Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=1)[N:5]([C:8](=[CH:14]O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=O.C([O-])(=O)C1C=CC=CC=1.[NH4+:31].C1(C)C(C)=CC=CC=1.O>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([N:5]2[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:31]=[CH:6]2)[C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(=CO)N(C=O)c1c(CC)ccc(Cl)c1C
Reactant: [NH4+]
Agent: O=C([O-])c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cncn1-c1c(CC)ccc(Cl)c1C
Yield: 76.4 %

Procedure:
19.2 g (0.068 mol) of ethyl 2-(3-chloro-6-ethyl-2-methyl-N-formylanilino)-3-hydroxy-acrylate were heated to an internal temperature of 153° C. with 12.3 g (0.088 mol) of ammonium benzoate in 100 ml of xylene with removal of the xylene/water mixture by distillation. The mixture was allowed to cool and was taken up in toluene, and the organic phase was washed twice with 2N sodium hydroxide solution and twice with water, dried over sodium sulfate and evaporated. 15.2 g (85% of theory) of ethyl 1-(3-chloro-6-ethyl-2-methylphenyl)-imidazole-5-carboxylate were obtained as a pale brown oil. Identification was effected by 1H NMR spectroscopy.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:36])([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:27][C:26]=1[O:37][CH3:38])(C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:32]([C:31]([C:28]1[CH:29]=[CH:30][C:25]([OH:24])=[C:26]([O:37][CH3:38])[CH:27]=1)([OH:36])[CH2:34][CH3:35])[CH3:33]
Reactant: CCC(O)(CC)c1ccc(O[Si](C)(C)C(C)(C)C)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (24.7 mL, 24.7 mmol) was added to a solution of 3-[4-(t-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-pentan-3-ol (Example 176-(2); 8.0 g, 24.7 mmol) in tetrahydrofuran (30 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=1:1) to give the title compound (4.25 g, 83%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2
Reactant: COc1ccc2[nH]ncc2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 713.1 %

Procedure:
5-Methoxyindazole (1.7 g, 11.5 mmol), (Tetrahedron, 1994, 50, 3529), was dissolved in methylene chloride (35 ml) and cooled in an ice/water bath. Boron tribromide (57.4 ml of a 1M solution in methylene chloride, 57.4 mmol) was added over 10 minutes and then the mixture allowed to warm to ambient temperature. The mixture was stirred for 2 hours and then re-cooled in an ice/water bath. 2N Sodium hydroxide was slowly added until pH8. The precipitated solid was filtered off and dried under vacuum at 60° C. overnight. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 5-hydroxyindazole (11.0 g, 65%) as a brown solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:15])[C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(c1ncccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Reaction time: 120 h

Procedure:
A mixture of 1-benzyl-4-methylaminopiperidine (EXAMPLE 9, 10.8 g), 2-chloro-3-nitropyridine (6.7 g) and anhydrous potassium carbonate (14.6 g) in dry acetonitrile (211 ml) is stirred under nitrogen at 20°-25° for 5 days. The mixture is then concentrated under reduced pressure, diluted with methylene chloride (200 ml) and water (50 ml), and the phases are separated. The organic phase is washed with saline (50 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed (silica gel, 70-230 mesh, 100 g; eluting with ethyl acetate/hexane (50/50) to give the title compound, mp=92°-95°.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:11]=1)#[N:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:11]=1)#[N:2]
Reactant: CCOC(=O)c1cnc2ccc(CCCC#N)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#CCCCc1ccc2ncc(C(=O)O)n2c1
Temperature: 50 °C

