Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:28]([OH:30])=[O:29])[CH2:20][NH:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.[Cl:37][C:38]1[CH:46]=[C:45]([C:47]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([OH:57])[CH:52]=2)=[O:48])[CH:44]=[CH:43][C:39]=1[C:40]([OH:42])=O.C1C=NC2N(O)N=NC=2C=1>CN1CCCC1=O>[Cl:37][C:38]1[CH:46]=[C:45]([C:47]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([OH:57])[CH:52]=2)=[O:48])[CH:44]=[CH:43][C:39]=1[C:40]([NH:18][C@H:19]([C:28]([OH:30])=[O:29])[CH2:20][NH:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[O:42]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C=CCOC(=O)NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: On1nnc2cccnc21
Solvent: C1CCNCC1
Solvent: CN1CCCC1=O
Product: C=CCOC(=O)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A150 mL cylidrical glass vessel equipped with a coarse glass frit was charged with N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-[(2-propenyloxy)carbonyl]amino-L-alanine resin (Example 64; 5 g) and 25% piperidine in N-methylpyrrolidinone (50 mL). The mixture was agitated at room temperature for 30 min. The resin was filtered and treated again with fresh 25% piperidine in N-methylpyrrolidinone (50 mL) at room temperature for 30 min. After filtration, the resin was washed with dichloromethane and methanol. To the resin was added a solution prepared from 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 26; 2.5 g, 8.2 mmol), HOAT (3.7 g, 27.2 mmol) and DICI (4.3 mL, 27.5 mmol) in N-methylpyrrolidinone (50 mL). The reaction mixture was agitated at room temperature for 1 h, and then filtered. The resin was washed with dichloromethane and methanol, and dried under vacuum to afford resin-bound N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(2-propenyioxy) carbonyl]amino-L-alanine.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:23]([NH:25][C@H:26]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:30][CH:29]=2)[CH3:27])=[O:24])[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:13][CH:14]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:23]([NH:25][C@H:26]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:39][CH:40]=2)[CH3:27])=[O:24])[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:13][CH:14]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl 4-[(1S)-1-({[5-Chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoate (step 4, 2.1 g; 4.3 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature until the starting material was fully consumed (4 h). The solvent and most of the trifluoroacetic acid were removed under reduced pressure. The residue was purified by flush silica gel column chromatography on silica gel (50 g) eluting with dichloromethane/methanol (20/1) and recrystallization (ethyl acetate-diisopropyl ether) to give 1.24 g, (86%) of the title compounds as white crystals: mp 198.2° C.;
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[C:12]([NH:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)=[O:24])[CH:18]=[CH:19][C:20]=1[CH3:21])=[O:13].[CH3:40][N:41]1[CH2:47][CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>O>[CH3:40][N:41]1[CH2:47][CH2:46][CH2:45][N:44]([CH2:8][C:9]2[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=2)[C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[CH3:21])=[O:13])[CH2:43][CH2:42]1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CCl)c1
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CN2CCCN(C)CC2)c1
Temperature: 80 °C

Procedure:
Potassium carbonate (0.138 g) was added to a mixture of N-[3-(3-chloromethylbenzamido)-4-methylphenyl]-2-morpholinopyridine-4-carboxamide (0.232 g) and 1-methylhomopiperazine (1 ml) and the mixture was stirred and heated to 80° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature and water (25 ml) was added. The resultant solid was isolated, washed with water and dried under vacuum at 55° C. There was thus obtained the title compound (0.176 g); NMR Spectrum: (DMSOd6) 1.72 (m, 2H), 2.21 (s, 3H), 2.24 (s, 3H), 2.6 (m, 8H), 3.53 (m, 4H), 3.67 (s, 2H), 3.74 (m, 4H), 7.1 (d, 1H), 7.23 (m, 2H), 7.51 (m, 3H), 7.8 (s, 1H), 7.84 (d, 1H), 7.9 (s, 1H), 8.25 (d, 1H), 9.86 (s, 1H), 10.28 (s, 1H): Mass Spectrum: M+H 543.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.Cl.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24]Cl)[CH:19]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>O.CO>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([S:9][CH2:24][C:20]3[CH:19]=[C:18]([O:17][CH2:16][CH:13]4[CH2:15][CH2:14]4)[CH:23]=[CH:22][N:21]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2[nH]c(S)nc2c1
Reactant: ClCc1cc(OCC2CC2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc2[nH]c(SCc3cc(OCC4CC4)ccn3)nc2c1
Yield: 82.5 %

