Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].O.[OH-].[Li+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].O>CN(C=O)C>[CH2:1]([C:3]1[N:12]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCc1nc2c(C)ccnc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)ccnc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.33 h

Procedure:
2-Ethyl-7-methyl-3H-imidazo[4,5-b]pyridine (1.00 g, 6.20 mmol) was dissolved in DMF (15 mL) and lithium hydroxide monohydrate (0.391 g, 9.31 mmol) was added at room temperature followed by stirring for 20 minutes. Then, 4-nitrobenzylbromide (1.34 g, 6.20 mmol) was slowly added to the mixture, and stirred at room temperature. After 30 minutes, water (20 mL) was added and precipitated crystals were collected by filtration, followed by washing with water. The crystals were dried under reduced pressure to obtain Compound P34 (0.819 g, 2.76 mmol, 45%).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[C:13]3[CH:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:29][NH:30][CH2:31][CH2:32][NH:33][CH3:34]>>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[C:13]3[CH:14]=[N:15][C:16]([N:30]([CH3:29])[CH2:31][CH2:32][NH:33][CH3:34])=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccc2oc(Cl)cc2c1
Reactant: CNCCNC
Product: CCC(=C(c1ccc(O)cc1)c1ccc(N(C)CCNC)nc1)c1ccc2oc(Cl)cc2c1

Procedure:
According to the same procedure as example 16, step C described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(6-chloropyridin-3-yl)but-1-enyl)phenol (70 mg, 1.0 eq) was reacted with N,N′-dimethylethane-1,2-diamine (150 mg, 10 eq) to give the desired product (Z/E=1/1). m/z=462[M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.FC(F)(F)C(O)=O.[OH:17][CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1>>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([O:17][CH:18]2[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21]2)[N:3]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(OC2CN(C(=O)OC(C)(C)C)C2)n1

Procedure:
Compound P24 was prepared according to the general procedure described in the preparation of P21, except that 2-chloro-4,6-dimethylpyrimidine was used in place of 2-bromopyridine, to afford P24. LCMS (ESI) m/z 280.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.39 (s, 9H), 2.34 (s, 6H), 3.96 (m, 2H), 4.25 (m, 2H), 5.26 (m, 1H), 6.66 (s, 1H). Compound P24 was deprotected with trifluoroacetic acid as described for tert-butyl 3-hydroxyazetidine-1-carboxylate in the preparation of C19, Example 3 before being used in the coupling step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]=[C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:15][CH2:14]2)[S:11][CH:12]=1)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[NH2:7][C:8]1[N:9]=[C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:15][CH2:14]2)[S:11][CH:12]=1
Reactant: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(NC(=O)OC(C)(C)C)cs3)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(N)cs3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-carbamic acid tert-butyl ester (5.65 g, 13.15 mmol) is added a solution of 4M HCl in dioxane (35 mL) at RT. After stirring 3 days at RT, the solvent is evaporated under reduce pressure. The resulting solid is triturated with diethylether, and filtered to give 1-[4-(4-amino-thiazol-2-yl)piperidin-1-yl]-2-(2,5-dimethyl-phenyl)-ethanone hydrochloride salt, which is suspended in aqueous saturated sodium bicarbonate (500 mL). After stirring 30 min at RT, the reaction mixture is extracted with ethyl acetate (500 mL). The combined organic layers are washed with water (100 mL) and brine (100 mL), filtered, dried over sodium sulfate, and evaporated under reduced pressure to give 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(2,5-dimethyl-phenyl)-ethanone (3.27 g, 75%). 1H-NMR (400 MHz, CDCl3): δ=1.53-1.61 (m, 1H), 1.67-1.79 (m, 1H), 1.95-2.04 (m, 1H), 2.08-2.13 (m, 1H), 2.25 (s, 3H), 2.30 (s, 3H), 2.78-2.88 (m, 1H), 3.06-3.20 (m, 2H), 3.68 (s, 2H), 3.80-3.89 (m, 1H), 4.05 (s, 1H), 4.68-4.74 (m, 1H), 6.95 (s, 1H), 6.98 (d, 1H), 7.07 (d, 1H), 7.23 (s, 1H). MS: m/z=330 (M+1). MS: m/z=330 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:29]=[CH:28][C:14]([CH2:15][S:16][C:17]3[N:18]([CH3:27])[C:19](=[O:26])[C:20]4[S:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].O>C1COCC1>[OH:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:29]=[CH:28][C:14]([CH2:15][S:16][C:17]3[N:18]([CH3:27])[C:19](=[O:26])[C:20]4[S:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(CSc3nc4ccsc4c(=O)n3C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(O)cc3)cc2)nc2ccsc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
To a solution of 2-[4-(4-acetoxybenzoyl) benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (3.51 g) in THF (20 ml) was added 1N-sodium hydroxide/water (10 ml) and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was concentrated, the residue was dissolved in water, and 1N-hydrochloric acid was added. The resulting crystals were collected by filtration, rinsed with water, and dried to provide the title compound as colorless solid (3.22 g).
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][O:11][C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:18]=4[N:17](COCC[Si](C)(C)C)[C:16]=3[N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)[CH3:2].Br.[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([C:3]1([CH2:10][O:11][C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([C:25]#[N:26])[N:23]=[CH:24][C:18]=4[NH:17][C:16]=3[N:15]=[CH:14][CH:13]=2)[CH2:4][CH2:5][N:6]([CH3:9])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCC1(COc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CCN(C)CC1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC1(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CCN(C)CC1
Temperature: 75 °C
Yield: 39.3 %

Procedure:
4-((4-ethyl-1-methylpiperidin-4-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (152 mg, 0.32 mmol) was dissolved in 1,4-dioxane (0.5 mL) and then treated with 48% HBr(aq) (0.5 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (44 mg, 40%). 1H NMR (500 MHz, d6-DMSO) δ 8.98 (s, 1H), 8.55 (d, J=5.7, 1 H), 8.32 (s, 1H), 7.12 (d, J=5.8, 1H), 4.18 (s, 2H), 2.37 (m, 4H), 2.19 (s, 3H), 1.75-1.68 (m, 2H), 1.67 (m, 2H), 1.65-1.57 (m, 2H), 0.86 (t, J=7.5, 3 H). LCMS (Method D): RT=7.36 min, M+H+=350.2.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:19]([NH:21][C@H:22]([C:40]([N:42]1[CH2:81][CH2:80][CH2:79][C@H:43]1[C:44]([NH:46][C@H:47]([C:49]([NH:51][C@H:52]([C:69]([O:71]CC1C=CC=CC=1)=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][NH:57]C(OCC1C=CC=CC=1Cl)=O)=[O:50])[CH3:48])=[O:45])=[O:41])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:39])[NH:28]S(C1C=CC(C)=CC=1)(=O)=O)=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1Cl)=O.C1(OC)C=CC=CC=1>>[NH2:1][C@H:2]([C:19]([NH:21][C@H:22]([C:40]([N:42]1[CH2:81][CH2:80][CH2:79][C@H:43]1[C:44]([NH:46][C@H:47]([C:49]([NH:51][C@H:52]([C:69]([OH:71])=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][NH2:57])=[O:50])[CH3:48])=[O:45])=[O:41])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:28])[NH2:39])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2Cl)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Solvent: COc1ccccc1
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
The solution of 290 mg (0.227 mmol) of Boc-Lys(ClZ)-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 15), 1 ml of anisole and 2 ml of HF was stirred at 0° C. for 2 h. The reaction mixture was evaporated under reduced pressure to remove HF. To the residue 2 ml of HF were added and the solution was stirred at 0° C. for another 1 h. The reaction mixture was evaporated under reduced pressure to remove HF. The residue was triturated with ether and the resulted solid was purified on the Sephadex G-10 column. The collected fractions were lyophilized to provide 130 mg (96%) of the title compound. Mp. 168–170° C., FAB-MS (m/e) 599[M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:14]2[CH:15]=[C:16]([C:27](=[O:29])[NH2:28])[C:17]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]1[C:14]2[CH:15]=[C:16]([C:27]([NH2:28])=[O:29])[C:17]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCCCc2cc(OCC3CCCCC3)c(C(N)=O)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc2c(cc1OCC1CCCCC1)CCCCC2N
Reaction time: 1 h

Procedure:
To (3-carbamoyl-2-cyclohexylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-carbamic acid tert-butyl ester (0.60 g, 144 mmol) in CH2Cl2 (8 mL) was added TFA (2 mL). The mixture was stirred for 1 h, evaporated under a stream of N2, diluted with CH2Cl2 and washed with 1 N NaOH. The organic layer was dried over magnesium sulfate and concentrated to a tan solid (0.45 g, 99%). MS [M+H]+ 316, m.p. 170-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][CH:18]=[CH2:19])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].B.[O:21]1CCCC1.O.ClC(Cl)(Cl)C1N2CCCC2C(=O)O1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][CH2:19][OH:21])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:4]
Reactant: C=CCC1(C(=O)OC)CCCN1C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: B
Agent: O=C1OC(C(Cl)(Cl)Cl)N2CCCC12
Solvent: O
Product: COC(=O)C1(CCCO)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-allylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (25.0 g) in tetrahydrofuran (125 ml) cooled to 0° C. was added dropwise borane-tetrahydrofuran complex (1.0M tetrahydrofuran solution, 105 ml) over 30 minutes, and the mixture was stirred at the same temperature for 2.5 hours. To the reaction mixture was added dropwise additional borane-tetrahydrofuran complex (1.0M tetrahydrofuran solution, 11 ml), and the mixture was stirred at the same temperature for 50 minutes. To the reaction mixture was added dropwise water (180 ml) over 30 minutes and added sodium peroxoborate 1 hydrate (12.0 g) in small batches. The mixture was warmed to room temperature and stirred overnight, and then thereto was added water (500 ml). The mixture was extracted with ethyl acetate (600 ml). The separated organic layer was washed with 20% aqueous sodium thiosulfate solution (600 ml) and saturated aqueous sodium chloride solution. The separated aqueous layer was extracted with ethyl acetate (300 ml, 200 ml) twice. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1 to 1/1) to give the titled compound (17.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[CH2:11][C:12]([N:14]=[C:15]=[O:16])=[O:13].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:16]=[C:15]1[NH:14][C:12](=[O:13])[CH2:11][N:1]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: O=C=NC(=O)CCl
Reactant: N#Cc1cccc(N)c1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cccc(N2CC(=O)NC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
g of 3-Aminobenzonitril were dissolved in 60 ml Dioxan and 0.8 ml of Chloro-acetyl isocyanate added. The reaction mixture was stirred at rt for 2 h. 2.5 ml of DBU were added and the reaction mixture stirred at rt for 40 h. The product was extracted with DCM. MS(ISO): 202.2 (MH+)
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+]>C(O)C.O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([S:13][CH2:12][C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]3)=[CH:19][CH:18]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1(CSc2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(CSc2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To a solution of 4-[4-(4-chlorophenoxy)phenylthiomethyl]tetrahydropyran-4-carboxylic acid ethyl ester (70 mg, 0.17 mmol) in ethanol (2 mL) containing two drops of water, was added potassium hydroxide (58.3 mg, 1.04 mmol). The mixture was refluxed for 13 hours, cooled to room temperature, acidified to pH 4, and extracted with ethyl acetate (4×50 mL). The combined organic layers were dried over magnesium sulfate, and concentrated to afford 4-[4-(4-chlorophenoxy)phenylthiomethyl]-tetrahydropyran-4-carboxylic acid (66 mg, 100%), which is spectroscopically identical to that isolated from the prior procedure of Example 7D.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:28]([CH2:34][CH2:35][CH3:36])=[N:27][C:21]=3[C:22]([NH2:26])=[N:23][C:24]=2[CH:25]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:26][C:22]1[C:21]2[N:27]=[C:28]([CH2:34][CH2:35][CH3:36])[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:20]=2[C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][CH2:12][NH:11][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)=[CH:25][C:24]=2[N:23]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(OCCCNC(=O)c4cccnc4)ccc3c2n1CC(C)C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
Nicotinoyl chloride hydrochloride (0.23 g, 1.29 mmol) was added in one portion to a solution of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.460 g, 1.29 mmol) and triethylamine (0.383 mL, 2.75 mmol) in chloroform (15 mL), and the reaction was stirred for 16 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and stirred for 30 minutes. The aqueous layer was separated and extracted with chloroform. The combined organic fractions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting pale yellow oil was triturated with acetonitrile, which was removed under reduced pressure. The resulting solid was recrystallized from acetonitrile to yield 0.310 g of N-{3-[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}nicotinamide as off-white, granular crystals, mp 172-174° C.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[C:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>CN1C(=O)CCC1.O>[C:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:4]2[CH:3]=[C:2]([NH2:1])[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]=2[C:6](=[O:7])[NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH2:33][CH2:32]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 100 °C

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 154) in NMP (2 mL) was added piperidin-4-yl-carbamic acid tert-butyl ester (4 mmol). The resulting mixture was heated at 100° C. for 10 h. The reaction mixture was cooled to room temperature, and diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo. The crude product was purified on a silica gel column chromatography using EtOAc/hexane as eluent to provide {1-[5-Amino-2-(1H-indazol-6-ylcarbamoyl)-4-nitro-phenyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]#[C:5][CH2:6][O:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.[CH:19]1([N:26]=[N+:27]=[N-:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1(Br)CCCCCC1.[N-]=[N+]=[N-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[N:26]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:27]=[N:28][C:5]=1[CH2:6][O:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:18]
Reactant: COC(=O)C#CCOC12CC3CC(CC(C3)C1)C2
Reactant: [N-]=[N+]=NC1CCCCCC1
Agent: BrC1CCCCCC1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1c(COC23CC4CC(CC(C4)C2)C3)nnn1C1CCCCCC1
Yield: 36 %

Procedure:
A solution of the product from step b (2.74 g, 11.1 mmol) and cycloheptyl azide (prepared by the reaction of cycloheptyl bromide and sodium azide) (1.54 g, 11.1 mmol) in toluene (14 ml) was heated under reflux for 42 hours. The solvent was removed invacuo and the residue purified by flash column chromatography (hexane:EtOAc 3:1) to yield 5-(adamantan-1-yloxymethyl)-3-cycloheptyl-3H-[1,2,3]triazole-4-carboxylic acid methyl ester (1.53 g, 36%). 1H NMR (CDCl3) 5.27-5.21 (1H, m), 4.73 (2H, s), 3.94 (3H, s), 2.20-2.11 (7H, m), 1.86-1.85 (8H, m), 1.69-1.60 (12H, m). Further eluation gave rise to 5-(adamantan-1-yloxymethyl)-1-cycloheptyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (2.00 g, 47%). 1H NMR (CDCl3) 4.93 (2H, s), 4.74-4.65 (1H, m), 3.94 (3H, s), 2.32-2.04 (8H, m), 2.00-1.54 (19H, m).
Reaction SMILES: O[CH:2]=[C:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])[C:4]#[N:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>N1C=CC=CC=1>[CH3:15][S:16]([CH:2]=[C:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])[C:4]#[N:5])(=[O:18])=[O:17]
Reactant: Cc1cc(C)c(C(C#N)=CO)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(C)c(C(C#N)=CS(C)(=O)=O)c(C)c1
Reaction time: 1 h
Yield: 105.1 %

Procedure:
A solution of intermediate 1 (1 g) in 10 ml pyridine was cooled to 0° C. under nitrogen and then treated with methanesulfonyl chloride (0.67 g) with good stirring. The solution was allowed to come to room temperature and stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with 1 M HCl, water and brine, dried (MgSO4) and concentrated to give 3-methanesulfonyl-2-(2,4,6-trimethylphenyl)acrylonitrile (intermediate 2) as a brown solid (1.4 g).
Reaction SMILES: [CH2:1]([O:3]/[N:4]=[C:5](/[C:36]1[N:37]=[C:38]([NH:41]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:39][CH:40]=1)\[C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:19])=[C:13]([CH2:16]I)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].[CH3:61][S:62][C:63]1[S:64][CH:65]=[CH:66][N:67]=1>C(Cl)Cl.C(Cl)(Cl)Cl.[B-](F)(F)(F)F.[Ag+]>[NH2:41][C:38]1[S:39][CH:40]=[C:36](/[C:5](=[N:4]/[O:3][CH2:1][CH3:2])/[C:6]([NH:8][CH:9]2[C:34](=[O:35])[N:11]3[C:12]([C:18]([O-:20])=[O:19])=[C:13]([CH2:16][N+:67]4[CH:66]=[CH:65][S:64][C:63]=4[S:62][CH3:61])[CH2:14][S:15][C@H:10]23)=[O:7])[N:37]=1
Reactant: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CSc1nccs1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccsc3SC)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 145.6 %

Procedure:
To an ice-cooled solution of diphenylmethyl 7-[(Z)-2-(ethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VII-2] (517 mg, 0.55 mmole) and 2-methylthiothiazole (85.3 mg, 0.65 mmole) in CH2Cl2 (10 ml) was added AgBF4 (117 mg, 0.60 mmole) and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with CHCl3 (100 mL), and the resulting precipitate was recovered by filtration and washed with CHCl3 (100 mL). The filtrate and the washings were combined and washed with water, dried over MgSO4 and evaporated. The residue was triturated with ether (50 mL) to give an amorphous solid (433 mg), which was dissolved in 90% TFA. The mixture was allowed to stand for 45 minutes at room temperature and then evaporated in vacuo at 10° C. The residue was triturated with ether to give crude Id (291 mg) which was dissolved in a small amount of methanol and passed through an HP-20 (20 mL) column by eluting with 30% aqueous methanol, to give 63.3 mg (29%) of the title compound [Id]. Estimated purity 70%.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][CH:35](O)[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccc(F)cc1F)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1ccc(F)cc1F)O2

Procedure:
2-(2,4-Difluorophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 800 mg of 2-(2,4-difluorophenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 8.83 (s, 1H), 7.56 (m, 1H), 7.28 (m, 1H), 7.13 (m, 1H), 6.63 (m, 1H), 6.53-6.50 (m, 2H), 5.17 (dd, 1H, J 10.3, 2.3 Hz), 2.92 (ddd, 1H, J −17.0, 11.5, 5.8 Hz), 2.66 (ddd, 1H, J −17.0, 5.0, 2.7 Hz), 2.09 (m, 1H), 1.98 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:17][OH:18])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:22].[K+]>O>[CH2:1]([O:8][C:9]1[C:10]([C:17]([OH:22])=[O:18])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccnc(CO)c1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccnc(C(=O)O)c1OCc1ccccc1
Yield: 83.9 %

Procedure:
3-Benzyloxy-2-hydroxymethyl-4-methoxypyridine (7.1 g) and 2.5 g of potassium hydroxide were suspended in 100 ml of water. While heating the suspension in a water bath, potassium permanganate (7.3 g) was added thereto, and the mixture was stirred. The precipitate was filtered, and was washed with 100 ml of methanol. The filtrate and the washings were combined, followed by concentration under the reduced pressure. The concentrate was adjusted to pH 1 by the addition of concentrated hydrochloric acid. The precipitate was filtered, washed with water, and then dried to give 6.3 g (yield 83.9%) of the title compound as colorless powder.