Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:33](=[O:41])[C:32]=1[C:42]#[N:43]>O1CCOCC1.CCOC(C)=O.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>[CH:38]1([CH2:37][N:34]2[CH:35]=[CH:36][C:31]([C:6]3[CH:5]=[CH:4][C:3]([NH:17][CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[C:2]([Cl:1])[CH:7]=3)=[C:32]([C:42]#[N:43])[C:33]2=[O:41])[CH2:39][CH2:40]1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)c(Cl)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(NC3CCOCC3)c(Cl)c2)ccn(CC2CC2)c1=O
Yield: 15.8 %

Procedure:
To a solution of intermediate 16 (0.57 g, 1.7 mmol) in 1,4-dioxane (2 ml) and a saturated solution of Na2CO3 (2 ml) was added intermediate 8 (0.43 g, 1.7 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.19 mg, 0.17 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 2 (0.103 g, 16%).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[C:5]([O:9][C:10]([C:12]1[CH:28]=[C:27]([OH:29])[C:15]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:5]([O:9][C:10]([C:12]1[CH:28]=[C:27]([O:29][CH:2]([CH3:4])[CH3:3])[C:15]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(COc1ccccc1)C2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(COc1ccccc1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
2-Iodopropane (174 mg, 1.02 mmol)) was added to a mixture of 4-hydroxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (214b) (350 mg, 1.02 mmol) and K2CO3 (141 mg, 1.02 mmol) in DMF (5 mL). The reaction mixture was stirred at 60° C. overnight. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with H2O (2×70 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 5% EtOAc in hexanes to give a white solid (182 mg, 46% yield). 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J=1.26 Hz, 1 H) 7.22-7.26 (m, 1 H) 7.13 (s, 1 H) 7.07 (s, 1 H) 6.91-7.00 (m, 3 H) 6.85 (d, J=7.58 Hz, 1 H) 5.17-5.25 (m, 1 H) 4.59-4.68 (m, 1 H) 4.07-4.17 (m, 1 H) 3.34 (dd, J=16.55, 9.47 Hz, 1 H) 3.09 (dd, J=16.55, 6.95 Hz, 1 H) 1.58 (s, 9 H) 1.35 (d, J=6.06 Hz, 6 H); LCMS for C23H28O5 m/z 385.20 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Product: O=C(O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 15 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (900 mg, 3.0 mmol), using methyl 4-fluorobenzoate instead of 4-fluoroacetophenone, was converted to the title compound (190 mg, 15%) which was obtained as a white solid. MS: m/e=416.3 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[N:2]1.F[B-](F)(F)F.[CH3:19][O+](C)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:19][N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[C:5]2[C:10]([O:12][CH3:13])=[O:11])=[N:1]1
Reactant: C[O+](C)C
Reactant: COC(=O)c1cccc2[nH]ncc12
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To a solution of methyl 1H-indazole-4-carboxylate (63.0 g, 358 mmol) in ethyl acetate (1.19 L) was added trimethyloxonium tetrafluoroborate (68.8 g, 465 mmol), and the mixture was stirred under nitrogen atmosphere at room temperature for 12 hr. The reaction solution was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (ethyl acetate/hexane) to give the title compound (57.0 g, yield 84%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[CH2:4][O:3][CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% NaH (2.66 g) in DMF (20 mL) was added methyl hydroxyacetate (5.00 g) under ice-water cooling, and the mixture was stirred at 0° C. for 0.5 hour. To this was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (12.8 g) under ice-water cooling, and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (10:1-3:1) to give methyl[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate pale yellow oil (4.45 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CC(C)=O>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: BrCCCCCCCBr
Reactant: Oc1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(-n2ccc3cc(OCCCCCCCBr)ccc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
410 mg (1.8 mmol) 1-(4-Fluoro-phenyl)-1H-indol-5-ol in 6 ml acetone were treated with 500 mg (3.6 mmol) powdered K2CO3 and 610 μl (3.6 mmol) 1,7-dibromoheptane. The suspension was stirred at 60° C. overnight, cooled to RT, filtered and concentrated. Column chromatography on silica gel with hexane/EtOAc 49:1 yielded 526 mg (72%) 5-(7-Bromo-heptyloxy)-1-(4-fluoro-phenyl)-1H-indole as colorless solid, mp 63-65° C., MS: 403 (M, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[C:9]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23](O)=[O:24])[CH2:18][CH2:17]2)=[N:10][CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:6].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[C:9]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]([N:33]3[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]3)=[O:24])[CH2:18][CH2:17]2)=[N:10][CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:6]
Reactant: N#Cc1cnc(N2CCC(CC(=O)O)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cnc(N2CCC(CC(=O)N3CCC(O)CC3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
A mixture of 0.015 g (0.038 mmol) of [3′-(3-chloro-benzoylamino)-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.019 g (0.19 mmol) of 4-hydroxypiperdine, 0.016 g (0.049 mmol) of 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.016 mL (0.11 mmol) of triethylamine in N,N-dimethylformamide (2 mL) is allowed to stir at room temperature overnight. The mixture is concentrated under reduced pressure and the residue is diluted with water which results in a solid precipitating. The light red solid is collected by filtration and washed with water. The collected material is purified using preparative reverse phase HPLC to give 0.011 g (61%) of the title compound (145) as a colorless solid. [M+H]+=482.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21].C(NC(C)C)(C)C>O1CCOCC1.[Cu](I)I.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:22]1([C:20]#[C:21][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Br)cc2)CCC1
Reactant: C#Cc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: I[Cu]I
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(C#Cc3ccccc3)cc2)CCC1
Temperature: 90 °C
Yield: 52.1 %

