Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[C:10]([CH:26]=[O:27])[CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][CH2:16]2)[CH:8]=1)[CH3:5].[BH4-].[Na+]>O>[CH2:4]([O:6][C:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[C:10]([CH2:26][OH:27])[CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][CH2:16]2)[CH:8]=1)[CH3:5]
Reactant: CCOC1=CC2=C(C=O)C[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC1=CC2=C(CO)C[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In 30 ml. of ethanol are dissolved 1 g. of 3-ethoxy-6-formylandrosta-3,5-diene according to reaction (2), and while the solution is stirred at room temperature, 0.1 g. of sodium borohydride is added. After 20 minutes, the reaction mixture is poured into water and extracted with ether. Then, the extract is washed with water and dried with anhydrous sodium sulfate. Finally the solvent is concentrated, whereupon 1 g. of 3-ethoxy-6-hydroxymethylandrosta-3,5-diene is obtained as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19]O)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:22]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][Br:22])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc2cc(OCc3ccccc3)ccc2c1
Solvent: ClCCl
Product: BrCc1ccc2cc(OCc3ccccc3)ccc2c1
Reaction time: 24 h

Procedure:
To a solution of (6-benzyloxy-naphthalen-2-yl)-methanol (17) (1 equi.) in CH2Cl2 (4 mL/mmole), a solution of phosphorus tribromide (4 mL/mmole), (0.4 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with dichloromethane, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (dichloromethane) and recrystallization from acetonitrile afforded 2-benzyloxy-6-bromomethyl-naphthalene (18) a white solid (92%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][C@@H:13]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[NH:12][CH2:11][C@@H:10]2[O:27][CH:28]([C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:43]=3[CH:53]=2)[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:5][CH:4]=1.[CH3:54][O:55][CH2:56][C@H:57]([CH3:60])[CH2:58][OH:59].[H-].[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C=O)C.O>[CH3:54][O:55][CH2:56][C@H:57]([CH3:60])[CH2:58][O:59][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][C@@H:13]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[NH:12][CH2:11][C@@H:10]2[O:27][CH:28]([C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:43]=3[CH:53]=2)[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(C(O[C@H]3CN[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)C[C@@H]3c3ccc(CCl)cc3)S(=O)(=O)c3ccc(C)cc3)cc21
Reactant: COC[C@H](C)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCN1CCOc2ccc(C(O[C@H]3CN[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)S(=O)(=O)c3ccc(C)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0 mmol of 6-[(3R,4R,6S)-4-(4-chloromethyl-phenyl)-1-(toluene-4-sulfonyl)-6-triisopropylsilanyloxymethyl-piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine, 1.5 mmol of (R)-3-methoxy-2-methyl-propan-1-ol [911855-78-2] and 0.1 mmol of TBAI in 5 ml of DMF are added 1.65 mmol of NaH (55% in dispersion oil) at 0° C. The reaction mixture is allowed to warm to RT and stirred overnight, diluted with water, extracted with TBME and the organic phase is dried over Na2SO4. The organic phase is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a pale yellow oil. Rf=0.20 (EtOAc/heptane 1:2).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]2[CH2:39][NH:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:25])=[CH:19][CH:18]=1>CO>[ClH:1].[ClH:1].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH:27]2[CH2:39][NH:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:25])=[CH:21][CH:22]=1
Reactant: COc1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2CNc2cccnc2)cc1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)N2CCNCC2CNc2cccnc2)cc1
Reaction time: 1 h
Yield: 82 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4-methoxyphenylcarbamoyl)-3-((pyridin-3-ylamino)methyl)piperazine-1-carboxylate TFA salt (81.7 mg, 0.147 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated under reduced pressure to give 49.9 mg (82%) of the title compound as a white solid. LC-MS: RT=1.95 min, [M+H]+=342.1.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: Oc1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(Oc2ccccc2)cccc1[N+](=O)[O-]
Yield: 76.9 %

