Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[OH-].[NH4+:23].O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]([C:6]([NH2:23])=[O:7])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-c1cc(Cl)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 8.0 g (32.3 mMol) 6-chloro-4-o-tolyl-nicotinic acid in 48.0 ml THF were added 3.1 ml (42.0 mMol) thionylchloride and 143 μl (1.8 mMol) DMF. After 2 hours at 50° C., the reaction mixture was cooled to room temperature and added to a solution of 72.5 ml aqueous ammonium hydroxide 25% and 96 ml water cooled to 0° C. After 30 minutes at 0° C., THF was removed under reduced pressure and the aqueous layer was extracted with ethyl acetate. Removal of the solvent yielded 7.8 g (98%) 6-chloro-4-o-tolyl-nicotinamide as a beige crystalline foam.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>ClCCl>[CH3:48][S:49]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:6][CH:7]=1)(=[O:51])=[O:50]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(OS(C)(=O)=O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reaction time: 2.5 h
Yield: 26.3 %

Procedure:
4-(4-Hydroxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (178 mg, 0.330 mmol) was suspended in dichloromethane (14 mL), and the suspension was added with triethylamine (0.092 mL, 0.66 mmol) and methanesulfonyl chloride (0.031 mL, 0.40 mmol) under ice-cooling, followed by stirring for 2.5 hours. The reaction mixture was filtered, and the filtrate was added with water and extracted with ethyl acetate and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=10/0.5/0.5) to obtain 4-(4-methanesulfonyloxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (53.4 mg, yield 26%).
Reaction SMILES: [CH3:1][N:2]([CH3:59])[CH2:3][CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]4[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][C:41]4=[O:53])=[CH:35][C:34]=3[O:54][CH3:55])=[CH:29][CH:28]=2)=[O:26])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:56]([O-:58])=[O:57])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1.Cl>[CH3:59][N:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]4[CH2:45][CH2:44][NH:43][CH2:42][C:41]4=[O:53])=[CH:35][C:34]=3[O:54][CH3:55])=[CH:31][CH:32]=2)=[O:26])(=[O:22])=[O:23])=[CH:17][C:16]=1[N+:56]([O-:58])=[O:57])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2=O)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@H](CCN(C)C)CSc3ccccc3)c([N+](=O)[O-])c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(CN2CCNCC2=O)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@H](CCN(C)C)CSc3ccccc3)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of Example 500F (73 mg, 0.09 mmol) in dioxane (1 mL) and 4M HCl (1 mL) at room temperature was stirred for 16 hours, and purified by flash column chromatography on silica gel with 80:20:0.5 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product. MS (ESI) m/e 745, 747 (M−H)−, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ2.07 (m, 2H), 2.54 (d, 6H), 2.74 (m, 1H), 3.04 (m, 2H), 3.17 (d, 2H), 3.23 (t, 2H), 3.32 (t, 2H), 3.47 (s, 2H), 3.74 (s, 3H), 4.09 (m, 1H), 4.54 (s, 2H), 6.89-6.99 (m, 3H), 7.17 (tt, 2H), 7.22-7.34 (m, 4H), 7.39 (d, 2H), 7.81 (dd, 1H), 7.88 (dd, 2H), 8.21 (d, 1H), 8.47 (d, 1H).
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]#[N:13].[N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[N:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1.[Cl-].[NH4+]>[CH3:34][C:31]([O:30][C:28]([N:19]([C:9]1[CH:10]=[C:11]([C:12]#[N:13])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:29])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: COc1ccc(C#N)cc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (1.3 M in THF, 21.8 mL, 28.3 mmol) was added dropwise to a cold (−78° C.) solution of 3-bromo-4-methoxybenzonitrile (5 g, 23.6 mmol) in THF (100 mL), under argon. The reaction mixture was allowed to warm to rt. Di-tertbutyl azodicarboxylate (5.43 g, 23.58 mmol) was added. The reaction mixture was stirred for 3 h at rt, diluted with a saturated aqueous solution of ammonium chloride (175 mL), and extracted with EtOAc. The organic layers were combined, washed with a saturated solution of sodium bicarbonate, dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5→7:3) to provide 5.5 g of the title compound. tR: 1.16 min (LC-MS 4); ESI-MS: 362.2 [M−H]− (LC-MS 4); Rf=0.55 (hexane/EtOAc, 1:1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[BH4-].[Na+]>CO.ClCCl>[F:1][C:2]([F:20])([F:21])[C:3]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([OH:8])[C:4]([F:5])([F:7])[F:6]
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-2-propylbenzaldehyde (0.636 mmol, 200 mg) was dissolved in methanol (4 mL)/dichloromethane (1 mL) and sodium borohydride (1.909 mmol, 72.2 mg) was added. The mixture was stirred at room temperature for 90 minutes then was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed with a saturated solution of sodium bicarbonate (25 mL). The organic phase was filtered through a hydrophobic frit and concentrated to afford the title compound (161 mg). MS (ESI) m/z 315.1 [M−H]
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[CH:21](C1OC(C)=CC(=O)C=1OCC1C=CC=CC=1)[CH2:22]C>>[CH3:1][O:2][CH:3]([C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:21][CH3:22]
Reactant: CCC(O)c1oc(C)cc(=O)c1OCc1ccccc1
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Product: CCC(OC)c1oc(C)cc(=O)c1OCc1ccccc1
Yield: 90.3 %