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclobutylcarbamate (1.53 g, 4.7 mmol), ethynylbenzene (2.5 mL, 22.6 mmol), copper iodide (36 mg, 0.24 mmol) and diisopropylamine (3.2 mL, 22.6 mmol) in dioxane (3 mL) was degassed for 30 min, followed by the addition of bis(tri-tert-butylphosphine)palladium (144 mg, 0.36 mmol). The resulting mixture was heated at 90° C. for 16 h, after cooled down to RT, concentrated to dryness. The crude residue was purified by column chromatography (eluting with 10% DCM in heptane) to give the title compound (0.85 g, 52%). 1H NMR (500 MHz, CDCl3): 7.58-7.54 (m, 4H), 7.48-7.43 (m, 2H), 7.39-7.20 (m, 3H), 2.55-2.40 (m, 4H), 2.15-2.10 (m, 1H), 1.93-1.84 (m, 1H), 1.45-1.20 (br s, 9H).
Reaction SMILES: C1CC1.[CH2:4]([O:6][C:7]([CH:9]1[CH2:11][C:10]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH3:5].OS(O)(=O)=O.[N:29]([O-])=[O:30].[Na+]>CC(O)=O.O>[CH2:4]([O:6][C:7]([C:9]1[CH2:11][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:30][N:29]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)C1CC1(c1ccccc1)c1ccccc1
Reactant: O=N[O-]
Agent: C1CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1=NOC(c2ccccc2)(c2ccccc2)C1
Temperature: 18 °C
Yield: 92 %

Procedure:
The crude cyclopropane derivative, 2,2-diphenylcyclopropanyl carboxylate ethyl ester (generated through the reported one step procedure as a crude product in 107% yield) (21.3 g, 80 mmol) was dissolved in 80.0 mL AcOH at room temperature (18° C.). Into the solution was carefully added 40.0 mL concentrated H2SO4, followed by adding NaNO2 (6.1 g, 88 mmol, 1.1 eq) in several portions so that the reaction temperature did not excess 40° C. After addition, the reactants were stirred at room temperature (about 18° C.) for half an hour. And the reactants were poured into an iced water and extracted with diethyl ether (2×200 mL), the ethereal solutions were combined and washed with sat. NaHCO3 (2×100 mL), then water (100 mL) and brine (50 mL) in sequence. The washed ethereal solution was then dried over Na2SO4. After removing the desiccant, the ethereal solution was concentrated to furnish a thick oily crude product. The 1H NMR of the crude product showed that the reaction was clean and a virtual 100% yield. The thick oily crude product was stirred with 10 mL petrol to give a pale yellow solid 21.7 g, 92% yield (98% over yield in two steps based on diphenyl ketone hydrazine).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:26])[N:22]=[C:23](O)[CH:24]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:26])[N:22]=[C:23]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:15])[CH:24]=1)=[O:19]
Reactant: COC(=O)c1cc(O)nn1C
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(C)nnn2-c2ccc(F)cc2)nn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To a solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (500 mg, 2 mmol) in THF (30 mL) was added 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (377 mg, 2 mmol) and triphenylphosphine (823 mg, 3 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.44 mL, 3 mmol) was added and the reaction mixture was stirred for 24 h at room temperature. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane and then 2% methanol in dichloromethane) afforded the title compound (671 mg, 81%) as a white solid. MS: m/e=346.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[CH:6][CH:5]=[C:4]([CH3:13])[N:3]=1.[P:14]([O-:26])([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([O:16][CH3:17])=[O:15].[K+].CC(C)=O>CCOCC>[P:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([O:16][CH3:17])([O:26][CH2:10][C:9]([NH:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:13])=[CH:5][CH:6]=1)=[O:12])=[O:15]
Reactant: Cc1ccc(NC(=O)CCl)c(C)n1
Reactant: COP(=O)([O-])Oc1ccc(Cl)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: COP(=O)(OCC(=O)Nc1ccc(C)nc1C)Oc1ccc(Cl)cc1