Procedure:
A solution of 2,6-dinitrobenzonitrile (2.0 g, 10.5 mmol), phenol (1.42 g, 15.1 mmol) and K2CO3 (1.45 g, 10.5 mmol) in DMF (20 mL) was stirred at rt under N2 for 4.5 hours. Upon completion, the reaction was diluted with EtOAc (100 mL), washed with H2O, dried over MgSO4, filtered and concentrated. The residue was recrystallized from Hexane/EtOAc to provide 2-nitro-6-phenoxybenzonitrile (1.94 g, 77%). 1H NMR (400 MHz, MeOD) δ 7.20 (m, 2H), 7.28 (dd, J=8.6, 1.1 Hz, 1H), 7.34 (m, 1H), 7.51 (m, 2H), 7.78 (t, J=8.7 Hz, 1H), 8.05 (dd, J=8.2, 0.8 Hz, 1H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl>[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44]([O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](OCCOCCOCCOCCO)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.2 %

Procedure:
To a solution of 10 (1.06 g, 2.46 mmol) in 30 mL of CH2Cl2 was added triethylamine (0.62 mL, 4.45 mmol). 4-Toluenesulfonyl chloride (TsCl, 567 mg, 2.97 mmol) was added to this solution in one portion at 0° C., and the mixture was stirred at under Ar for 24 h allowing it to warm to room temperature slowly. The reaction was quenched by pouring into a mixture of water (100 mL) and chloroform (70 mL), separated organic layer, and the aqueous layer was further extracted with chloroform (100 mL). The combined organic layers were dried over sodium sulfate (Na2SO4) and concentrated. The crude product was chromatographed (SiO2, gradient, hexane/EtOAc 5:1 to 2:1) to give 1.08 g (1.85 mmol, 75%) of 11 as a clear colorless oil. Rf 0.65 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) 7.79 (d, 2H, J=8.3 Hz, H-2 of tosyl), 7.68 (m, 4H, H-2 of phenyl), 7.44-7.35 (m, 6H, H-3 and H-4 of phenyl), 7.32 (d, 2H, J=8.7 Hz, H-3 of tosyl), 4.14 (t, 2H, J=4.9 Hz, TsOCH2CH2), 3.80 (t, 2H, J=5.3 Hz, CH2OSi), 3.66 (t, 2H, J=4.9 Hz, TsOCH2CH2), 3.64-3.54 (m, 10H, (OCH2CH2)2OCH2CH2OSi), 2.43 (s, 3H, CH3 of tosyl), 1.04 (s, 9H, C(CH3)3); MS (ESI) Calcd for C31H42O7SSiNa (M+Na+): 609.2. Found: 609.2.
Reaction SMILES: [N:1]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:5][CH2:4][CH:3]([C:6]([O:8]C(C)(C)C)=[O:7])[N:2]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O>ClCCl>[C:24]1([CH2:23][O:22][C:20]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[NH:2]2)=[O:21])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
1-Benzyl 2,3-di-tert-butyl pyrazolidine-1,2,3-tricarboxylate (14.15 g, 34.8 mmol) was dissolved in dichloromethane (68.6 ml) under N2 at room temperature. TFA (80 ml, 1045 mmol) and water (9.41 ml, 522 mmol) were then added in one portion. The reaction was stirred at 25° C. for 2 days. The solvent was then removed under reduced pressure to give 1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (8.72 g, 34.8 mmol, 100% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13](I)[N:14]=[C:7]3[C:6]=2[CH:16]=1.C[Si](N[Si](C)(C)C)(C)C.C[N:28](C)[CH:29]=[O:30]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:29]([NH2:28])=[O:30])[N:14]=[C:7]3[C:6]=2[CH:16]=1
Reactant: Fc1cc2c(cc1Br)-c1nc(I)cn1CCO2
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Temperature: 70 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Similar to as described in Example 10, A suspension of 10-bromo-9-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (16.0 g, 39.12 mmol, 1.00 equiv)(US2012/245144A1), HMDS (19.3 g, 119.88 mmol, 3.06 equiv) and Pd(dppf)Cl2 CH2Cl2 (1.6 g, 1.95 mmol, 0.05 equiv) in N,N-dimethylformamide (240 mL) was stirred for 2 h at 70° C. under a carbon monoxide atmosphere (1 atm). After cooling to room temperature the reaction was quenched by addition of methanol (5 mL), diluted by ethyl acetate (1 L), washed with water (200×4 mL) and brine (200 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was further purified by FC(Silica and ethyl acetate/petroether 2:1) to give 7.0 g (55%) of the titled compound as a grey solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.O>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:3][CH2:2][CH2:1][OH:4])=[CH:10][CH:11]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCCOCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 47.8 %

