Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS([O-])(=O)=O.[Na+].[CH3:25][CH2:26]OCC>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:25][CH3:26])([OH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: CCC1(O)CCN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a flame-dried b 25-mL rb flask containing ethylmagnesium bromide (4.0 mL of a 3.0M solution in Et2O, 12.0 mmol, 3.0 equiv), at -10° C. was added dropwise a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolone (1.0 g, 4.0 mmol) in Et2O (4 mL). The reaction mixture was stirred at -10° C. for 15 min, then allowed to warm to rt over 10 min. A 1.0M solution of NaHSO4 (10 mL) was then rapidly added. The resulting biphasic mixture was extracted with EtOAc (3×10 mL), and the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, 4:1), affording 800 mg (71%) of the desired product as a clear yellow oil (Rf 0.14, hexanes/EtOAc, 4:1). Data for 1-tert-butoxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-4-hydroxyquinoline: 1H NMR (400 MHz, CDCl3) 7.68 (d, 1H, J=8.4, 8-H), 7.47 (dd, 1H, J=7.9, 1.7, 5-H), 7.21 (ddd, 1H, J=7.4, 7.4, 1.6, 6-H), 7.09 (ddd, 1H, J=7.8, 7.8, 1.1, 7-H), 4.03 (ddd, 1H, J=12.9, 7.1, 4.7, 2-H), 3.47 (ddd, 1H, J=13.1, 8.6, 4.3; 2-H), 2.11 (ddd, 1H, J=13.5, 8.6, 4.8, 3-H), 1.86 (m, 3H, 3-H, CH2CH3), 1.52 [s, 9H, C(CH3)3 ], 0.89 (t, 3H, J=7.5, CH3).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6](C(OC)=O)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(=O)c2ccccc21
Reaction time: 16 h

Procedure:
To a solution of methyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (Compound E2, 1.05 g, 4.5 mmol) in 10 mL of ethanol and THF (10 mL) was added sodiumhydroxide 9 mL (1M solution). The solution was stirred for 16 h and thereafter acidified with 10% HCl. The mixture was extracted with ethyl acetate, the combined organic layer was washed with water and brine, and dried over MgSO4. The solvent was distilled off under reduced pressure to afford the title compound as a white solid. 1H NMR (Acetone-D6): δ 1.44 (s, 6H), 2.07 (t, J=6.7 Hz, 2H), 2.73 (t, J=6.7 Hz, 2H), 7.70 (d, J=8.2 Hz, 1H), 8.19 (dd, J=1.9, 8.2 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[NH:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)=[N+]=[N-].N([C@H]1CC[C@H](C(O)=O)CC1)=[N+]=[N-].C1(C2C=CC(N)=C(N)C=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:70][S:71](Cl)(=[O:73])=[O:72].N>C(N(CC)CC)C.O.C1COCC1>[CH3:70][S:71]([NH:1][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[NH:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)(=[O:73])=[O:72]
Reactant: CS(=O)(=O)Cl
Reactant: [N-]=[N+]=N[C@H]1CC[C@H](c2nc3ccc(-c4ccccc4)cc3[nH]2)CC1
Agent: N
Agent: Nc1ccc(-c2ccccc2)cc1N
Agent: [N-]=[N+]=N[C@H]1CC[C@H](C(=O)O)CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H]1CC[C@H](c2nc3ccc(-c4ccccc4)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution in a solvent mixture of THF (4.0 mL) and water (1.0 mL) of 2-(trans-4-azidocyclohexyl)-5-phenylbenzimidazole (73.1 mg) as prepared by reacting trans-4-azidocyclohexanecarboxylic acid with 4-phenyl-1,2-phenylenediamine under the same conditions as described in Example 1-3) was added triphenylphosphine (72.0 mg), followed by stirring at room temperature for 1 hr. A portion of the reaction solution was admixed with methanesulfonyl chloride and triethylamine, followed by stirring at the same temperature for 1 hr., and the resultant reaction solution was admixed with conc. aqueous ammonia, followed by concentration under reduced pressure. The residue was separated and purified on a collective thin-layer chromatograph (chloroform:methanol=15:1) to give the title compound.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH3:6][Si:7]([CH3:10])(Cl)Cl>C(OCC)C>[C:1]([O:4][Si:7]([O:4][C:1](=[O:3])[CH3:2])([CH3:10])[CH3:6])(=[O:3])[CH3:2]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)O[Si](C)(C)OC(C)=O
Yield: 69.2 %

