/ethanol=20:8:2). The product-containing fractions are concentrated by evaporation.