Procedure:
N-(2,6-Dimethyl-3-pyridyl)-α-chloroacetamide (32.2 grams), potassium O-methyl O-(4-chlorophenyl) phosphate (26 grams) and acetone (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 24 hours. After this time the mixture is stripped of solvent on a steam bath and the resulting residue is dissolved in ether. The ether solution is washed with water and is dried over magnesium sulfate. The dried solution is then evaporated under vacuum to yield the desired product O-[2-(2,6-dimethyl-3-pyridylamino)-2-ketoethyl] O-methyl O-(4-chlorophenyl) phosphate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:9]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])([CH3:4])([CH3:3])[CH3:2].[CH3:25][CH2:26][C:27](=O)[CH2:28][CH3:29].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:13]([NH:14][CH:27]([CH2:28][CH3:29])[CH2:26][CH3:25])=[CH:12][CH:11]=[CH:10][C:9]=1[C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)CC
Reactant: Cc1cc(C)c(-c2cccc(N)c2NC(=O)OC(C)(C)C)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(CC)Nc1cccc(-c2c(C)cc(C)cc2C)c1NC(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 75.6 %

Procedure:
Under a nitrogen atmosphere was combined 5 ml of acetic acid, 205 mg (0.62 mmol) of the title compound of Example 4 and 126 μl (1.25 mmol) of 3-pentanone, followed by 890 mg (6.29 mmol) of powdered sodium sulfate (Na2SO4). The solution was allowed to stir for 20 minutes, at which point 158 mg (0.75 mmol) of sodium triacetoxyborohydride (NaBH(OAc)3) was added. The solution was allowed to stir for 45 minutes and was then quenched with aqueous bicarbonate (75 ml) and was extracted with ethyl acetate (2×30 ml). The organic extract was washed with water (1×25 ml) and then brine (1×25 ml), and then dried over Na2SO4, filtered and concentrated in vacuo to afford 232 mg of crude product, which was chromatographed on silica gel using 9:1 hexane:ethyl acetate to afford 186 mg (74.7%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.I([O-])(=O)(=O)=[O:39].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:37])=[O:39])=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(-c2nc3c(Cl)nc4ccccc4c3n2CCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)c1ccc(-c2nc3c(Cl)nc4ccccc4c3n2CCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 50 °C
Reaction time: 13 h
Yield: 72.4 %