Procedure:
In an analogous procedure in the preparation of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using 2-(1-hydroxypropyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one (5.48 g, 20 mmol, 1 eq.) yielded the title compound (5.2 g, 90.3%) as an orange oil which solidified on cooling. Recrystallisation from CH2Cl2/Pet. ether 40/60 afforded the pure product as a white crystalline solid. m.p. 63-65° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]C)=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(C(=O)O)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 80.4 %

Procedure:
To a solution of methyl 6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.05 g, 11 mmol) in methanol (30 mL) was added an aqueous solution (10 mL) of lithium hydroxide monohydrate (1.38 g, 33 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water, and, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (3.94 g, 80.5%) as crystals.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.CN(C=O)C.[NH:35]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]1>CCOC(C)=O>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([N:35]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]2)=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Reactant: OC1CCNC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N2CCC(O)C2)cc1F
Temperature: 110 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (40 mg, 0.088 mmol) in pyrrolidin-3-ol (0.4 ml) was added DMF (0.5 ml). The mixture was stirred for 12 hours at 110° C. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was column-chromatographed to yield the title compound (40 mg, 91%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:26])(=[O:25])[N:22]([CH3:24])[CH3:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[CH3:36])[CH2:31][NH2:32]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[CH3:36])[CH2:31][NH:32][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:26])(=[O:25])[N:22]([CH3:23])[CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: Cc1ccc(CN)cc1Cl
Reactant: CCOC(=O)c1nc(-c2ccccc2S(=O)(=O)N(C)C)n(C)c(=O)c1O
Product: Cc1ccc(CNC(=O)c2nc(-c3ccccc3S(=O)(=O)N(C)C)n(C)c(=O)c2O)cc1Cl

Procedure:
Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3-chloro-4-methylbenzylamine (0.14 mL, 1.0 mmol). The title product was obtained as white needles (0.0601 g, 61% yield). 1HNMR (500 MHz, CDCl3) δ: 12.05 (1H, s), 7.92 (1H, dd, J=7.47, 1.83 Hz), 7.72–7.66 (3H, m), 7.38 (1H, dd, J=7.17, 2.29 Hz), 7.19 (1H, s), 7.16 (1H, d, J=7.63 Hz), 7.04 (1H, d, J=7.63 Hz), 4.61 (1H, dd, J=14.95, 7.02 Hz), 4.36 (1H, dd, J=14.96, 5.19 Hz), 3.24 (3H, s), 2.66 (6H, s), 2.32 (3H, s). HRMS (ESI) calcd for C22H24ClN4O5S (M+H): 491.1156; found: 491.1159.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1>CO.O>[Cl:14][C:15]1[N:20]=[C:19]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Sc2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a sodium hydroxide (2.38 g, 59 mmol) solution in methanol (50 mL) and water (5 mL), was added dropwise a solution of methyl 4-mercaptobenzoate (9.00 g, 54 mmol) in methanol (100 mL). The mixture was stirred at room temperature for 1 hour, to this was added methanol solution (100 mL) of 2,4-dichloropyrimidine (8.77 g, 59 mmol) over 5 minutes. The whole was stirred at room temperature for 16 hours. Methanol was removed in vacuo, and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated and dried (Na2SO4). Removal of the solvent in vacuo yielded the product (14.60 g, 97%).
Reaction SMILES: C([NH:8][C:9]1([CH:13]([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10]1)C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C:9]1([CH:13]([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10]1
Reactant: CC(CO)C1(NCc2ccccc2)CCC1
Agent: [Pd]
Solvent: CCO
Product: CC(CO)C1(N)CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
10% Pd—C (700 mg) was added to a solution of 2-[1-(benzylamino)cyclobutyl]propanol (6.81 g, 31.1 mmol) in EtOH (150 mL) and the mixture was stirred under H2 gas 5 kgf/cm2 at room temperature for 6 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. Distillation of the residue gave the title compound as a colorless oil (2.96 g, 74%). 1H-NMR (400 MHz, CDCl3) δ 1.03 (3H, d, J=7.3 Hz), 1.63-1.74 (3H, m), 1.78-1.94 (2H, m), 2.10-2.28 (2H, m), 3.50 (1H, dd, J=11.0 and 4.3 Hz), 3.91 (1H, dd, J=11.0 and 3.1 Hz).
Reaction SMILES: [CH2:1]([C:11]1([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:23]2[CH:22]=[C:21]([I:24])[CH:20]=[CH:19][C:18]=2C2C1=CC(I)=CC=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:36]1([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:26]([C:11]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:45]2[CH:44]=[C:43]([N:42]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:48]=[CH:47][C:46]=2[C:18]2[C:23]1=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(I)ccc2-c2ccc(I)cc21
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(I)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reaction time: 96 h

