Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH2:16][C:17]1[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)=[O:4].O.C[O-].[Na+].Cl.[F:29][C:30]([F:34])([F:33])[CH2:31][OH:32]>>[F:29][C:30]([F:34])([F:33])[CH2:31][O:32][C:20]1[N:19]=[CH:18][C:17]([CH2:16][O:15][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:5]=2[C:3]([OH:2])=[O:4])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2ccccc2c1OCc1ccc(Cl)nc1
Reactant: OCC(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1
Temperature: 165 °C

Procedure:
To a solution of 0.30 g of 1-(6-chloro-pyridin-3-ylmethoxy)-naphthalene-2-carboxylic acid methyl ester in 4 ml 2,2,2-trifluoroethanol containing 5% of water was added 0.55 g sodium methoxide. The reaction was heated to 165° C. for 1 h using a microwave reactor. The reaction was then poured into ice-water, the pH was adjusted to 4 using 2 M hydrochloric acid and the precipitated product was collected by filtration and dried in vacuo yielding 0.22 g of 1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carboxylic acid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.[Cl:26][CH2:27][CH2:28][CH2:29][CH:30]([C:35]1[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][C:36]=1[F:43])[C:31]([NH:33][NH2:34])=[O:32].[CH3:44][O:45][C:46]1[CH:47]=[C:48](/[CH:58]=[CH:59]/[C:60](O)=[O:61])[CH:49]=[CH:50][C:51]=1[N:52]1[CH:56]=[C:55]([CH3:57])[N:54]=[CH:53]1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:44][O:45][C:46]1[CH:47]=[C:48](/[CH:58]=[CH:59]/[C:60]([NH:34][NH:33][C:31](=[O:32])[CH:30]([C:35]2[C:36]([F:43])=[CH:37][C:38]([F:42])=[CH:39][C:40]=2[F:41])[CH2:29][CH2:28][CH2:27][Cl:26])=[O:61])[CH:49]=[CH:50][C:51]=1[N:52]1[CH:56]=[C:55]([CH3:57])[N:54]=[CH:53]1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NNC(=O)C(CCCCl)c1c(F)cc(F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2c(F)cc(F)cc2F)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
IPEA (0.46 mL) and BOPCl (333 mg) were added to a solution of 5-chloro-2-(2,4,6-trifluorophenyl)pentanoic acid hydrazide hydrochloride (277 mg) and (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (225 mg) in methylene chloride (10 mL), and the reaction solution was stirred at room temperature for two hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl acetate:methanol=9:1) to obtain 286 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:28]1([CH2:34][C:35]([N:37]=[C:38]=[O:39])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.CCCCCC>[N:22]1([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[O:39])=[CH:27][CH:26]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:25][CH2:24][CH2:23]1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(azetidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (62.8 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.71 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (50.0 mg, 55%) as white powder.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[ClH:7].Cl.[CH:9]1[CH:18]=[CH:17][C:16]2[CH2:19][CH2:20][CH2:21][N:14]3[C:15]=2[C:10]=1[C@H:11]1[CH2:24][NH:23][CH2:22][C@H:12]1[CH2:13]3>>[ClH:7].[ClH:7].[CH3:5][C:4]([CH3:6])=[CH:3][CH2:2][N:23]1[CH2:24][C@H:11]2[C@H:12]([CH2:13][N:14]3[CH2:21][CH2:20][CH2:19][C:16]4[CH:17]=[CH:18][CH:9]=[C:10]2[C:15]3=4)[CH2:22]1
Reactant: CC(C)=CCBr
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CCC2
Agent: Cl
Product: CC(C)=CCN1C[C@H]2CN3CCCc4cccc(c43)[C@H]2C1

Procedure:
Using 4-bromo-2-methyl-2-butene and following the procedures described in EXAMPLE 104, (±)-cis-5,6,8,8a,9,10,11,11a-octahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline free base from EXAMPLE 11 was converted into the title compound of EXAMPLE 106 as an off-white powder. 1H NMR (dmso-D6) δ: 11.05 (broad s, 1H), 6.86 (t, 1H, J=6.2 Hz), 6.81 (t, 1H, J=7.0 Hz), 6.59 (q, 1H, J=7.3 Hz), 5.33-5.27 (m, 1H), 3.90-3.60 (m, 4H), 3.50-3.25 (m, 2H), 3.10-2.95 (m, 3H), 2.90-2.75 (m, 3H), 2.72-2.65 (m, 2H), 1.95-1.85 (m, 2H), 1.72 (s, 3H), 1.64 (s, 3H). LRMS (ES)+: 283.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][C:3]=1[O:13][CH3:14]>CS(O)(=O)=O>[OH:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][C:10]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(CCC(=O)O)ccc1O
Agent: CS(=O)(=O)O
Product: COc1cc2c(cc1O)C(=O)CC2
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 825.8 %