Procedure:
Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol, 95% in oil) in THF (3 mL). 1-(Bromomethyl)-4-fluorobenzene (0.19 mL, 1.5 mmol) was added to the reaction, and the residual 1-(bromomethyl)-4-fluorobenzene was transferred to the reaction tube with additional THF (1 mL). (Bu)4NI (55 mg, 0.15 mmol) was added, and the reaction was heated at 60° C. for 18 h and then rt for 4 h. H2O (2 mL) and EtOAc (2 mL) were added, and the layers were separated via pipette. The aqueous layer was extracted with EtOAc (1×1 mL), and the combined organic layers were concentrated. The crude product was purified on a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: 30% EtOAc/hexanes (fractions 1,2), 50% EtOAc/hexanes (fraction 3), and 75% EtOAc/hexanes (fraction 4) to give the title compound (122 mg, 48%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[Br:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:39][C:38]1[CH:42]=[CH:43][C:35]([Br:34])=[CH:36][CH:37]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Br)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)cc3)c3c(Br)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The titled compound was prepared from 4-bromo-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 22-(1) and 4-bromobenzoyl chloride in a manner similar to Example 3 as a colorless powder. APCI-Mass m/Z 526/528/530 (M+H). 1H-NMR (DMSO-d6) δ 3.20-3.48 (m, 4H), 3.66 (m, 2H), 4.27 (s, 2H), 4.54 (t, J=5.4 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 5.17 (d, J=5.0 Hz, 1H), 5.23 (d, J=5.8 Hz, 1H), 5.41 (d, J=9.0 Hz, 1H), 7.04 (t, J=7.9 Hz, 1H), 7.16 (d, J=8.3 Hz, 2H), 7.21 (d, J=7.5 Hz, 1H), 7.33 (s, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.2 Hz, 1H).
Reaction SMILES: [NH3:1].[C:2]([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[OH:26])[O:9][CH2:10][CH:11]([NH:13][CH2:14][CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:12])(OC)=[O:3]>O1CCOCC1>[C:2]([C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[OH:26])[O:9][CH2:10][CH:11]([NH:13][CH2:14][CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:12])(=[O:3])[NH2:1]
Reactant: N
Reactant: COC(=O)c1cc(OCC(C)NCC(O)c2ccccc2)ccc1O
Solvent: C1COCCO1
Product: CC(COc1ccc(O)c(C(N)=O)c1)NCC(O)c1ccccc1
Reaction time: 65 h

Procedure:
20 ml of concentrated ammonia solution are added to a solution of 1.7 g of crude α-[N-[2-(3-carbomethoxy-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-benzyl alcohol in 10 ml of dioxan and the mixture is left to stand at room temperature for 60-70 hours. The reaction mixture is evaporated, the residue is dissolved in 75 ml of ethyl acetate and the solution is washed with 10 ml of saturated, aqueous sodium chloride solution. Evaporation of the organic phase yields crude α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]aminomethyl]-benzyl alcohol as a mixture of diastereoisomers in the form of an oil and the latter is crystallised from a little ethyl acetate and is identical to the product obtained, for example, in Example 1; melting point 120°-140°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22]([NH:24][C:25](=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:39]=1)OC1C=CC=CC=1)#[N:23]>>[C:22]([NH:24][C:25]([NH:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15])=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]2)[CH:39]=1)#[N:23]
Reactant: CN(CCN)CCC(c1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.7 g (2.4 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine and 0.95 g (2.4 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=586 ([M+H]+, 1), 214 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:25]1[C:50](=[O:51])[N:27]2[C:28]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:29]([CH:32]=[CH2:33])[CH2:30][S:31][C@H:26]12)[C:9](=[O:24])[CH:10]([C:12]1[N:13]=[C:14]([NH:17]C(=O)C(F)(F)F)[S:15][CH:16]=1)[NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+]>O1CCCC1.CC(C)=O.O>[C:1]([O:5][C:6]([N:8]([CH:25]1[C:50](=[O:51])[N:27]2[C:28]([C:34]([O:36][CH:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:35])=[C:29]([CH:32]=[CH2:33])[CH2:30][S:31][C@H:26]12)[C:9](=[O:24])[CH:10]([C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1)[NH2:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N(C(=O)OC(C)(C)C)C(=O)C(N)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N(C(=O)OC(C)(C)C)C(=O)C(N)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture of benzhydryl 7-[N-tert-butoxycarbonyl-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}glycinamido]-3-vinyl-3-cephem-4-carboxylate (2.5 g) and sodium acetate (2.8 g) in tetrahydrofuran (20 ml), acetone (20 ml) and water (40 ml) was stirred at ambient temperature for 2 hours. After the reaction mixture was evaporated, the residue was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to give a residue, which was subjected to column chromatography on silica gel (50 g). Elution was carried out with methylene chloride and then a mixture of methylene chloride and diethyl ether (9:1 by volume), and the fractions containing the desired compound were collected and evaporated to give benzhydryl 7-[N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate (1.0 g).
Reaction SMILES: Cl[C:2]1[C:3]([CH:12]=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[SH:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(OCC)C>CN(C)C=O.ClCCl>[F:11][C:8]([F:9])([F:10])[C:6]1[CH:7]=[C:2]2[S:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][C:3]2=[N:4][CH:5]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1ncc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ncc(C(F)(F)F)cc2s1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
3-Chloro-5-(trifluoromethyl)-2-pyridinecarbaldehyde (Chemical Abstracts number 175277-50-6, purchase from Maybridge), potassium carbonate (4.95 g), and ethyl mercaptoacetate (2.52 g) were combined in N,N-dimethylformamide (25 mL) at 25° C. and stirred for 18 hours. The mixture was then heated at 50° C. for 6 hours, allowed to cool to room temperature, poured into a mixture of diethyl ether (80 mL) and dichloromethane (25 mL), and washed with aqueous sodium carbonate. The organic phase was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered to remove solids. The filtrate was concentrated and the residue purified by flash chromatography (dichloromethane) to provide the title compound. MS (DCI/NH3) m/z 276.0 (M+H)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:25][OH:26])[S:18][C:17]=1[C:28]([NH2:30])=[O:29].[C:31]1(O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:25][O:26][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:18][C:17]=1[C:28]([NH2:30])=[O:29]
Reactant: Oc1ccccc1
Reactant: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccccc2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.8 %