Procedure:
9,9-Didecyl-7-iodofluoren-2-yl)diphenylamine (15) (0.49 g, 0.66 mmol) was subjected to similar Ullmann condensation reaction with 9,9-didecyl-2,7-bis(phenylamino)fluorene (0.17 g, 0.27 mmol) to yield the desired product. (9,9-Didecyl-7-iodofluoren-2-yl)diphenylamine (15) was prepared by reaction of 9,9-didecyl-2,7-diiodofluorene (reported in Example 7) with one equivalent of diphenylamine. TLC analysis (60:40 hexanes/CH2Cl2) indicated condensation was complete after 4 days. The orange-brown oil was further purified by column chromatography on silica gel using first (70:30) hexanes/CH2Cl2 followed by (80:20) hexanes/CH2Cl2 resulting in 0.42 g of yellow solid (85% yd). Anal. Calcd for C135H174N4: C, 87.51%, H, 9.46%, N, 3.02%. Found: C, 87.37; H, 9.53%, N, 3.02%. 1H NMR (300 MHz. C6D) δ: 7.09 (d, 2H), 7.04 (s, 1H), 7.0 (dd, 5H), 6.93 (s, 1H), 6.85 (t, 6H), 6.73 (t, 6H), 6.53 (m, 3H), 1.33 (m, 4H), 0.87 (bd, 28H), 0.52 (bt, 10H). 13C NMR (300 MHz, C6D6) δ: 152.4, 148.5. 147.0, 136.6, 129.4, 124.2, 123.9, 120.2, 119.6, 119.1, 55.2, 40.3, 32.2, 30.4, 30.0, 29.8, 29.7, 29.6, 24.4, 22.9, 14.2. FT-IR (KBr, cm1): 3036 (vArCH), 2926; 2854 (valCH), 1593 (vArC═C).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12]O)=[O:9])[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:18]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][Cl:18])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CO)NC(=O)c1cccc(N)n1
Solvent: ClC(Cl)Cl
Product: CC(C)(CCl)NC(=O)c1cccc(N)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 6-amino-N-(1-hydroxy-2-methylpropan-2-yl)picolinamide (0.35 mmol, 74 mg) in CHCl3 was cooled to 0° C. and SOCl2 (2.8 mmol, 200 μL) was added. The mixture was refluxed overnight. After cooling to room temperature, the reaction was quenched with 1 M NaOH. The aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried with MgSO4. The crude product was purified by column chromatography on silica gel (Hexanes:ethyl acetate=2:1 as eluent). White solid, 76 mg, 95% yield. 1H NMR (500 MHz, CDCl3): 7.93 (br, 1H), 7.57-7.54 (m, 1H), 7.52-7.51 (m, 1H), 6.62 (d, 1H, J=8.0 Hz), 4.51 (br, 2H), 3.94 (s, 2H), 1.52 (s, 6H). 13C NMR (125 MHz, CDCl3): 163.97, 156.83, 148.37, 138.88, 112.33, 111.63, 53.72, 51.19, 25.08. MS (ESI, MeOH): 228 (100%, (M+1)+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:33])/[C:19](/[C:23]3[N:24]=[C:25]([NH:28][C:29](=[O:32])[CH2:30][Cl:31])[S:26][CH:27]=3)=[N:20]\[O:21][CH3:22])[C:15](=[O:34])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C(=O)([O-])O.[Na+].[Cl-].[Ca+2].[Cl-].Cl>CO>[Cl:31][CH2:30][C:29]([NH:28][C:25]1[S:26][CH:27]=[C:23](/[C:19](=[N:20]/[O:21][CH3:22])/[C:18]([NH:17][CH:16]2[C:15](=[O:34])[N:10]3[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][O:4][CH3:1])[CH2:7][S:8][C@H:9]23)=[O:33])[N:24]=1)=[O:32]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(=O)CCl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Ca+2]
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
5 g of 3-acetoxymethyl-7-[2-(2-chloroacetamidothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-cephem-4-carboxylic acid and 800 mg of sodium hydrogen carbonate were dissolved in 50 ml of 70% v/v aqueous methanol. 75 g of anhydrous calcium chloride were added to the solution, and the mixture was stirred at 70° C. for 1 hour. The mixture was then diluted with 100 ml of ice-water, acidified by the addition of 1 ml of concentrated hydrochloric acid, and extracted three times, each time with 100 ml of ethyl acetate. The extracts were combined and the combined extracts were extracted three times, each time with 50 ml of a 10% w/v aqueous solution of dipotassium phosphate. The extracts were combined and the combined extracts were washed with a small amount of ethyl acetate, acidified with a saturated aqueous solution of potassium hydrogen sulphate, and extracted twice with 100 ml portions of ethyl acetate and then once with 50 ml of ethyl acetate. The extracts were combined and the combined extracts were washed with an aqueous solution of sodium chloride, dehydrated over anhydrous magnesium sulphate and concentrated by evaporation under reduced pressure. When the volume of the mixture had reduced to about 50 ml, the evaporation was stopped, as crystals began to precipitate. The concentrate was first heated to redissolve the crystals and then ice-cooled and allowed to stand for 3 hours. The resulting crystals were collected by filtration, washed with ethyl acetate and dried, to give 3.01 g (yield 63.5%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[N:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:8][N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1cccc(Cl)n1
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccccn1Cc1cccc(Cl)n1
Reaction time: 8 h