Procedure:
The 3-(4-Hydroxy-3-methoxy-phenyl)-propionic acid (2 g×10) was dissolved in methanesulfonic acid (10 ml×10) in microwave process vial (20 ml×10), the mixture was heated at 90° C. for 10 minutes under microwave irradiation. The mixture was poured into ice (500 g), and then stirred for 20 minutes. The precipitate was collected and dried to give 6-Hydroxy-5-methoxy-indan-1-one (15 g, 82.6%). LC-MS: m/e 179 (MH+)
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7]CC)=O.[Cl-].[NH4+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:21]([CH:23]1[CH2:28][CH2:27]C(N)[CH2:25][CH2:24]1)[CH3:22]>O1CCCC1.C(OCC)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>[CH2:21]([CH:23]1[CH2:28][CH2:27][CH:12]([N:2]2[CH:3]=[C:4]([CH2:5][OH:7])[N:10]=[CH:11]2)[CH2:25][CH2:24]1)[CH3:22]
Reactant: CCC1CCC(N)CC1
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC1CCC(n2cnc(CO)c2)CC1
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 54.5 %

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (2.00 g) was dissolved in 4-ethylcyclohexylamine (3.37 g), and the solution was stirred at 70° C. for 4.5 hours. To the reaction solution, saturated aqueous ammonium chloride was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. Lithium aluminum hydride (92%, 0.490 g) was suspended in tetrahydrofuran (12 mL). The produced crude product was dissolved in tetrahydrofuran (12 mL), and this solution was slowly added dropwise to the suspension at 0° C. After stirring at 0° C. for 30 minutes, the reaction solution was diluted with diethyl ether, and saturated aqueous sodium sulfate was added thereto. After stirring at room temperature for 1 hour, the formed inorganic salt was removed by filtration through celite. The filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: methylene chloride-methylene chloride/methanol=9/1) to obtain the title compound (1.35 g, diastereomeric mixture, trans:cis=4:1).
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C=O>O>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][S:26][C:23]2[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(SOC(=O)CCC2CCN(C(=N)N)CC2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 45.2 %

Procedure:
A mixture of 3 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.2 g of p-t-butyl thiophenol, 2.6 g of dicyclohexylcarbodiimide and 18 ml of dry dimethylformamide was stirred at room temperature for 10 hours. After removal of any insoluble materials, the solvent was removed under reduced pressure. The residue was washed with ether and dissolved in t-butanol. Ether was added to the solution to give an oily substance. Water was added to the oily substance, and the mixture was allowed to stand overnight in cold conditions to give crystals. The crystals were washed with ethyl acetate and then with ether and air-dried to obtain 2.3 g (yield: 46.9%) of p-t-butylphenylthio 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 86° to 88° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15]C(C)(C)C)=O)[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:21](F)(F)C(O)=O.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:21])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccnc2F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(c2cccnc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 3-(2-fluoropyridin-3-yl)pyrrolidine-1-carboxylate (0.25 g, 0.939 mmol) dissolved in DCM (3.1 mL) was added trifluoroacetic acid (1.05 mL, 14.1 mmol). The reaction mixture was stirred at RT for 1 h. The solvent was evaporated in vacuo and to the residue dissolved in DCM (1 mL) was added acetic anhydride (0.44 mL, 4.7 mmol) and sodium bicarbonate (0.4 g, 4.7 mmol). The reaction mixture was stirred at RT under N2 for 3 h. The reaction mixture was partitioned between 1N NaOH and DCM. The aqueous layer was back extracted with DCM (3×) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 10% MeOH in EtOAc, to provide 1-(3-(2-fluoropyridin-3-yl)pyrrolidin-1-yl)ethanone as tan oil. [M+H]=209.2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].ClCCl>CC(C)=O.O>[C:22]([O:28][CH2:29][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C@H:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1cccc([C@H](C)c2nccn2COC(=O)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of the compound of Example 58 (500 mg, 2.5 mmol) and caesium carbonate (1.79 g, 5.5 mmol) in anhydrous acetone (10 ml) was added chloromethyl pivalate (0.43 ml, 3.0 mmol). The reaction mixture was stirred at room temperature for 18 h. To the mixture was added dichloromethane (10 ml) and water (10 ml) and the two layers were separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [O:1]=[C:2]1[NH:18][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([O:15]CC)=[O:14])[NH:10][C:11]=3[CH:12]=[C:4]2[NH:3]1>O>[O:1]=[C:2]1[NH:18][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[NH:10][C:11]=3[CH:12]=[C:4]2[NH:3]1
Reactant: CCOC(=O)c1cc2cc3[nH]c(=O)[nH]c3cc2[nH]1
Solvent: O
Product: O=C(O)c1cc2cc3[nH]c(=O)[nH]c3cc2[nH]1