Procedure:
To a slurry of sodium acetate (8.2 g, 100 mmol, 2.0 equiv.) in anhydrous diethyl ether (40 mL) was slowly added a solution of dimethyldichloro silane 11A (6.45 g, 50 mmol, 1.0 equiv.) in anhydrous diethyl ether (10 mL). After addition was completed, the mixture was heated at reflux for 2 hours, and then filtered under N2. The filtrate was concentrated under vacuum at 40° C. to give diacetate 11B as a colorless oil (6.1 g, 70%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4].Cl[C:9]1[N:14]2[N:15]=[CH:16][N:17]=[C:13]2[N:12]=[CH:11][CH:10]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[N:15]1[N:14]2[C:9]([N:1]3[CH2:7][CH2:6][CH2:5][C@@H:2]3[CH2:3][OH:4])=[CH:10][CH:11]=[N:12][C:13]2=[N:17][CH:16]=1
Reactant: OC[C@H]1CCCN1
Reactant: Clc1ccnc2ncnn12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H]1CCCN1c1ccnc2ncnn12

Procedure:
1 g of commercially available (D)-prolinol, 1.5 g of 7-chloro-[1,2,4]triazolo-[1,5-a]pyrimidine and 2.6 g of N-ethyldiisopropylamine are heated at 130° C. in a microwave for 3 h in 60 ml of 1-butanol. The butanol is subsequently removed in vacuo, the residue is taken up in ethyl acetate, mixed with water, adjusted to pH 12 using 1 N NaOH solution, phases are separated, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel, giving 1.7 g of ((R)-1-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylpyrrolidin-2-yl)methanol as beige crystals;
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:29]4[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=4[Cl:27])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc4nc(N(C)CCN(C)C)sc4c3)cc2)c(Cl)c1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.05 g, 0.12 mmol) and 2-chloro-4-methoxy-phenyl boronic acid (0.026 g, 0.14 mmol) to afford 0.036 g (60%). LC/MS, Retention time=4.53 min; (m/z): calcd for C26H27ClN4O2S (M+H)+: 496.1; found: 496.0.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24][CH2:25][CH3:26])[N:15]([CH3:27])[C:12]2=[N:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:25]([S:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:15]([CH3:27])[C:12]2=[N:13][CH:14]=[C:9]([OH:8])[CH:10]=[C:11]2[N:17]=1)[CH3:26]
Reactant: CCSc1ccccc1-c1nc2cc(OCc3ccccc3)cnc2n1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCSc1ccccc1-c1nc2cc(O)cnc2n1C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
To a mixture of 6-benzyloxy-2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine 262 mg, and chloroform (3 mL), boron tribromide (1M in dichloromethane) (698 μL) was added under ice-cooling, and stirred for 3 hours. Into the mixture, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with chloroform then ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 168 mg of 2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-6-ol (hereinafter, Present Compound 268).
Reaction SMILES: Br[CH:2]([C:4]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[CH3:18])[C:8]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[S:21][C:7]=2[C:6](=[O:28])[N:5]=1)[CH3:3].[P:29]([O:36]CC)([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>>[Cl:17][C:13]1[C:12]([CH3:18])=[C:11]([CH2:10][N:9]2[C:8]3[N:19]=[C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[S:21][C:7]=3[C:6](=[O:28])[N:5]=[C:4]2[CH:2]([P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH3:3])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOP(OCC)OCC
Reactant: Cc1c(Cl)cccc1Cn1c(C(C)Br)nc(=O)c2sc(N3CCOCC3)nc21
Product: CCOP(=O)(OCC)C(C)c1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.4 %