Procedure:
To 5-fluoro-2-mercapto-1H-benzimidazole (0.88 g, 0.0051 mol) in methanol (25 ml) NaOH (0.2 g, 0.0051 mol) dissolved in H2O (1 ml) and 4-cyclopropylmethoxy-2-chloromethylpyridine hydrochloride (0.91 g, 0.0046 mol) dissolved in methanol (10 ml) were added in the given order. The mixture was heated to boiling and NaOH (0.2 g, 0.005 mol) dissolved in H2O (1 ml) was added and the mixture was refluxed for 1 hour. After evaporation of methanol, CH2Cl2 (75 ml) and H2O (50 ml) were added and pH adjusted to 10. The mixture was vigorously stirred, the phases were separated, the organic phase was dried over Na2SO4 and evaporated giving the desired product (1.25 g, 72%). NMR data for the product is given below.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]([F:36])[F:35])=[N:32][CH:33]=1>C(#N)C.O>[F:35][CH:34]([F:36])[C:31]1[N:32]=[CH:33][C:28]([CH2:27][O:1][C:2]2[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=2[O:17][CH3:18])=[CH:29][CH:30]=1
Reactant: FC(F)c1ccc(CCl)cn1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate (4.70 g, 18.56 mmol) and potassium carbonate (7.64 g, 55.28 mmol) in acetonitrile (50 mL) was added 5-(chloromethyl)-2-(difluoromethyl)pyridine hydrochloride (4.58 g, 21.40 mmol). The mixture was heated to reflux. After 3 h, the off-white suspension was allowed to cool to room temperature and was diluted with water (200 mL). The mixture was extracted with dichloromethane (3×75 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 7.74 g (>100%) of tert-butyl 4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzylcarbamate as a waxy yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[C:13]([Cl:25])[CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:26]3[CH2:31][CH2:30][C@H:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:28][CH2:27]3)[N:9]=2)=[CH:12][C:13]=1[Cl:25]
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NC(=O)OC(C)(C)C)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(N)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate (1.993 g, 0.00368 mol) was added to a solution of 20% trifluoracetic acid in dichloromethane. The mixture was stirred for 2 hours at ambient temperature. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (50 mL) and washed with 1.0 M aqueous sodium hydroxide (2×25 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give trans 3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.564 g, 0.00355 mol) as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>C1COCC1>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCCO
Solvent: C1CCOC1
Product: N#Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Yield: 101 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzonitrile (10 g, 0.06 mol) in THF (50 mL) was added in portions, via syringe, 3-aminopropanol (5 mL, 0.07 mol) and the mixture was stirred at room temperature. After one hour of reaction the crude mixture was evaporated to dryness and AcOEt was added (300 mL). The organic layer was washed with aqueous sodium bicarbonate (250 mL of a 4% aqueous solution) and the aqueous phase was further extracted with AcOEt (2×100 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the title compound as an orange solid (13.4 g, 99% yield) which was used in the next step without further purification.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](Cl)([Cl:13])=[O:12]>C1C=CC=CC=1>[C:1]1([S:7][CH2:8][CH2:9][O:10][C:11]([Cl:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCSc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)OCCSc1ccccc1

