Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].O.C(=O)(O)[O-].[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>CC(C)=O>[O:20]=[C:19]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10][CH2:18]1
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-amino-4-hydroxybenzonitrile (g, 10 mmol was dissolved in acetone (20 mL) and water (20 mL) containing sodium bicarbonate (4 g). 2-chloroacetyl chloride was added slowly and the mixture heated to reflux for 4 h and then allowed to stir overnight at 25 ° C. The layers were separated, and the water layer was extracted with ethyl acetate. The organic layers were combined and evaporated to give 3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carbonitrile as an oil (1.3 g): 1H NMR (400 M ; DMSO-D6): 7.4 (d, 1H); 7.2 (s, 1H); 7.1 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: O=C(Cl)Cc1ccccc1
Product: Cc1nc(-c2sc(NC(=O)Cc3ccccc3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and phenyl-acetyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([N:21]([CH2:26][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)[C:22](=[O:25])[CH2:23]Cl)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].C[N:38]1[CH2:43][CH2:42]O[CH2:40][CH2:39]1>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([N:21]([CH2:26][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)[C:22](=[O:25])[CH2:23][N:12]4[CH2:13][CH2:42][CH:43]([NH:38][C:39]5[CH:40]=[CH:5][CH:4]=[CH:3][CH:1]=5)[CH2:10][CH2:11]4)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N(Cc3cccc4ccccc34)C(=O)CCl)ccc21
Reactant: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N(Cc3cccc4ccccc34)C(=O)CN3CCC(Nc4ccccc4)CC3)ccc21

Procedure:
A solution of 2.1 g (4.3 mmol) of N-{2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-(naphth-1-ylmethyl)-2-chloroacetamide, 1.5 g (6.0 mmol) of 4-phenylamino-1-piperidine and 2.2 mL of N-methylmorpholine in 15 mL of dimethylformamide was stirred for 8 hours at 70-80° C. The mixture was then poured onto ice, extracted with ethyl acetate and washed with water, dried and distilled off. The product was chromatographed on silica gel.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]>ClCCl>[CH2:1]([N:3]1[C:15]2[CH:14]=[C:13]3[C:16]4[C:17]([C:22]5[CH:23]=[C:24]([O:28][CH3:29])[CH:25]=[CH:26][C:27]=5[C:12]3=[CH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH3:2]
Reactant: CCn1c2ccccc2c2ccc(-c3ccccc3-c3cccc(OC)c3)cc21
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc3c4ccc(OC)cc4c4ccccc4c3cc21
Reaction time: 12 h
Yield: 64.4 %