Procedure:
To a stirring solution of ethyl 6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxylate (24w) (375 mg, 1.46 mmol) in THF:MeOH (4:1, 5 mL) was added 2N LiOH (500 μL). The reaction was heated at 50° C. for 45 minutes then cooled to room temperature and the pH was adjusted between 3-4 with 1N HCl. The solvent was partially concentrated and the remaining aqueous was lyophilized to yield 6-(3-cyanopropyl)imidazo[1,2-a]pyridine-3-carboxylic acid (25). 1H NMR (400 MHz, d6-DMSO) δ 9.21-9.19 (m, 1 H), 8.45 (s, 1 H), 7.85 (dd, J=0.8, 9.2 Hz, 1 H), 7.70 (dd, J=1.6, 9.2 Hz, 1 H), 2.82 (t, J=7.2 Hz, 2 H), 2.55 (t, J=7.2 Hz, 2 H), 1.97-1.90 (m, 2 H). MS m/z 230.3 (M+1)+.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][OH:16])[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2ccnc(CO)c2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ccnc(COS(C)(=O)=O)c2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [4-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-yl]-methanol (950 mg, 4.87 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.88 mL, 6.29 mmol) followed by DMAP (60 mg, 0.49 mmol) and Ms-Cl (0.49 mL, 6.15 mmol). After stirring at rt for 2 h, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a yellow oil. LC-MS-conditions 02: tR=0.76 min, [M+H]+=274.30.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:20])=[CH:6][C:5]=1[O:11][S:12]([C:15]([F:17])([F:16])[F:18])(=[O:14])=[O:13]
Reactant: COC(=O)c1ccc(C)cc1OS(=O)(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OS(=O)(=O)C(F)(F)F
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a stirred solution of 2-(trifluoromethanesulfonyloxy)-4-methylbenzoic acid methyl ester (19.6 g, 65.8 mmol), prepared as in Example 204A, in 250 mL CCl4 was added N-bromosuccinimide (12.29 g, 69.1 mmol) followed by 2,2′-azobisisobutyronitrile (108 mg, 0.658 mmol) and the reaction was heated to reflux. After 16 hours, the reaction was evaporated and the residue was purified by flash chromatography over silica gel (10% ethyl acetate-hexanes) to give 19.9 g (80%) of 2-(trifluoromethanesulfonyloxy)-4-bromomethylbenzoic acid methyl ester as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=3)[C:15]#[N:16])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:21])[O:3]1.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[Br:28][C:11]1[C:6]2[NH:5][C:4](=[O:21])[O:3][C:2]([CH3:22])([CH3:1])[C:7]=2[CH:8]=[C:9]([C:12]2[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=2)[C:15]#[N:16])[CH:10]=1
Reactant: BrBr
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)OC(=O)Nc2c(Br)cc(-c3cc(F)cc(C#N)c3)cc21
Temperature: 0 °C
Reaction time: 20 h
Yield: 75.3 %

Procedure:
To a mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile (0.5 g, 1.7 mmol) and sodium acetate (0.2 g, 2.4 mmol) in acetic acid (5 mL) was added, at room temperature under nitrogen, bromine (0.12 mL, 2.34 mmol). The reaction mixture was stirred for 20 hours and then poured into ice water (30 mL). The precipitate was collected on a filter and washed with water (3×5 mL) to yield 3-(8-bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile as an off-white solid (0.48 g, 75%): mp 216–217° C.; 1H-NMR (DMSO-d6) δ 9.78 (s, 1H), 8.18 (t, 1H, J=1.6 Hz), 8.02–8.08 (m, 2H), 7.81 (m, 1H), 7.75 (d, 1H, J=1.8 Hz), 1.66 (s, 6H). MS (ESI) m/z 373, 375 [M−H]−.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:5]([F:18])[CH:4]=1.[C-:19]#[N:20].[Na+]>CO>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:19]#[N:20])=[CH:4][C:5]=1[F:18]
Reactant: [C-]#N
Reactant: Fc1cc(CBr)ccc1-c1nc2ccccc2o1
Agent: [Na+]
Solvent: CO
Product: N#CCc1ccc(-c2nc3ccccc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1.0 gm. of 2-(4-bromomethyl-2-fluorophenyl)benzoxazole in 50 cc. of dry methanol which has been cooled in an ice-water bath is added 1.5 gm. of sodium cyanide. The reaction mixture is stirred cold for 10 minutes, allowed to warm to room temperature and finally heated on the steam bath. Solution of the starting material occurs and after 5 minutes reflux the reaction mixture is cooled, concentrated to about 25 cc., and poured into 100 cc. of ice cold 2.5 N hydrochloric acid. The resulting precipitate is filtered and air dried to give crude 4-(benzoxazol-2-yl)-3-fluorophenylacetonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13](C(O)=O)[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2C(=CC=1)[N:32]([C:36](N)=[O:37])C=C2N=C=O)C=C>>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([N:32]=[C:36]=[O:37])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: O=C(OCc1ccccc1)c1cc(C(=O)O)n2ccccc12
Product: O=C=Nc1cc(C(=O)OCc2ccccc2)c2ccccn12