Procedure:
To the solution of 2-chloro-6-chloromethylpyridine (1.62 g g, 10 mmol) in DMF (10 mL) was added 2-hydroxypyridine (0.95 g, 10 mmol) and Cs2CO3 (6.52 g, 20 mmol). The mixture was stirred overnight, then diluted with water and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (2-4% MeOH in CH2Cl2) to give 1-[(6-chloropyridin-2-yl)methyl]pyridin-2(1H)-one. 1H-NMR (500 MHz, CDCl3) δ 7.62 (t, 1H, J=7.8), 7.51 (dd, 1H, J=6.8, 2.0), 7.31-7.37 (m, 2H), 7.25 (d, 1H, 3=8.3), 6.59 (d, 1H, J=9.2), 6.21 (td, 1H, J=6.6, 1.3), 5.19 (s, 2H). LRMS m/z (M+H) Calcd: 221.7. found: 221.0.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[C:13]([O:17][C:18]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[CH:7]([C:6]1[C:5]([C:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:24]=[CH:23][CH:22]=2)=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=Cc1cccnc1Br
Agent: OBO
Product: CC(C)(C)OC(=O)n1cccc1-c1ncccc1C=O

Procedure:
tert-butyl 2-(3-formylpyridin-2-yl)-1H-pyrrole-1-carboxylate was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (66 mg, 146.5 mg theoretical, 45.1%). LC-MS m/z 273.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]2.C(OC(=O)C)(=O)C.[N+:27]([O-])([OH:29])=[O:28].C(=O)(O)[O-].[Na+]>[N+](C)([O-])=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:27]([O-:29])=[O:28])[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)OC(C)(C)C)CC2
Reaction time: 3 h

Procedure:
To a solution of the product of Example 53D (2.46 g, 9.35 mmol) in nitromethane (30 mL) at −10° C. was added acetic anhydride (5.7 g, 56.1 mmol) and concentrated nitric acid (0.88 g, 14 mmol). After stirring for 3 hours, the mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution and extracted with dichloromethane (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography eluting with 5:1 hexane:ethyl acetate to give the title compound. MS: 309 (M+H+).