Procedure:
The title compound is prepared from ethyl 2-oxo-1,2,3,5-tetrahydro-imidazo[4,5-f]indole-6-carboxylate _according to the method described in Example 1/b. Mp.: >270° C. (water).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[N:28]=[C:29]=[O:30]>O1CCOCC1>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:17][C:29]([NH:28][C:22]3[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])=[O:30])[CH:16]=2)=[CH:8][CH:9]=1)[CH3:19]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: CCN(CC)c1ccc(Nc2cc(N)ncn2)cc1
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(Nc2cc(NC(=O)Nc3c(F)cccc3F)ncn2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-(4-diethylamino-phenyl)-pyrimidine-4,6-diamine (257.4 mg, 1 mmol), 2,6-difluorophenyl isocyanate (170.6 mg, 1.1 mmol) in dry dioxane (4 mL) is shaken for 1.5 h at 80° C. After evaporation of the solvent in vacuo, the residue is distributed between CH2Cl2 and half-saturated K2CO3 solution. The organic layer is dried over Na2SO4, evaporated, and the residue purified by flash chromatography (CH2Cl2/CH3OH). The combined pure fractions are evaporated, the residue triturated with CH2Cl2 and the solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[NH:8][C:9]1[N:14]=[C:13]([C:15]2[N:19]([CH2:20][CH2:21][N:22]3C(=O)C4=CC=CC=C4C3=O)[CH:18]=[N:17][CH:16]=2)[CH:12]=[CH:11][N:10]=1>CCO>[NH2:22][CH2:21][CH2:20][N:19]1[C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:7]3[CH:33]=[CH:34][CH:35]=[C:5]([Cl:4])[CH:6]=3)[N:14]=2)=[CH:16][N:17]=[CH:18]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Yield: 59.2 %

Procedure:
Hydrazine hydrate (54 ml, 1.73 mmol) was added to a suspension of 2-(3-chloroanilino)-4-[1-(2-phthalimidoethyl)imidazol-5-yl]pyrimidine (Example 10; 163 mg, 0.37 mmol) in EtOH (5 ml) and the mixture was heated at reflux for 2 hours. The mixture was allowed to cool, the volatiles removed by evaporation and the residue purified by column chromatography eluting with DCM and 7M methanolic ammonia solution (90:10) to give the title compound 69 mg, (59%) as a solid product. NMR: 1.41 (brs, 2H), 2.99 (t, 2H), 4.55 (t, 2H), 7.00-7.09 (m, 2H), 7.22-7.35 (m, 3H), 7.65-7.70 (m, 2H), 7.73-7.78 (m, 1H), 8.39 (d, 1H); m/z: 315.
Reaction SMILES: C(S[C@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[C:43]([Cl:45])[C:42]([Cl:46])=[CH:41][C:40]=3[Cl:47])=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:48])[C@@H:5]1[C@H:49]([OH:51])[CH3:50])C.[Cl:52]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:52][C@@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[C:43]([Cl:45])[C:42]([Cl:46])=[CH:41][C:40]=3[Cl:47])=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[S:10])[C:6](=[O:48])[C@@H:5]1[C@H:49]([OH:51])[CH3:50]
Reactant: ClCl
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(C(=O)Sc2cc(Cl)c(Cl)cc2Cl)cc1)C(=O)C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccc(C(=O)Sc3cc(Cl)c(Cl)cc3Cl)cc2)C(=O)C(C)(C)C)[C@H]1Cl
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a stirred solution of 1.26 g of 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-(1(R)-hydroxyethyl)-azetidin-2-on-1-yl]-3-[4-(2,4,5-trichlorophenylthio-(carbonyl))-phenoxy]-3-trimethylacetylthiopropenoate in 30 ml of dry chloroform at -40° C. was added a solution of 1.83 mmol chlorine in 4 ml of carbon tetrachloride, and the solution was stirred for 30 minutes. The reaction mixture was allowed to reach room temperature and evaporated to dryness. Chromatography of the residue (silica gel, hexane/ethyl acetate mixtures as eluant) gave the title compound as a pale yellow foam (0.706 g). νmax (CHCl3) 1784 cm-1.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.C(OCC)(=O)C>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(O)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(tert-butyldimethylsilyl)oxy-1-cyclohexanol (12.5 g) and triethylamine (9.8 ml) in dichloromethane (200 ml) was added dropwise methylsulfonyl chloride (4.6 ml) at 5° C. under nitrogen atmosphere. A reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. Insoluble material was removed by filtration and mother liquor was concentrated under reduced pressure to give residue, which was dissolved in ethyl acetate (200 ml) and washed in turn with 1N-aqueous hydrochloric acid (50 ml×2), saturated sodium hydrogen carbonate in water (50 ml×2) and saturated sodium chloride in water (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (300 ml) eluting with 10% ethyl acetate in n-hexane to give 3-(tert-butyldimethylsilyl)oxy-1-(methylsulfonyloxy)-cyclohexane(cis and trans mixture, 16.0 g).
Reaction SMILES: O[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC(C)=O.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CN(C=O)C>[N+:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CS(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1