Procedure:
A solution of 2-phenylthioethanol (3 g, 19 mmol) in benzene (5 mL) was added dropwise, at room temperature, to a solution of phosgene (1 mL, 1.9 M toluene, 1.9 mmol). After stirring for 3 h the excess phosgene and solvents were removed under vacuum to give 2-phenylthioethyl-chloroformate as a yellow oil which was used without further purification. A solution of alcohol 24 (27 mg, 45 μmol) and DMAP (38 mg, 0.31 mmol)in CH2Cl2 (5 mL) was treated, at 0° C., with 2-phenylthioethyl-chloroformate (38 mg, 0.18 mmol) and the mixture was stirred for 4 h. The reaction mixture was poured into brine (10 mL), extracted with CH2Cl2 (3×5 mL), dried (Na2SO4), concentrated, and purified by preparative TLC (20% EtOAc in benzene) to give carbonate 26 (30.7 mg, 88%):pale yellow oil; Rf =0.69 (20% EtOAc in benzene); [α]25D -150 (c0.20, CH2Cl2); IR (neat) νmax 2954, 2876, 1738, 1721, 1492, 1458, 1257, 1164 cm-1 ; 1H NMR (500 MHz, CDCl3) 7.41-7.40 (m, 2 H, Ph), 7.40-7.27 (m, 2 H, Ph), 7.26-7.19 (m, 1 H, Ph), 6.10 (rid, J=3.27, 9.02 Hz, 1 H, C=CHCH2), 5.87 (d, J=9.71 Hz, 1 H, CH=CHC≡CCH), 5.77 (b d, J=9.71 Hz, 1 H, CH=CHC≡CCH), 5.77 (b s, 1 H, CHOSi), 4.88 (dd, J=3.33, 13.52 Hz, 1 H, CHHOCO), 4.79 (dd, J=9.04, 13.54 Hz, 1 H, CHHOCO), 4.28-4.23 (m, 2 H, OCOCH2CH2SPh), 4.10-4.07 (m, 1 H, ehtylene ketal), 3.99-3.91 (m, 2 H, ethylene ketal), 3.88-3.84 (m, 1 H, ethylene ketal), 3.18 (dd, J=7.23, 7.40 Hz, 2 H, OCOCH2CH2SPh), 2.48 (d, J=13.24 Hz, 1 H, CHH-eq), 2.11 (d, J=13.25 Hz, 1 H, CHH-ax), 1.00-0.96 (m, 18 H, 2 x (Si(CH2CH3)3)), 0.79-0.67 (m, 12 H, 2 x (Si(CH2CH3)3)); 13C NMR (125 MHz, CDCl3) δ154.70, 138.17, 129.81, 129.07, 126.58, 124.11, 122.91, 122.46, 105.72, 68.04, 65.75, 65.52, 65.22, 63.71, 52.34, 31.95, 29.70, 7.07, 6.72, 6.16, 4.53; FAB HRMS (NBA/Csl) m/e 914.2180, (M+Cs+) calcd for C40H55NO9SSi:914.2190.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[C:20](O)=[O:21].Cl.[CH2:24]([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29])[CH3:25]>>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([C:20]([NH:29][C@H:28]([C:27]([O:26][CH2:24][CH3:25])=[O:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:21])=[C:4]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cn1c(C(=O)O)c(-c2ccccc2)c2cc([N+](=O)[O-])ccc21
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C

Procedure:
Ethyl N-[(5-amino-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-phenylalaninate was prepared from 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylic acid and L-phenylalanine ethyl ester hydrochloride followed the procedure of Example 8 Step 2 as a pale yellow solid: MS (ESI) m/z 442 (MH+); HRMS calcd for C27H28N3O3: 442.2128; found (ESI+): 442.2122.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+]>[CH2:21]([O:20][C:18]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]1[C:14]([OH:16])=[O:15])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
0.1 g of 4-(tert.butoxycarbonyl)-piperazine- 2-carboxylic acid was dissolved in 10 ml of 1N sodium hydroxide solution, cooled to 0° C. and treated with 0.2 g of benzyl chloroformate. The mixture was allowed to warm to room temperature and was then stirred overnight. The mixture was extracted with diethyl ether. The aqueous phase was then acidified to pH 4 with 2M hydrochloric acid and extracted with ethyl acetate to give 0.06 g of 1-(benzyloxycarbonyl)-4-(tert.butoxycarbonyl)-2-piperazinecarboxylic acid as a white solid; MS: m/e 365 [M+H]+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]1([O:17][C:7](=[O:8])[C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 23.19 g (0.15 mol) of m-toluoyl chloride in 70 mL of methylene chloride was added dropwise to a solution containing 14.12 g (0.15 mol) of phenol and 16.7 g (0.165 mol) of triethylamine in 70 mL of methylene chloride at ice bath temperature. A precipitate formed upon addition. The reaction mixture was stirred overnight at room temperature and was then filtered. The filtrate was washed successively by water (100 mL) and then by brine (75 mL) The organic layer was removed and dried over magnesium sulfate, filtered and evaporated in a rotary evaporator. The clear liquid product amounted to 29.91 g.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[N:15]1([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28]([CH:33]=O)=[CH:27]3)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.N1CCCCC1>C(O)C>[N:15]1([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28]([CH:33]=[C:10]2[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=4)[NH:3][C:2]2=[O:1])=[CH:27]3)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCOCC4)ccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 73.7 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide (27 mg, 0.12 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (30 mg, 0.11 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 90° C. for 2 hours. The reaction was cooled at 0° C. for overnight. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 38 mg (62%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH3:15])[CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH3:15])=[O:28])=[CH:25][N:24]=1
Reactant: Cc1cccnc1CN(CCCN)C(C)c1ccccn1
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(CCCNC(=O)c1ccc(O)nc1)C(C)c1ccccn1
Yield: 37.6 %