Procedure:
To a suspension of 0.63 g of tert-butyl 4-[2-[4-chloro-2-(4-methylthio-phenyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl]-1-piperidinecarboxylate in 18 ml of 1,4-dioxane, a solution of 0.38 g of sodium periodate in 6 ml of water was added dropwise, and the mixture was stirred at 50° C. for 13 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography using 1,2-dichloroethane—methanol (10:1) as an eluting solvent to give 0.47 g of a colorless solid. Recrystallization from a mixture of isopropanol and water gave colorless crystals having the melting point of from 183 to 186° C.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=4[O:25][CH3:26])=[N:11][C:10]=3[C:9]([CH3:27])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCCl>[CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:24]=[CH:23][C:20]([CH2:21][N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[CH:19][C:18]=4[O:25][CH3:26])=[N:11][C:10]=3[C:9]([CH3:27])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C=O)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(CN2CCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a 2 ml 1,2-dichloroethane solution of 61 mg (0.166 mmol) of the compound obtained in Example 233, 37 μl (0.332 mmol) of N-methylpiperazine, 10 μl of acetic acid, and 53 mg (0.252 mmol) of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain 57 mg (76%) of the captioned compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]([CH3:33])[C:12]([N:15]2[CH2:32][CH2:31][C:18]3([C:22](=[O:23])[N:21]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1.CC(C)([O-])C.[K+]>CN(C)C1C=CN=CC=1.ClCCl.O1CCCC1>[OH:30][C@@H:27]1[CH2:26][CH2:25][C@H:24]([N:21]2[CH2:20][CH2:19][C:18]3([CH2:31][CH2:32][N:15]([C:12]4[C:11]([CH3:33])=[CH:10][C:9]([N:8]5[CH2:2][CH2:3][CH2:4][C:5]5=[O:6])=[CH:14][N:13]=4)[CH2:16][CH2:17]3)[C:22]2=[O:23])[CH2:29][CH2:28]1
Reactant: O=C(Cl)CCCBr
Reactant: Cc1cc(N)cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(N2CCCC2=O)cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Reaction time: 3 h

Procedure:
4-Bromobutanoyl chloride (13.0 μL) was added to a mixture of 8-(5-amino-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (18.0 mg) and 4-dimethylaminopyridine (14.5 mg) in dichloromethane (1.0 mL). The mixture was stirred for 3 h. Then potassium tert-butoxide in tetrahydrofuran (1.0 M, 0.20 mL) was added. The mixture was stirred for an additional hour. The solvent was evaporated. The residue was dissolved in methanol (1.8 mL), and purified by prep.-HPLC under basic condition to afford 2-(cis-4-hydroxycyclohexyl)-8-[3-methyl-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-1-one. LCMS: (M+H)+=427.20.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH3:10][C:9]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:11]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)ON1C(=O)CCC1=O

Procedure:
N-Hydroxysuccinimide (17.33 g, 0.5 mol) was suspended in 120 ml tetrahydrofuran and cooled in an ice bath. Acetic anhydride (16 ml, 0.17 ml) and then triethylamine (22 ml, 0.16 mol) were added slowly. A solution formed, and then gradually a white precipitate appeared. After one half hour an equal volume of petroleum ether was added, and the crystalline product was collected. Yield 21.22 g (90%, mp 128°-130° C., lit. 15 mp 131°-132° C.). Analysis (C6H7NO4): calc. 45.87% C, 4.49% H, 8.91% N; found 45.86%, C, 4.31% H, 8.61% N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: COC(=O)CCc1ccccc1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CCc1ccccc1OCCCCCBr
Yield: 586.1 %

Procedure:
A mixture of 3.6 g (20 mmol) of 2-hydroxybenzenepropanoic acid methyl ester, 22 mL (160 mmol) of 1,5-dibromopentane, 8.73 g (63.3 mmol) of anhydrous granular potassium carbonate, and 145 mL of acetonitrile was stirred and refluxed for 24 hr. The resulting slurry was cooled and diluted with 300 mL of ether. The solids were removed by suction filtration and the filter cake was washed well with ether. The filtrate and washes were combined and concentrated in vacuo giving 38.59 g of a brown oil which was chromatographed on 200 g of silica gel, eluting with 49:1 and 19:1 hexane-ether. The fractions containing the desired product were combined and concentrated giving 5.86 g of an oil which was dissolved in 50 mL of methanol containing 0.2 g of p-toluenesulfonic acid monohydrate. The solution was stirred at room temperature for 17 hr and refluxed for 5 hr before being cooled and concentrated in vacuo. The residue was dissolved in ether and the solution was washed with saturated sodium bicarbonate solution and worked-up in the usual manner. The oily residue was chromatographed on 100 g of silica gel. Elution with 19:1 hexane-ether afforded 4.85 g (73.7%) of 2-[5-bromopentyl)oxy]benzenepropanoic acid methyl ester as a colorless oil.