Procedure:
Added 5-(1-bromoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (179 mg, 0.370 mmol) and triethyl phosphite (4 mL, 22.87 mmol) to a 20 mL screw capped vial and stirred overnight (14 hours) at room temperature. The next morning, starting material was still present, so the contents were transferred to a 25 mL round bottom flask and the contents were heated to 155° C. for 2 hours, whereupon LC/MS showed that the bromo starting material was consumed and a molecular ion corresponding to the desired product was present along with an impurity (believed to be the des-bromo compound by LC/MS). The yellow solution was distilled to remove the unreacted triethyl phosphite, then the residue was purified by column chromatography on silica gel eluted with 0-10% of a (2N solution of NH3 in methanol)/chloroform. The fractions containing product by TLC were combined, then concentrated to provide diethyl {1-[4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-7-oxo-4,7-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl]ethyl}phosphonate (51 mg, 0.094 mmol, 25.5% yield) as a light tan solid. LC/MS m/z MH+=541 (theoretical), found=541.1, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.36 (m, 6H) 1.47 (dd, J=17.31, 6.95 Hz, 3H) 2.46 (s, 3H) 3.02-3.18 (m, 1H) 3.49-3.60 (m, 4H) 3.71-3.82 (m, 4H) 4.00-4.27 (m, 4H) 5.67 (d, J=−17.68 Hz, 1H) 5.90 (d, J=17.68 Hz, 1H) 6.41 (d, J=7.58 Hz, 1H) 7.05 (t, J=7.83 Hz, 1H) 7.32 (d, J=7.58 Hz, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][OH:37]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][CH2:35][CH2:36][OH:37])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCCCO)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (0.6 g) obtained in Example 2 was suspended in dimethyl sulfoxide (40 ml), and to the suspension was added potassium carbonate (0.8 g), and the mixture was stirred at room temperature for 30 minutes. 3-bromo-1-propanol (0.3 ml) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (500 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, washed with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol) to produce the title compound (0.25 g, 37%).
Reaction SMILES: [C:1](=[O:19])(SCC)[O:2][CH2:3][O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:6].[Cl:20]Cl>>[Cl:20][C:1]([O:2][CH2:3][O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:6])=[O:19]
Reactant: ClCl
Reactant: CCCCCCCCCC(=O)OCOC(=O)SCC
Product: CCCCCCCCCC(=O)OCOC(=O)Cl
Reaction time: 0.25 h

Procedure:
SO2Cl2 (1.17 g, 8.65 mmol) was added to O-nonylcarbonyloxymethyl S-ethyl carbonothioate (Example 1ad(ii), 2.10 g, 7.22 mmol) in CH2 Cl2 (5 ml) at 0° C. with stirring during 15 min. followed by stirring at ambient temperature for 17 hours. Evaporation of EtSCl at 30° C. and 20 mmHg gave a yellow liquid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[O:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:17]>CO>[ClH:17].[O:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[CH:16]=[CH:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2occc2C1
Agent: Cl
Solvent: CO
Product: c1cc2c(o1)CCNC2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 100 %