Procedure:
3.90 g (10.34 mmol) of 9-ethyl-2-(3′-methoxybiphenyl-2-yl)carbazole was dissolved in 50 ml of dichloromethane 50 ml, and 3.52 g (21.71 mmol) of FeCl3 was slowly put thereinto at normal temperature and agitated for 12 hours. After agitation, 3.52 g (21.71 mmol) of FeCl3 was further put thereinto and agitated for 1 hour. After the reaction was finished, quenching was performed by distilled water and ethanol, the organic layer was separated, filtering was performed by silica gel, and the column was used at a ratio of hexane:MC=7:3 (v/v) to obtain 2.5 g of 10-ethyl-3-methoxy-10H-phenanthro[9,10-b]carbazole (yield 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH:17]=[C:16]2[CH:31]=[C:32]1[S:36][C:35](=[O:37])[NH:34][C:33]1=[O:38]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:11])[NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH:17]=[C:16]3[CH:31]=[C:32]2[S:36][C:35](=[O:37])[NH:34][C:33]2=[O:38])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc2c(c1)c(C=C1SC(=O)NC1=O)cn2Cc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)Nc1ccc2c(c1)c(C=C1SC(=O)NC1=O)cn2Cc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared by General Procedure 7 with 3,4-dichlorophenyl isocyanate and the amino compound from Example 47 as reactants. Nmr and ms data were consistent; ms m/e 607 (M+1). HPLC (System 1): purity greater than 80%.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](/[CH:53]=[CH:54]/[CH2:55][C:56]([NH:58][C:59]([CH3:63])([CH3:62])[CH2:60][OH:61])=[O:57])=[CH:49][CH:48]=2)[C:43]([CH3:64])=[CH:42][C:41]=1[O:65]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].CO>[OH:65][C:41]1[CH:42]=[C:43]([CH3:64])[C:44]([CH2:46][C:47]2[CH:48]=[CH:49][C:50]([CH2:53][CH2:54][CH2:55][C:56]([NH:58][C:59]([CH3:63])([CH3:62])[CH2:60][OH:61])=[O:57])=[CH:51][CH:52]=2)=[CH:45][C:40]=1[C@@H:10]1[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]1[OH:8]
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CC(=O)NC(C)(C)CO)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(O)c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(CCCC(=O)NC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a methanol solution (1.2 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4-[(2-hydroxy-1,1-dimethylethyl)amino]-4-oxobut-1-en-1-yl]benzyl]-4-methylphenyl]-D-glucitol (120 mg, 0.124 mmol) was added 10% palladium-activated carbon (22 mg), and the mixture was stirred overnight under a hydrogen atmosphere at room temperature. The reaction solution was filtered through celite, and evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified with silica gel column chromatography (chloroform:methanol=20:1 to 5:1) to obtain the title compound (58 mg, 90%) as a colorless powder. NMR data and MS data of the compound are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:37]2[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:14]=[C:13]([CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:12]2[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:11]=2[C:10]=1[C:35]#[N:36].O.C(=O)([O-])[O-:52].[Na+].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([N:37]2[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:14]=[C:13]([CH2:15][C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])[C:12]2[N:24]=[CH:25][NH:26][C:11]=2[C:10]=1[C:35]([NH2:36])=[O:52]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Cc4c(Cl)cccc4Cl)c4ncn(COCC[Si](C)(C)C)c4c3C#N)c(Cl)c2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Nc2ccc(N3CCNCC3)cc2Cl)nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c12
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To the product of Example 42E (200 mg, 0.27 mmol) in concentrated sulfuric acid (4 mL) at 0° C. was added water (0.4 mL) and the mixture was stirred at 0° C. for 10 minutes and at 80° C. for 40 minutes. After cooling to ambient temperature, the mixture was poured into ice-water, adjusted to pH 9 by saturated aqueous sodium carbonate and extracted with dichloromethane. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 13.66 (s, 1H), 11.86 (s, 1H), 9.58 (s, 1H), 8.76 (brs, 2H), 8.63 (s, 1H), 7.83-7.78 (m, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.49-7.43 (m, 2H), 7.01 (d, J=2.4 Hz, 1H), 6.43 (dd, J=9.0, 2.4 Hz, 1H), 4.73 (s, 2H), 3.27 (s, 8H). MS: 530 (M+H+).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:54][C:55]([CH3:60])([CH3:59])[CH2:56][CH2:57][NH2:58]>C1COCC1.CO.O>[CH3:54][C:55]([CH3:60])([CH3:59])[CH2:56][CH2:57][NH:58][C:13](=[O:15])[C:12]1[CH:17]=[CH:18][C:9]([CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10][CH:11]=1
Reactant: CC(C)(C)CCN
Reactant: COC(=O)c1ccc(COc2ccccc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCNC(=O)c1ccc(COc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ester 1.2a (800 mg, 3.29 mmol) in THF (16 ml) and MeOH (4 mL) was added a solution of LiOH (316 mg, 13.2 mmol) in water (4 mL) and stirred at room temperature for 4 h. The reaction was quenched upon addition of 1 N HCl (12 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over MgSO4 and concentrated under vacuum. The residue was dissolved in DMF (24 mL) and DIPEA (1.22 mL, 6.80 mmol) and HATU (1.29 g, 3.40) added sequentially. The solution was placed into multiple vials and reacted with 3,3-dimethylbutylamine (0.18 mmol) and allowed to stir at rt for 20 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (2×3 mL). The combined organic extracts were dried, concentrated and purified by mass-directed prep reverse-phase HPLC: 1H-NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.04 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.36-7.26 (m, 2H), 7.06-6.97 (m, 3H), 6.24 (s, 1H), 5.30 (s, 2H), 3.58-3.50 (m, 2H), 1.81-1.75 (m, 1H), 1.59-1.49 (m, 2H), 0.99 (d, J=7.0 Hz, 6H); LC-MS (214 nm) >98%, 313.2 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25](OCC)=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:31][C@H:32]([CH3:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25]([NH:31][C@H:32]([CH3:35])[CH2:33][OH:34])=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 95 %

Procedure:
In a manner similar to that described in example 571, from from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (38 mg, 0.089 mmol) and (2R)-2-amino-1-propanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (40 mg, 95% yield) as a white solid. Analytical data was identical to example 571.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]([C:16](N1C(C)C(C2C=CC=CC=2)OC1=O)=[O:17])[CH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-:33].OO>>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([CH2:9][C:10]([CH3:14])([CH3:15])[CH2:11][CH2:12][CH3:13])[C:16]([OH:17])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(C)(C)CC(CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC(c2ccccc2)C1C
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Product: CCCC(C)(C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Yield: 112.5 %