Procedure:
The title compound was prepared from indolizine-1,3-dicarboxylic acid 1-benzyl ester using the protocol described in step E scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.CS[C:25]1[NH:29][C:28](=[O:30])[CH2:27][N:26]=1.[OH-].[Na+]>C(O)C>[O:30]=[C:28]1[NH:29][C:25]([NH:1][CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:8]3)=[N:26][CH2:27]1
Reactant: CSC1=NCC(=O)N1
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN=C(NCc2cccc3cc(NS(=O)(=O)c4ccccc4)ccc23)N1

Procedure:
A mixture of N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide, 2-methylsulfanyl-3,5-dihydro-imidazol-4-one (prepared by the method reported by Chen et al., WO9736859) and sodium hydroxide in ethanol is heated to reflux, then concentrated under reduced pressure, diluted with ethyl acetate, and washed with aqueous sodium carbonate. The organic phase is dried (magnesium sulfate) and concentrated under reduced pressure to give N-{5-[(5-Oxo-4,5-dihydro-1H-imidazol-2-ylamino)-methyl]-naphthalen-2-yl}-benzenesulfonamide. 5-[(5-Oxo-4,5-dihydro-1H-imidazol-2-ylamino)-methyl]-naphthalene-2-sulfonic acid phenylamide may be similarly prepared.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:20]([CH3:21])=[N:19][NH:18][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]>[Li+].[OH-].CO>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]3[C:20]([CH3:21])=[N:19][NH:18][C:7]=3[N:8]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Yield: 93.9 %

Procedure:
1.4 g of 6-(4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester were dissolved in 50 mL of a mixture of 2N LiOH and methanol (1:1). After the reaction was complete, methanol was removed in vacuo, water was added and the solution acidified to pH 1 by addition of hydrochloric acid. The resulting precipitate was filtered off to give 1.25 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1.O=[C:29]([CH3:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31]([C:30]1[C:29]([CH3:36])=[N:1][C:2]2[C:3]([C:26]=1[NH2:27])=[C:4]([O:5][CH2:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH:23]=[CH:24][CH:25]=2)=[O:32])[CH3:35]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCN(C(=O)OCc2ccccc2)CC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCNCC3)c2c1N

Procedure:
Prepared as in Example 2a from benzyl 4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 35c) and ethyl 3-oxobutanoate as an orange solid (25%). 1H NMR (400 MHz, DMSO-d6) δ 1.29-1.37 (m, 5H), 1.77-1.80 (m, 2H), 2.07 (brs, 1H), 2.53 (s, 3H), 2.55-2.65 (m, 3H), 3.06-3.09 (m, 2H), 4.06 (d, J=8.0 Hz, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.08 (s, 2H). MS 344 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:9]2=[NH:12])=[CH:4][CH:3]=1.O=[C:21]([CH3:25])[C:22](=[S:24])[NH2:23]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([C:9]42[NH:23][C:22](=[S:24])[C:21]([CH3:25])=[N:12]4)[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)=[CH:4][CH:3]=1
Reactant: CC(=O)C(N)=S
Reactant: COC1CCC2(CCc3ccc(Br)cc3C2=N)CC1
Solvent: CO
Product: COC1CCC2(CCc3ccc(Br)cc3C23N=C(C)C(=S)N3)CC1
Temperature: 60 °C
Yield: 43.2 %