Procedure:
The intermediate nitrobenzenes with the alkoxycarbonylalkoxy W substituent are formed from 2-hydroxy-4-fluoronitrobenzene. 2-Hydroxy-4-fluoronitrobenzene is reacted with a haloalkylcarboxylate (e.g., ethyl 2-bromopropionate) in a suitable solvent (e.g., acetone, acetonitrile, DMF, or DMSO) in the presence of a base (e.g., potassium carbonate) for an extended period (e.g., 3 days). The intermediate nitrobenzene is then isolated by standard laboratory techniques.
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1([F:30])[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)[CH2:11][CH2:10]1.CO.[OH-].[Na+]>C(OCC)(=O)C>[F:30][C:9]1([F:8])[CH2:10][CH2:11][CH:12]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([NH2:22])[CH2:20][CH2:21]2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCC(F)(F)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC1CCN(CC2CCC(F)(F)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A 4 N hydrogen chloride/1,4-dioxane solution (11 ml, 43 mmol) was added to a mixture of tert-butyl N-{1-[(4,4-difluorocyclohexyl)methyl]piperidin-4-yl}carbamate obtained in Example 2c (650 mg, 1.96 mmol) and methanol (11 ml), followed by stirring at room temperature for three hours. After concentrating the reaction liquid, the residue was dissolved in ethyl acetate, a 1N aqueous sodium hydroxide solution was added, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate twice, the organic layers were dried over sodium sulfate, and the solvent was then distilled off to give the title compound (419 mg, yield 92%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[O:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl.CCCCCC>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[O:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1nc2oc3c(c2c(=O)[nH]1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(Cl)c2c3c(oc2n1)CCCC3
Yield: 82 %

Procedure:
To a 50 mL flask was added 3 (2.04 g, 10 mmol) and 10 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 3 g of silica gel. The solvent was evaporated to afford a plug. Column chromatography of the plug with hexane: acetyl acetate=20:1 as eluent afford 1.67 g (82%) of 4 as a yellow solid: TLC Rf 0.41 (Hexane/EtOAc 15:1); mp 42.4-43.8° C.; 1H NMR (DMSO-d6) δ 1.79 (q, 2H, J=8 Hz), 1.87 (q, 2H, J=8 Hz), 2.63 (s, 3H), 2.75 (d, 4H, J=8 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([CH:24]([CH3:26])[CH3:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH3:22])[C:14]1=[O:23].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH:24]([C:13]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:36]2[CH2:35][CH2:34][N:33]([CH2:32][C:31]3[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:29]([O:28][CH3:27])[CH:30]=3)[CH2:38][CH2:37]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH3:22])[C:14]1=[O:23])([CH3:26])[CH3:25]
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: CC(C)C1(c2ccccc2OCCCCBr)C(=O)N(C)c2ccccc21
Product: COc1cc(CN2CCN(CCCCOc3ccccc3C3(C(C)C)C(=O)N(C)c4ccccc43)CC2)cc(OC)c1OC

Procedure:
Preparation in analogy to Example (3d) from 3-[2-(4-bromobutoxy) phenyl]-3-isopropyl-1-methylindolin-2-one and 3,4,5-trimethoxybenzylpiperazine. Melting point 235°-237° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O>[Si:18]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OCc1cc(Br)c2occc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)c2occc2c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A mixture of 0.40 gm (1.76 mMol) 5-(hydroxymethyl)-7-bromobenzofuran, 0.24 gm (30.5 mMol) imidazole, and 0.26 gm (1.76 mMol) tert-butyldimethylsilyl chloride in 2 ml dimethylformamide was stirred at room temperature over night. The reaction mixture was then partitioned between hexane and water. The organic phase was washed with well with water, dried over magnesium sulfate and concentrated under reduced pressure to provide 0.51 gm (85%) of the desired compound.