Procedure:
To 6,7-dihydro-4H-furo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.56 g, 2.51 mmol) in methanol (50 mL) was added concentrated hydrochloric acid solution (37%, 1.4 mL). The mixture stirred at room temperature for 5.5 hours, monitored by TLC. The methanol was evaporated under reduced pressure to yield 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride (0.5 g, 100% yield) as a yellow powder. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.47 (s, 1H), 6.42 (s, 1H), 4.20 (s, 2H), 3.57 (m, 2H), 3.03 (m, 2H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 147.23, 143.89, 112.23, 109.50, 43.10, 42.37, 21.70.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:17]=[C:18]2[C:23](=O)[O:22][C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1>>[F:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:25][CH:26]=1)[C:20](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:23]2=[O:22]
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2ccc(F)cc2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.77 g, 56%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 3.94 mmol) and 4-fluorophthalic anhydride (0.78 g, 4.72 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[C:13]1([C:10]2[O:9][C:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(Cc2ccc(-c3ccccc3)o2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(Cc2ccc(-c3ccccc3)o2)cc1
Yield: 101.7 %

Procedure:
The title compound (280 mg, 99%) was prepared from the product of step 3 (0.3 g, 1.1 mmol) and BBr3 (0.85 g, 3.4 mmol) using the procedure of Example 159, step 4.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:15][CH2:16][NH2:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[C:13]C.C(N(C(C)C)C(C)C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([OH:39])([CH3:38])[C:35](O)=[O:36])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([OH:39])([CH3:38])[C:35]([NH:17][CH2:16][CH2:15][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:36])=[CH:32][CH:33]=1
Reactant: CC#CCOc1ccc(CCN)cc1OC
Reactant: CC(O)(C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(CCNC(=O)C(C)(O)c2ccc(Cl)cc2)cc1OC

Procedure:
To a stirred solution of 906 mg of 2-(3-methoxy-4-but-2-ynyloxy-phenyl)-ethylamine hydrochloride and 2.75 ml N-ethyldiisopropylamine are subsequently added 752 mg 2-(4-chlorophenyl)-2-hydroxy propionic acid and 1.875 g benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate. The resulting clear solution is stirred over night, extracted with ethyl acetate. The extracts are washed several times with water, dried over sodium sulfate, filtered and evaporated. The resulting oily residue is purified on silicagel (hexanc ethyl acetate) to obtain the 2-(4-chlorophenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]propionamide.
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[F:8][C:9]1([F:55])[CH2:14][CH2:13][CH:12]([C:15]2[C:24]3[CH:23]([OH:25])[CH2:22][C:21]([CH3:27])([CH3:26])[CH2:20][C:19]=3[N:18]=[C:17]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]4[N:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][N:35]=4)[CH2:30][CH2:29]3)[C:16]=2[CH:43]([F:54])[C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)[CH2:11][CH2:10]1>>[F:55][C:9]1([F:8])[CH2:10][CH2:11][CH:12]([C:15]2[C:24]3[CH:23]([OH:25])[CH2:22][C:21]([CH3:27])([CH3:26])[CH2:20][C:19]=3[N:18]=[C:17]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]4[N:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:42])[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:36][N:35]=4)[CH2:32][CH2:33]3)[C:16]=2[CH:43]([F:54])[C:44]2[CH:45]=[CH:46][C:47]([C:50]([F:51])([F:53])[F:52])=[CH:48][CH:49]=2)[CH2:13][CH2:14]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CNCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Product: CC(C)S(=O)(=O)N(C)Cc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 51 were performed except for using isopropylsulfonyl chloride instead of methanesulfonyl chloride, and from 64 mg (94 μmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1-{5-[(methylamino)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 58, 14 mg of the title compound was obtained as a white solid (yield: 19%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]3[NH:18][C:17](=[O:19])[C:16]3([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[CH2:26]([O:33][C:34]([C:36]1[CH:45]=[CH:44][C:39]([CH2:40][N:41]=[C:42]=[O:43])=[CH:38][CH:37]=1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]3[N:18]([C:42]([NH:41][CH2:40][C:39]4[CH:44]=[CH:45][C:36]([C:34]([O:33][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:35])=[CH:37][CH:38]=4)=[O:43])[C:17](=[O:19])[C:16]3([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C=NCc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: CCC1(CC)C(=O)NC1Oc1ccc(C(=O)N2CCN(C)CC2)cc1
Product: CCC1(CC)C(=O)N(C(=O)NCc2ccc(C(=O)OCc3ccccc3)cc2)C1Oc1ccc(C(=O)N2CCN(C)CC2)cc1