Procedure:
Diisopropyl azodicarboxylate (DIAD) (14 mg, 0.069 mmol) was added to a solution of 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (15 mg, 0.063 mmol), phenol (6 mg, 0.069 mmol), and Ph3P (18 mg, 0.069 mmol) in THF (1.5 mL) at 0° C. The mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was concentrated and fractionated by preparative TLC (10% MeOH/CH2Cl2) providing the title compound (12 mg, 61%) as an orange solid, m.p. 194-196° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([C:19]([NH2:33])([CH2:24][C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:20]([O:22]C)=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:4][C:3]=2[O:2]1.C1OC2C(=CC=C(B(O)O)C=2)O1>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([C:19]([NH2:33])([CH2:24][C:25]#[C:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:20]([OH:22])=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)C(N)(CC#Cc1ccccc1)S(=O)(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1
Agent: OB(O)c1ccc2c(c1)OCO2
Product: NC(CC#Cc1ccccc1)(C(=O)O)S(=O)(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1

Procedure:
Methyl 2-{[3′,4′-Methylenedioxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-amino-5-phenylpent-4-ynoate: The starting sulfonamide 3a (804 mg, 1.72 mmol) and 4-methylenedioxyphenylboronic acid (430 mg, 2.59 mmol) are coupled to give the title compound as described for compound 3b. The crude product is adsorbed onto silica and eluted through flash silica with hexanes:EtOAc (2:1 to 1:3) to give a pale yellow solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:49])[CH:18]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[NH:40][C:39]3=[O:48])[CH2:34][CH2:33]2)=[O:31])[CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][N:24]=[CH:23]3)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C>CO>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([CH2:19][CH:18]([NH:29][C:30]([N:32]3[CH2:33][CH2:34][CH:35]([N:38]4[CH2:47][C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[NH:40][C:39]4=[O:48])[CH2:36][CH2:37]3)=[O:31])[C:17](=[O:49])[N:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: O=C(NC(Cc1ccc2[nH]ncc2c1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Solvent: CO
Product: O=C(NC(Cc1ccc2[nH]ncc2c1)C(=O)N1CCNCC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reaction time: 3 h
Yield: 91 %

Procedure:
To a degassed solution of 4-(3-(1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperazine-1-carboxylic acid benzyl ester (280 mg, 0.42 mmol) in methanol (50 ml) was added 10% palladized charcoal (50 mg). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen at 50 psi for 3 h. The mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the desired product in 91% yield. LC/MS: tR=1.22 min, 531 (MH)+.