Procedure:
According to example 1, 3.4 g (7.9 mmol) of 5,5-dimethyl-3-(4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoic acid tert-butyl ester, 16 mL (12.8 mmol) of 0.8N LiOH and 4.5 mL of 30% H2O2 gave 2.42 g (>100%) of the title compound as an oil. 1HNMR (400 MHz; CDCl3): 0.77–0.82 (m, 9H), 1.14–1.29 (m, 5H), 1.42 (s, 9H), 1.77 (dd, 1H, J=8 Hz, 16 Hz), 2.36 (dd, 1H, J=6 Hz, 16 Hz), 2.59 (dd, 1H, J=8 Hz, 16 Hz), 2.75–2.85 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]1=O.Cl>C1COCC1.CO>[CH3:3][C:4]1[CH2:12][C:11]2[C:6]([CH:5]=1)=[C:7]([C:13]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=1)[CH:8]=[CH:9][CH:10]=2
Reactant: CC1Cc2cccc(-c3cccc4ccccc34)c2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2c(cccc2-c2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.3 g (33 mmol) of sodium borohydride were added at 0° C. to a solution of 12 g (44 mmol) of (16) in 100 ml of THF/methanol 2:1 and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured onto 100 g of ice, concentrated hydrochloric acid was added until the pH was 1 and the mixture as extracted a number of times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The crude product was taken up in 200 ml of toluene, admixed with 0.5 g of p-toluenesulfonic acid and refluxed for 2 hours on a water separator. The reaction mixture was washed 3 times with 509 ml each time of saturated sodium hydrogen carbonate solution and the solvent was removed under reduced pressure. The solid residue was washed with a little pentane and dried under reduced pressure. This gave 10.3 g of (37) in the form of colorless crystals. m.p. 143° C.; 1H-NMR (300 MHz, CDCl3): 7.92-7.18 (10H), 6.11 (m, 1H), 3.42 (s, 2H), 2.07 (3H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:20]([O:22]C(C)(C)C)=[O:21])[CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NCC1CCN(CC2(C(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclopropanecarboxylate (211 mg, 0.57 mmol, step 2 of Example 3) was dissolved in 10% HCl in dioxane (5 mL) and the mixture was stirred for 4 h at room temperature. Resultant brown suspension was concentrated to give 150 mg (quant.) of the title compound as a pale brown solid. This was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[C:23]([F:26])([F:25])[F:24])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:58][C:59]1[CH:70]=[CH:69][C:62]2[NH:63][C:64]([C@@H:66]([NH2:68])[CH3:67])=[N:65][C:61]=2[CH:60]=1.ClCl>CS(C)=O.ClCCl.CO>[Cl:58][C:59]1[CH:70]=[CH:69][C:62]2[NH:63][C:64]([C@@H:66]([NH:68][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([N:6]4[C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[CH:13]=[C:5]4[CH2:4][N:2]([CH3:3])[CH3:1])=[C:15]([C:23]([F:25])([F:26])[F:24])[CH:16]=3)[CH3:67])=[N:65][C:61]=2[CH:60]=1
Reactant: CN(C)Cc1cc2ccccc2n1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc(-n2c(CN(C)C)cc3ccccc32)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 37 %

Procedure:
Prepared analogously to Example 1g from 4-(2-dimethylaminomethyl-indol-1-yl)-3-trifluoromethylbenzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylsulfoxide. Yield: 37%; Rf value: 0.36 (silica gel: dichloromethane/methanol=10:1); C28H25ClF3N5O (539.987); mass spectrum: (M+H)+=540/542 (chlorine isotope).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]1=[O:25].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([NH:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[N:4]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:3]1=[O:25])(=[O:35])=[O:34]
Reactant: COc1ccc(CCN2C(=O)N(N)C[C@H]2c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CCN2C(=O)N(NS(C)(=O)=O)C[C@H]2c2ccc(OC)cc2)cc1
Reaction time: 2.5 h
Yield: 75 %

Procedure:
A solution of 1-amino-3-[2-(4-methoxyphenyl)-ethyl]-4-(R)-(4-methoxyphenyl)-2-imidazolidinone (247 g, 0.72 mol) in dichloromethane (2.35 L) and pyridine (174 mL, 2.15 mol) is cooled in an ice bath to 18° C. Methanesulfonyl chloride (73 mL, 0.94 mol) is added dropwise. The reaction is stirred cold for 2.5 hours then washed with 0.5 N HCl (2×1.5 L), brine (2×1.5 L) and dried (Na2SO4). The solvent is then removed in vacuo to afford a mixture of the desired product (75%) and unreacted starting material (25%) which is separated by liquid chromatography. [α]20D −39.83 (c 0.89, CHCl3) 1H NMR (300 MHz, CDCl3) δ 7.16 (d, J=8.81, 2H, ArH), 7.02 (d, J=8.51, 2H, ArH), 6.91 (d, J=8.81, 2H, ArH), 6.80 (d, J=8.81, 2H, ArH), 4.41 (m, 1H), 3.92 (m, 1H), 3.82 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.60-3.72 (m, 1H), 3.30 (m, 1H), 3.03 (s, 3H, CH3), 2.87-2.98 (m, 1H), 2.53-2.79 (m, 3H). MS 418 (MH+). Anal. Calcd. for C21H27N3O4S¼H2O: C, 59.77, H, 6.57; N, 9.96. Found: C, 59.82, H, 6.06; N, 9.85. FAB-HRMS: anal. calcd for C21H27N3O4S: 418.18005. Found: 418.17960.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:33])[CH:12]([NH:13][C:14](=[O:32])[CH:15]([C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)[NH:16]C(OC(C)(C)C)=O)[C@H:4]2[S:3]1>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:33])[CH:12]([NH:13][C:14](=[O:32])[CH:15]([C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)[NH2:16])[C@H:4]2[S:3]1
Reactant: CSc1ccc(C(NC(=O)OC(C)(C)C)C(=O)NC2C(=O)N3C(C(=O)O)=CC(C)S[C@H]23)cc1
Solvent: O=CO
Product: CSc1ccc(C(N)C(=O)NC2C(=O)N3C(C(=O)O)=CC(C)S[C@H]23)cc1
Yield: 50.2 %