Procedure:
7′-Bromo-4-methoxy-3′,4′-dihydro-1′H-spiro[cyclohexane-1,2′-naphthalen]-1′-imine (Intermediate 14, 0.350 g, 1.09 mmol) and 2-oxopropanethioamide (Intermediate 1, 0.336 g, 3.26 mmol) were dissolved in dry MeOH (5 mL) and the resulting orange solution was heated at 60° C. under N2 (g) overnight. The mixture was concentrated and purified by flash column chromatography using a gradient of 0-10% EtOAc in heptane to give the title compound (0.192 g, 43% yield): MS (ES+) m/z 407.12 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][CH2:14][C:13]1=[O:21].[CH3:22][CH2:23][C:24](=O)[CH2:25][CH3:26].C([BH3-])#N.[Na+].CO>ClCCl.C(O)(=O)C>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]([N:12]2[C:16]([CH2:17][OH:18])([CH2:19][OH:20])[CH2:15][CH2:14][C:13]2=[O:21])=[C:2]([NH:1][CH:24]([CH2:25][CH3:26])[CH2:23][CH3:22])[CH:7]=1)=[O:9]
Reactant: COC(=O)c1ccc(N2C(=O)CCC2(CO)CO)c(N)c1
Reactant: CCC(=O)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCC(CC)Nc1cc(C(=O)OC)ccc1N1C(=O)CCC1(CO)CO
Reaction time: 12 h
Yield: 84.7 %

Procedure:
A solution of 1-(2-amino-4-methoxycarbonylphenyl)-5,5-bis-hydroxymethylpyrrolidin-2-one (0.1 g, 0.34 mmol) from Example 6 in 1 mL of dichloromethane and 0.5 mL of acetic acid was treated with 3-pentanone (0.2 g, 2.3 mmol) and sodium cyanoborohydride (0.075 g, 1.2 mmol). The resulting mixture was stirred at ambient temperature for 6 h after which time additional 3-pentanone (0.2 g, 2.3 mmol), sodium cyanoborohydride (0.075 g, 1.2 mmol) and methanol (0.5 mL) were added and stirring continued for 12 h. A third portion of 3-pentanone (0.3. g, 3.4 mmol) and sodium cyanoborohydride (0.15 g, 2.3 mmol) was added and the stirring continued for an additional 16 h. The reaction mixture was quenched with 10 mL of a saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried and concentrated. The residue was purified by chromatography (silica gel; 5% ethanol in ether) to give 0.105 g (82%) of 1-[4-methoxycarbonyl-2-(3-pentylamino)phenyl]-5,5-bis-(hydroxymethyl)pyrrolidin-2-one as a white solid, mp 183-185° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH3:35]>>[CH3:30][O:31][CH2:32][CH2:33][N:34]([CH3:35])[CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:29])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CNCCOC
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: COCCN(C)CCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and 2-Methoxyethylmethylamine were converted to yield (2-Methoxy-ethyl)-methyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amine as orange oil, MS: 433 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9](OCC=C)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[CH:24]=CC=C[C:20]=1Cl>>[CH:20]([C:9]1[CH:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:12]=[CH:11][C:10]=1[OH:13])=[CH:19][CH3:24]
Reactant: C=CCOc1cc(C2CCCCC2)ccc1O
Reactant: Clc1ccccc1Cl
Product: CC=Cc1cc(C2CCCCC2)ccc1O
Temperature: 25 °C

Procedure:
A solution of 4-cyclohexyl allyloxyphenol (12.3 g) in ortho-dichlorobenzene (50 mL) was kept at reflux for 36 h. The mixture was cooled to room temperature and chromatographed over silica gel to afford 2-propenyl-4-cyclohexylphenol (11.0 g). This material was dissolved in methanol (150 mL) and hydrogenated over Pd/C (1.2 g) at 50 psi. The reaction was filtered through Celite and concentrated in vacuo to afford the title compound (11.0 g).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C.[NH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1C(OC(C)(C)C)=O.I[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:42]=[C:41]([C:43]3[C:44]([NH2:61])=[N:45][CH:46]=[C:47]([C:49]4[CH:54]=[CH:53][C:52]([S:55]([CH:58]([CH3:60])[CH3:59])(=[O:57])=[O:56])=[CH:51][CH:50]=4)[N:48]=3)[O:40][N:39]=2)=[CH:34][CH:33]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl.[Cu]I>[CH:58]([S:55]([C:52]1[CH:51]=[CH:50][C:49]([C:47]2[N:48]=[C:43]([C:41]3[O:40][N:39]=[C:38]([C:35]4[CH:36]=[CH:37][C:32]([NH:17][CH2:18][CH:19]5[CH2:23][CH2:22][CH2:21][NH:20]5)=[CH:33][CH:34]=4)[CH:42]=3)[C:44]([NH2:61])=[N:45][CH:46]=2)=[CH:54][CH:53]=1)(=[O:56])=[O:57])([CH3:60])[CH3:59]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc(-c4ccc(I)cc4)no3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Agent: [Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc(-c4ccc(NCC5CCCN5)cc4)no3)n2)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 21.1 %