Procedure:
Using General Procedure G: To a solution of N-(3-Methyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-propane-1,3-diamine (0.33 g, 1.16 mmol) in dry DMF (3 mL) was added 6-hydroxy-nicotinic acid (0.174 g, 1.24 mmol) followed by EDCI (0.257 g, 1.34 mmol), HOBT (0.183 g, 1.35 mmol), and DIPEA (0.40 mL, 2.30 mmol). Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 177 mg (38%) of the free base of the title compound as a colorless oil. Conversion to the HBr salt gave COMPOUND 241 (270 mg, 83%) as a white solid. 1H NMR (D2O) δ 1.55 (d, 3H, J=6.6 Hz), 1.67 (quintet; 2H, J=7.2 Hz), 2.43 (s, 3H), 2.48-2.58 (m, 1H), 2.63-2.74 (m, 1H), 3.12-3.31 (m, 2H), 4.28 (s, 2H), 456 (q, 1H, J=6.6 Hz), 6.61 (d, 1H, J=9.3 Hz), 7.78-7.83 (m, 2H), 7.89-7.94 (m, 2H), 8.11 (d, 1H, J=8.1 Hz), 8.30 (d, 1H, J=8.1 Hz), 8.49-8.58 (m, 2H), 8.74 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 15.07, 16.98, 26.37, 37.59, 50.21, 50.95, 59.83, 115.31, 119.32, 125.82, 126.75, 126.83, 137.21, 137.53, 138.40, 140.83, 142.09, 148.06, 148.24, 152.11, 156.20, 165.43, 166.77; ES-MS m/z 406 (M+H). Anal. Calcd. for C23H27N5O2.3.3HBr.4.2H2O: C, 36.92; H, 5.21; N, 9.36; Br, 35.24. Found: C, 36.85; H, 5.39; N, 9.04; Br, 35.63.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:13].[Na+]>C(O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][OH:13])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(CO)c1ccc(F)cc1

Procedure:
2 g of 2-bromo-1-(4-fluorophenyl)ethanone, and 6 eq of sodium formate in 15 mL of Ethanol/Water are irradiated under microwave for 5 min at 150° C., 11 bars. After filtration and evaporation of ethanol, water is added. The expected product is isolated by filtration
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]>Cl>[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCCCCCl
Reactant: C1=COCCC1
Agent: Cl
Product: ClCCCCOC1CCCCO1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Dihydropyran (15.5 g) was added dropwise to a mixture of 4-chlorobutanol (20 g) and hydrochloric acid (18 M, 1 drop) at RT. The mixture was stirred for 30 min and washed with H2O (100 ml), aqueous NaHCO3 (1 M, 50 ml) and BR (50 ml). The dried liquid was heated under reduced pressure to leave the title compound as a colourless liquid (31.9 g). T.l.c. [L] Rf 0.5.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:34][C:28]1[CH:33]=[CH:32][C:31]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@H:9]3[S:8][CH:7]=2)=[CH:30][CH:29]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccc(O)cc3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
1.95 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid are dissolved in a solution of 4.7 g of phenol in 15 ml of trifluoroacetic acid, and the solution is left to stand for 15 minutes at room temperature and is then diluted with an equal amount of toluene. After evaporation under reduced pressure, the residue is taken up in 100 ml of acetic acid ethyl ester and 50 ml of an aqueous 10% strength dipotassium hydrogen phosphate solution, the mixture is well shaken and the organic phase is separated off. The aqueous layer is twice washed with 100 ml portions of acetic acid ethyl ester to remove the excess phenol and then covered with 100 ml of acetic acid ethyl ester, and its pH value is adjusted to 2 by means of 20% strength aqueous phosphonic acid. The organic layer is separated off after thorough shaking, the aqueous solution is twice extracted with 100 ml portions of acetic acid ethyl ester, and the combined organic extracts are washed three times with 50 ml portions of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue is triturated with acetic acid ethyl ester and yields 3-(4-hydroxy-benzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid, which after recrystallisation from a mixture of acetic acid ethyl ester and methanol melts at 210°C; thin layer chromatogram (silica gel): Rf = 0.72 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.77 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.49 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (in methanol): λmax = 224 mμ (ε = 15800) and 276 mμ (ε = 2400), and shoulder at 282 mμ (ε = 1900); infrared absorption spectrum (in mineral oil): characteristic bands at 3.01μ, 5.77μ, 5.80μ, 6.07μ and 6.62μ.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[S:28][C:29]([Br:32])=[CH:30][CH:31]=1)=O>>[Br:32][C:29]1[S:28][C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)=[CH:31][CH:30]=1
Reactant: O=C(CBr)c1ccc(Br)s1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3ccc(Br)s3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 33 %

Procedure:
4-[4-(5-Bromo-thiophen-2-yl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (180 mg, 33%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-(5-bromothiophen-2-yl)ethanone (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.50 (d, J=1.8 Hz, 1H), 8.13-8.22 (m, 3H), 7.52 (d, J=3.9 Hz, 1H), 7.40-7.48 (m, 2H), 7.28 (d, J=3.9 Hz, 1H).