Procedure:
A solution of 2-methyl-7-[N-(tert.-butoxycarbonyl)-2-(4-methylthiophenyl)glycyl]amino-3-cephem-4-carboxylic acid (3.0 g) in formic acid (100 ml) was stirred for 1 hour under anhydrous condition at room temperature. After the reaction was completed, the solvent was removed from the reaction mixture under reduced pressure, and the residue was dissolved in a mixture of water and ethyl acetate, after which the aqueous layer was separated. The aqueous layer was washed with ethyl acetate, and the organic solvent was completely removed under reduced pressure. The insoluble material was collected by filtration and lyophilized to give white powder of 2-methyl-7-[2-(4-methylthiophenyl)glycyl]amino-3-cephem-4-carboxylic acid (1.2 g), mp 165° to 175° C.
Reaction SMILES: [CH3:1][C:2]12[CH2:7][CH:6]1[CH2:5][CH:4]([CH2:8][CH:9]=O)[C:3]2([CH3:12])[CH3:11].[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16].[O-]CC.[Na+].[Na]>C(O)C>[CH2:15]([C:14](=[CH:9][CH2:8][CH:4]1[CH2:5][CH:6]2[C:2]([CH3:1])([CH2:7]2)[C:3]1([CH3:12])[CH3:11])[CH:13]=[O:17])[CH3:16]
Reactant: CCCC=O
Reactant: CC1(C)C(CC=O)CC2CC21C
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCC(C=O)=CCC1CC2CC2(C)C1(C)C
Yield: 37.7 %

Procedure:
The condensation of 20.0 g (0.12 mol) of (1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanal with 17.0 g (0.24 mol) of butyraldehyde catalyzed with sodium ethoxide prepared from 0.25 g of sodium in 35 ml of ethanol, according to Example 15, gave 9.98 g (38% yield) of 2-ethyl-4-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)but-2-enal.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([CH:18]=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1.CC(C)=[O:22].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O>CC(C)=O.O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([C:18]([OH:22])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(C)=O
Reactant: COCCOc1ccc(-c2ccccc2C=O)cc1
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Product: COCCOc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 4′-(2-methoxyethoxy)-1,1′-biphenyl-2-carbaldehyde from step b (3.691 g; 14.4 mmol) is dissolved in 45 ml of acetone, the mixture is cooled to 0° C. and 10.85 ml of Jones' reagent (solution of 3.5 g of chromium trioxide in a solution of 3.16 ml of sulfuric acid in 10 ml of water) are then added dropwise. After 1 hour at 0° C., the reaction medium is allowed to cool to room temperature over 8 hours. The reaction medium is evaporated to dryness, taken up in ether and filtered through silica. The organic phase is extracted with aqueous 1N sodium hydroxide solution, and the aqueous phase is then acidified with 1N hydrochloric acid and extracted with DCM. The organic phase is dried over sodium sulfate and evaporated to dryness to give 2.75 g of the expected product in the form of an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K+].[Cl:12][C:13]1[CH:14]=[C:15]([S:19]([NH-:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>CN1CCCC1=O>[Cl:12][C:13]1[CH:14]=[C:15]([S:19]([NH:22][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=2)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: [NH-]S(=O)(=O)c1cccc(Cl)c1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2cccc(Cl)c2)n1
Yield: 53.4 %

Procedure:
0.24 g (0.00135 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and 0.62 g (0.0027 mol) of 3-chloro-benzenesulfonamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 150° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was made acid with 4N HCl and extracted with dichloromethane. The residue was chromatographed over silica gel with cyclohexane/ethyl acetate 2:1 as the eluent. There was obtained 0.24 g (53%) of 3-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as yellow crystals; m.p. 120-130° C. (dec.).