Procedure:
A reaction mixture containing CuI (43.57 mg, 0.2288 mmol), Cs2CO3 (149.1 mg, 0.4576 mmol), 2-acetylcyclohexanone (64.15 mg, 0.4576 mmol), tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (137.5 mg, 0.6864 mmol) and 3-(3-(4-iodophenyl)isoxazol-5-yl)-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-amine (125 mg, 0.2288 mmol) in DMF (7.500 mL) was heated at 90° C. overnight. The reaction mixture was cooled to rt and partitioned between ethyl acetate (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×5 mL) and the combined organic extracts were washed sequentially with water (1×5 mL) and brine (1×5 mL), dried over MgSO4 and concentrated in vacuo which yielded an oil. The oil was purified by reverse phase preparative HPLC [Waters Sunfire C18, 100 Å column, 5 M, 19 mm×150 mm, (solvent A: 0.05% TFA in water; solvent B: 0.05% TFA in CH3CN) over 16 minutes at 20 mL/min]. The product fractions were combined and concentrated to leave a yellow solid. The solid was dissolved in CH2Cl2(10 mL) and TFA (2 mL) was added and the resulting solution stirred at rt for 5 h. The reaction mixture was concentrated in vacuo and the residue partitioned between CH2Cl2 (5 mL) and water (5 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo which was purified by reverse phase preparative HPLC [Waters Sunfire C18, 100 Å column, 5 M, 19 mm×150 mm, (solvent A: 0.05% TFA in water; solvent B: 0.05% TFA in CH3CN) over 16 minutes at 20 mL/min]. The product fractions were combined and concentrated to leave the title compound as a yellow solid (25 mg, 15% yield); 1H NMR (400.0 MHz, DMSO) d 1.19 (d, J=6.9 Hz, 6H), 1.68 (dd, J=8.2, 12.7 Hz, 1H), 1.93 (m, 2H), 2.15-2.11 (m, 1H), 3.23 (m, 2H), 3.45-3.39 (m, 1H), 3.56 (m, 1H), 3.71 (m, 2H), 6.80 (d, J=8.7 Hz, 2H), 7.18 (s, 1H), 7.65 (s, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 8.38 (d, J=8.5 Hz, 2H), 8.47 (bs, 1H) and 8.94 (s, 2H) ppm; MS (ES+) 519.
Reaction SMILES: [NH2:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([C:9]3[S:10][C:11]([N:14]([CH3:16])[CH3:15])=[N:12][N:13]=3)[CH2:7][S:8][C@H:3]12.[C:35]1([CH2:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>ClCCl>[C:35]1([CH2:41][C:42]([NH:1][CH:2]2[C:33](=[O:34])[N:4]3[C:5]([C:17]([O:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])=[C:6]([C:9]4[S:10][C:11]([N:14]([CH3:16])[CH3:15])=[N:12][N:13]=4)[CH2:7][S:8][C@H:3]23)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN(C)c1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)s1
Yield: 83.8 %

Procedure:
To a solution of 0.491 g of benzhydryl 7-amino-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate (obtained in Example 26) in 16 ml of dichloromethane is dropwise added 0.160 g of phenylacetylchloride and 0.10 g of triethylamine with stirring under ice-cooling, and stirring and cooling are maintained for 30 minutes. The reaction mixture is washed with water, dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residue is chromatographed on a column of silica gel [eluted with benzene-ethyl acetate(1:3)] to give 0.51 g of benzhydryl 7-phenylacetamido-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate.