Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([CH:12]=[CH2:13])[CH2:11][O:10][CH2:9][O:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH:12]([C:6]1([C:4]([OH:5])=[O:3])[CH2:7][O:8][CH2:9][O:10][CH2:11]1)=[CH2:13]
Reactant: C=CC1(C(=O)OCC)COCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CC1(C(=O)O)COCOC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
A solution of 5-vinyl-[1,3]dioxane-5-carboxylic acid ethyl ester (397.7 mg, 2.136 mmol) in tetrahydrofuran/methanol/water (15 mL, 2:2:1) was treated with lithium hydroxide monohydrate (269 mg, 6.408 mmol). After stirring at room temperature for 1.5 h, the volatiles were removed in vacuo and the residue was cooled to 0° C. and quenched with hydrochloric acid (1 M). The aqueous layer was saturated with sodium chloride, extracted with dichloromethane (3×). The combined organics were filtered through a phase separator and the volatiles were removed in vacuo to provide the title compound (320.3 mg, 95%) as a colourless solid. 1H NMR (300 MHz, CDCl3) δ 3.72 (d, J=11.6 Hz, 2H), 4.50 (d, J=11.4 Hz, 2H), 4.73 (d, J=6.2 Hz, 1H), 5.02 (d, J=6.0 Hz, 1H), 5.27-5.39 (m, 2H), 5.69 (dd, J=17.6, 10.9 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.[C:18]1([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]([CH3:41])C=O>[Cu]I.O>[C:25]1([N:24]([C:2]2[C:10]3[C:6](=[N:7][N:8]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)[N:9]=3)[C:5]([N:38]([C:41]3[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=3)[C:37]3[CH:6]=[CH:10][CH:2]=[CH:3][CH:4]=3)=[CH:4][CH:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Reactant: CN(C)C=O
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1ccc(N(c2ccccc2)c2ccc(N(c3ccccc3)c3ccccc3)c3nn(-c4ccncc4)nc23)cc1
Temperature: 160 °C

Procedure:
A mixture of Intermediate A (1.05 g, 3.0 mmol), diphenylamine (2.03 g, 12.0 mmol), potassium carbonate (1.66 g, 12.0 mmol), CuI (1.14 g, 6.0 mmol), and dimethylformamide (20 mL) was stirred under argon and heated at 160° C. for 3 days. After cooling, the reaction mixture was poured into water (100 mL) and stirred for 15 minutes. The precipitate was filtered off and washed with water (50 mL). A suspension of this solid in dichloromethane (100 mL) was treated with concentrated ammonium hydroxide (20 mL) and stirred for 1 hour. The dichloromethane layer was separated, dried over sodium sulfate and chromatographed (silica gel, dichloromethane/ethyl acetate 9:1). The obtained product was recrystallized from ethanol to give 4,7-bis(N,N-diphenylamino)-2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazole (Example 19), orange crystals, 55 mg (3%). 1H NMR (400 MHz, CDCl3): δ 8.57 (m, 2H, pyridine), 7.64 (m, 2H, pyridine), 7.28 (m, 8H, Ph), 7.15 (m, 8H, Ph), 7.06 (t, J=7.3 Hz, 4H, Ph), 6.96 (s, 2H, benzotriazole. UV-vis spectrum (dichloromethane): λmax=471 nm. Fluorimetry (dichloromethane): λmax=640 nm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].C(N(C(C)C)CC)(C)C.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33].C(OCC)(=O)C>CN(C)C=O>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])(=[O:33])=[O:34]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(OCCNS(=O)(=O)c2ccc3ccccc3c2)c1

Procedure:
163 mg of 3-(2-aminoethoxy)benzonitrile and 0.5 ml of diisopropylethylamine were dissolved in 10 ml of dimethylformamide. A solution of 250 mg (1.1 mmol) of 2-naphthalenesulfonyl chloride in dimethylformamide was added to the obtained solution under cooling with ice, and they were stirred under cooling with ice for 2 hours. The title compound was obtained by the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH:29]=O)=[CH:23]3)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH:28][CH:27]=2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 79.6 %

Procedure:
A mixture of 5-bromo-2-oxindole (42 mg, 0.2 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (52 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 72 mg (80%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:29][C@H:28]([CH2:30]O)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:29][C@H:28]([CH2:30][N:47]4[CH2:48][CH2:49][CH:44]([OH:43])[CH2:45][CH2:46]4)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Reactant: OC1CCNCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCC(O)CC2)C1

Procedure:
The title compound is prepared in analogy to Example 116 starting from 0.35 g (0.84 mmol) cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}methanol and 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml dry pyridine, followed by 0.87 g (8.44 mmol) 4-hydroxypiperidine (Fluka, Buchs, Switzerland). Analytical HPLC: tR=8.76 min (Grad 1); ES-MS: m/eo=498.2; NMR (DMSO-d6; not all signals reported): 8.07/s (1H), 7.25-7.5/several m's (6H), 7.01/“d” (1H); 6.94/s (1H); 6.89/“d” (1H); 5.13/s (2H); 4.76/m (1H); 4.51/d (OH); 2.22/s (3H).
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6](=[S:18])[C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:9])[CH3:8])[CH3:4].NOS(O)(=O)=O.N1C=CC=CC=1.CO>C(O)C>[CH3:4][C:3]1[N:5]=[C:6]([C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:9])[CH3:8])[S:18][N:2]=1
Reactant: CC(=NC(=S)C(C)(C)NC(=O)OC(C)(C)C)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1nsc(C(C)(C)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of tert-butyl 1-(1-(dimethylamino)ethylideneamino)-2-methyl-1-thioxopropan-2-ylcarbamate (2.9 g, 10 mmol), hydroxylamine-O-sulfonic acid (CAN 2950-43-8, 1.37 g, 12 mmol), pyridine (1.6 g, 20.2 mmol) and methanol (4 mL) in ethanol (20 mL) was stirred at room temperature for 2 h. After evaporation of solvents, the residue was diluted with ethyl acetate (40 mL) and water (40 mL). The organic layer was washed with brine (40 mL), dried over anhydrous sodium sulfate and concentrated to give crude product (2.5 g, 96%) as yellow oil. The product was used directly in the next step without further purification; MS (EI): m/e 258.2 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][C:32]=4[F:45])=[C:26]([CH2:46][CH2:47][CH3:48])[N:25]4[N:49]=[C:50]([CH3:52])[N:51]=[C:24]34)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[O:16]1[C:17]2([CH2:22][CH2:21][CH:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][C:32]=4[F:45])=[C:26]([CH2:46][CH2:47][CH3:48])[N:25]4[N:49]=[C:50]([CH3:52])[N:51]=[C:24]34)[CH2:19][CH2:18]2)[O:13][CH2:14][CH2:15]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.62 g), sodium hydrogen carbonate (1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.32 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.098 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.25 g, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[C:6]([C:14]#[N:15])=[CH:5]2.C[O-].[Na+].[Na].[NH3:20]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2=[CH:8][C:7]3[C:12](=[NH:13])[NH:15][C:14](=[NH:20])[C:6]=3[CH:5]=[C:4]2[CH:3]=1
Reactant: N
Reactant: N#Cc1cc2ccc(Br)cc2cc1C#N
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: N=C1NC(=N)c2cc3cc(Br)ccc3cc21

Procedure:
Under nitrogen, 44.1 g (0.172 mol) of 6-bromo-2,3-dicyanonaphthalene was added to a solution of sodium methoxide in methanol prepared by adding 1.92 g (84 mmols) of metallic sodium in 5 times to 270 ml of absolute methanol, and anhydrous ammonia gas was slowly bubbled into the resulting mixture with sufficient mixing at room temperature for about 1 hour. The mixture was refluxed for about 3 hours, while bubbling therethrough anhydrous ammonia gas. After cooling, the yellow solid precipitated was filtered and the residue was sufficiently washed with methanol and dried under reduced pressure to obtain 45 g of 6-bromo-1,3-diiminobenz[f]isoindoline as a yellow solid. IR specturm of this 6-bromo-1,3-diiminobenz[f]isoindoline is shown in in FIG. 3. The 6-bromo-1,3-diiminobenz[f]isoindoline was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8](Cl)(Cl)=[O:9])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(OCC)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:7]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[PH2:8]=[O:9])[CH3:2]
Reactant: CCOC(=O)CN(CP(=O)(Cl)Cl)C(=O)SCc1ccccc1
Reactant: C1CCNC1
Solvent: CCOCC
Product: CCOC(=O)CN(C(=O)SCc1ccccc1)C([PH2]=O)(N1CCCC1)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Freshly prepared ethyl-N-[(benzylthio)carbonyl]-N-[dichlorophosphinylmethyl]-glycinate (12.55 g.; 0.033mol.) dissolved in 100 ml. of diethyl ether was added to a solution of pyrrolidine (9.3 g.; 0.13 mol.) in 100 ml. of diethyl ether. The reaction mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with water, dried with magnesium sulfate and concentrated in vacuo. To remove any remaining solvent, the residue was concentrated at 25° C. and 0.05 mm. to yield ethyl-N-[(benzylthio)carbonyl]-N-[bis(pyrrolidyl)-phosphinylmethyl]-glycinate, hemi-hydrate as an oil (nD25 =1.5424) having the following analysis:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])C)(=O)[CH3:2].[OH:8][NH:9][CH2:10][CH2:11][CH2:12][P:13](=[O:16])([OH:15])[OH:14]>C(O)=O>[CH2:1]([CH2:2][NH2:9])[OH:4].[CH:5]([N:9]([CH2:10][CH2:11][CH2:12][P:13](=[O:14])([OH:16])[OH:15])[OH:8])=[O:7]
Reactant: O=P(O)(O)CCCNO
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: NCCO
Product: O=CN(O)CCCP(=O)(O)O
Reaction time: 0.5 h

Procedure:
Formic acid (1.0 ml.) was added dropwise to acetic anhydride (1.2 ml.) at ambient temperature with stirring. The stirring was continued at the same temperature for 30 minutes and then 3-(N-hydroxyamino)propylphosphonic acid (1.51 g.) was added to the mixture. The reaction mixture was stirred at ambient temperature for 1.5 hours and concentrated under reduced pressure to given an oily residue, which was dissolved in ethanol (20 ml.). To the aqueous solution was added ethanolamine (0.61 g.) to precipitate an oil, which was separated by decantation and crystallized with ethanol (20 ml.) to give crystals. The crystals were separated by filtration, washed with ethanol and dried to give crystalline monoethanolamine salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (1.75 g.), a part (1.5 g.) of which was recrystallized from 90% aqueous ethanol to give the purified object compound (1.15 g). M.p. 139°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=3)[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(C)(C)C3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)O)cc3)CC2)C1

Procedure:
reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate and aqueous sodium hydroxide at about 55° C. to about 75° C., and isolating or not isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid; and
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[C:35](=O)([O:45]C1C=CC([N+]([O-])=O)=CC=1)[O:36][C@@H:37]1[C@H:44]2[C@H:40]([O:41][CH2:42][CH2:43]2)[O:39][CH2:38]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][C@H:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:35]([O:36][C@@H:37]5[C@H:44]6[C@H:40]([O:41][CH2:42][CH2:43]6)[O:39][CH2:38]5)=[O:45])[CH2:23][CH2:24]4)[C@H:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
A mixture of 2-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (100 mg, 0.22 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate (78 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) in acetonitrile (3 mL) was stirred at rt for 16 h. The reaction mixture was concentrated and the residue in dichloromethane was washed with saturated sodium carbonate solution, dried, concentrated and chromatographed on silica gel eluting with 1:40 methanol:dichloromethane to give (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboxylate as a clear glass (0.064 g, 50%). 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 2H), 7.29 (m, 5H), 7.16 (m, 2H), 5.71 (m, 1H), 5.18 (m, 1H), 4.59 (m, 1H), 3.75-4.04 (m, 7H), 3.22 (m, 3H), 3.05 (m, 1H), 2.58 (m, 3H), 2.19-2.36 (m, 4H), 1.80-1.92 (m, 9H), 1.61 (m, 5H). HRMS C35H44N4O4 m/z 585.3441 (M+H)Cal., 585.3440 (M+H)Obs..
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH:5][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1cc(F)cc(F)c1)OCc1ccccc1
Reaction time: 16 h
Yield: 93.8 %

Procedure:
3,5-Difluoroaniline (4.89 g, 37 91 mM) in acetone (130 ml) and water (70 ml) at 0° C. was treated with sodium hydrogen carbonate (6.55 g, 78.0 mM) and then benzyl chloroformate (6.67 g, 5.6 ml, 39.23 mM) over 10 min. The mixture was stirred for 16 h and then poured into ice. The resultant precipitate was collected and washed with water to give the title carbamate (9.35 g, 94%);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Yield: 9.8 %

Procedure:
2-methoxy-5-nitroaniline (1) (10.1 g, 600 mmol) in 250 mL dichloromethane at 0°-5° C. was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 720 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[CH3:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:28][O:29][C:30](=[O:34])[CH2:31][O:32][CH3:33]>C1COCC1>[CH2:28]([O:29][C:30](=[O:34])[CH:31]([O:32][CH3:33])[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:20]([CH3:27])[CH:21]=1)[OH:24])[CH3:1]
Reactant: Cc1cc(C=O)ccc1OCc1ccccc1
Reactant: COCC(=O)OC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)c(C)c1

Procedure:
To a solution of NaHMDS (1.1 eq) in dry THF at −78° C. a mixture of 4-Benzyloxy-3-methyl-benzaldehyde (1 eq) and Methoxy-acetic acid methyl ester (1.25 eq) in THF were added dropwise and the mixture reaction at this temperature over 1.5 hours. Then the reaction was quenched with HCl 3N and allowed to rise room temperature. Washed with brine and extracted with ether. The organic layer was dried and concentrated to dryness to give after chromatography in silica gel the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:16])[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-:3])=[O:2].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br.C([O-])([O-])=O.[K+].[K+].CCOCC.CCCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([N:16]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)([O-:3])=[O:2]
Reactant: Nc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=[N+]([O-])c1cc(N2CCOCC2)ccc1N1CCCCC1
Yield: 70.3 %

Procedure:
The title compound was prepared following the procedure of Example 10, step (b) using 152 mg (0.687 mmol) of 3-nitro-4-piperidin-1-yl-phenylamine (as prepared in Example 10, step (a)), 78.6 mg (0.625 mmol) of 2-bromoethyl ether and 433 mg (3.13 mmol) of anh K2CO3 except the mixture was heated to reflux in 2 mL of toluene for 20 h. Chromatography on a 10-g silica SPE column with 40% Et2O-hexane afforded 128 mg (70%) of the title compound as a dark orange resin: Mass spectrum (ESI, m/z): Calcd. for C15H21N3O2, 292.2 (M+H), found 292.1.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([S:14][CH2:15][C:16](OCC)=[O:17])=[CH:7][C:6]=1[F:21])C.C(OC(=O)C1C=C([N+]([O-])=O)C(F)=CC=1F)C.CCN(CC)CC.SCC(OCC)=O>C(Cl)Cl>[F:21][C:6]1[C:5]([CH:4]=[O:3])=[CH:10][C:9]2[NH:11][C:16](=[O:17])[CH2:15][S:14][C:8]=2[CH:7]=1
Reactant: CCOC(=O)CSc1cc(F)c(C(=O)OCC)cc1[N+](=O)[O-]
Agent: CCOC(=O)CS
Agent: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cc2c(cc1F)SCC(=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
4-Ethoxycarbonylmethylsulfanyl-2-fluoro-5-nitro-benzoic acid ethyl ester. To a solution of 2,4-difluoro-5-nitro-benzoic acid ethyl ester (7.0 g, 0.030 mol) in CH2Cl2 (125 mL) was added Et3N (5.0 mL, 36 mmol) at 0° C. Following the addition of ethyl 2-mercaptoacetate (3.30 mL, 30.3 mmol), the solution was warmed to RT and stirred for 18 h. The reaction mixture was partitioned between H2O and CH2Cl2 (400 mL). The organic layer was washed with 0.05 M HCl (200 mL), brine (200 mL), dried (MgSO4), filtered and concentrated to provide 9.6 g (96%) of the title compound as a tan solid. MS (ESI): exact mass calculated for C13H14FNO6S, 331.05; m/z not found. 1H NMR (500 MHz, CDCl3): 8.88 (d, J=6.9, 1H), 7.14 (d, J=11.4, 1H), 4.41 (q, J=7.2, 2H), 4.29 (q, J=7.2, 2H), 3.75 (s, 2H), 1.40 (t, J=7.2, 3H), 1.29 (t, J=7.2, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:17])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[CH3:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:9]=3[CH2:10][NH:11][C:12]4=[O:17])=[CH:6][CH:7]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(-c2cccc3c2CNC3=O)cc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3cccc4c3CNC4=O)cc2)c1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
An 0° C. suspension of Example 1D (1.94 g, 8.68 mmol) in THF (44 mL) was sequentially treated dropwise with N-methylmorpholine (0.95 mL, 8.68 mmol) and 3-methylphenyl isocyanate (1.12 mL, 8.68 mmol). The mixture was stirred for 1 hour, diluted with THF (20 mL), stirred at room temperature for 3 hours, and quenched with water (20 mL). The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was suspended in 5% methanol/dichloromethane and filtered. The filter cake was washed with dichloromethane and dried to provide 2.94 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.52 (s, 2H), 6.80 (d, J=7.5 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.23–7.27 (m, 1H), 7.31 (s, 1H), 7.53–7.60 (m, 5H), 7.64–7.67 (m, 2H), 8.63 (s, 1H), 8.65 (s, 1H), 8.80 (s, 1H); MS (ESI(+)) m/e 358.1 (M+H)+.