Procedure:
According to the method of Shrenik et al (J. Med. Chem., 35, 3745-3754 (1992)), 4-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-2-azetidinone (160 mg, 0.463 mmol) and 4-(benzyloxycarbonyl)benzylisocyanate (261 mg, 0.98 mmol) gave, following purification by flash column chromatography (MeOH/EtOAc, 1:4), the title compound (171 mg, 60%) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:19]([C:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][C:26]=2[C:25]([NH2:35])=[C:24]([CH:36]([CH3:38])[CH3:37])[CH:23]=1)([CH3:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[CH:19]([C:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][C:26]=2[C:25]([N:35]2[CH2:2][CH2:3][N:4]=[C:5]2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:24]([CH:36]([CH3:38])[CH3:37])[CH:23]=1)([CH3:21])[CH3:20]
Reactant: O=C(NCCCl)c1ccccc1
Reactant: CC(C)c1cc(C(C)C)c2c(oc3ccccc32)c1N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(C(C)C)c2c(oc3ccccc32)c1N1CCN=C1c1ccccc1
Yield: 55.9 %

Procedure:
N-(2-chloroethyl)benzamide (6.3 g, 34 mmol) and PCl5 (7.9 g, 38 mmol) were suspended in xylene (75 mL) and refluxed for two hours. Then 1,3-diisopropyldibenzo[b,d]furan-4-amine (10 g, 38 mmol) was added. The mixture was refluxed overnight. After cooling by ice-bath, no precipitation was observed. The mixture was concentrated and the residue was washed with small amount of toluene and hexane. The crude 1-(1,3-diisopropyldibenzo[b,d]furan-4-yl)-2-phenyl-4,5-dihydro-1H-imidazole (7.5 g, 19 mmol, 54.8% yield) was used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C@@H:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][C@@H:19]([NH:26][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:15]
Reactant: CCOC(=O)C[C@@H](N)c1ccccc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C[C@@H](Nc1cc(C)nc(Cl)c1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.3 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-3-nitropyridine (900 mg, 4.35 mmol) in DMA (8 mL) were added (R)-3-amino-3-phenylpropionic acid ethyl ester HCl (799 mg, 3.48 mmol) and DIPEA (1.6 mL, 8.70 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction was then diluted with ethyl acetate and washed with water twice. The organic phase was dried over Na2SO4 and concentrated to give yellow oil. The resulting oily residue was purified by silica gel preparative TLC using 99:1 CH2Cl2:MeOH as an eluent to afford 650 mg (51%) of the title compound as a light orange oil. LCMS, M++1, m/z: 364.15.
Reaction SMILES: C(O[C:5]([O:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][CH3:17])=[O:15])[C@H:11]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[C@@H:10]([C:32]([O:34][CH3:35])=[O:33])[CH2:9]1)=O)C=C.O1CC[CH2:38][CH2:37]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:5]([O:7][C@@H:8]1[CH2:13][N:12]([C:14]([O:16][CH3:17])=[O:15])[C@H:11]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[O:19])[C@@H:10]([C:32]([O:34][CH3:35])=[O:33])[CH2:9]1)[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)O[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)N2CCN(c3ccccc3)CC2)N(C(=O)OC)C1
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCO[C@H]1C[C@H](C(=O)OC)[C@@H](C(=O)N2CCN(c3ccccc3)CC2)N(C(=O)OC)C1

Procedure:
A mixture of dimethyl (2S,3S,5S)-5-[(allyloxy)carbonyl]oxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (100 mg, 0.0002 mol) and tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.000020 mol) in tetrahydrofuran (5.00 mL, 0.0616 mol) was refluxed for 2 h. The mixture was concentrated to dry and used directly in next step.