Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][CH:20]3[O:24]C(=O)[N:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21]3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3>C1COCC1.O>[Br:18][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][CH:20]([OH:24])[CH2:21][NH:22][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:8]3[C:16]([C:15]=2[CH:14]=1)=[CH:17][C:5]([Br:4])=[CH:6][CH:7]=3
Reactant: O=C1OC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CN1c1ccccn1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: OC(CNc1ccccn1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 168 h
Yield: 82.1 %

Procedure:
LiOH.H2O (0.0076 g, 0.182 mmol, 10 equiv) was added to 5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-2-yl)oxazolidin-2-one (0.0091 g, 0.0182 mmol) in a mixture of 208 μL THF and 23 μL H2O (v/v=9:1). The mixture was stirred at room temperature for 7 days. The reaction mixture was purified by silica gel chromatography using CH2Cl2/EtOAc as elute to afford 0.0071 g white solid as product, yield 41.0%.
Reaction SMILES: O1CCCC1.[CH:6]1([C:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33]O)[CH3:31])=[CH:24][C:23]=4[O:36][CH3:37])=[N:16][C:15]=3[N:14]([CH3:38])[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.N(C(N(C)C)=O)=NC(N(C)C)=O>O>[CH:6]1([C:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:30]([CH3:31])[C:29]5=[O:35])=[CH:24][C:23]=4[O:36][CH3:37])=[N:16][C:15]=3[N:14]([CH3:38])[N:13]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1cc(NC(=O)N(C)CCO)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N2CCN(C)C2=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.6 %

Procedure:
To a 3 ml tetrahydrofuran suspension of 114 mg (0.25 mmol) of the compound obtained in Example 151, 52 mg (0.30 mmol) of 1,1′-azobis(N,N-dimethylformamide) and 75 μl (0.30 mmol) of n-tributylphosphine were added, and the mixture was stirred at room temperature for 20 hours. Then, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 71.6 mg (66%) of the captioned compound.
Reaction SMILES: Br[CH2:2][C:3]([CH2:26][CH3:27])=[CH:4][CH2:5][C:6]1[C:14]([O:15]CC[Si](C)(C)C)=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:22])=[C:8]([CH3:23])[C:7]=1[CH2:24][CH3:25].C[Si](Br)(C)C.C[O:34][P:35]([O:38]C)[O:36]C>CC#N>[CH2:26]([C:3](=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9](=[C:8]([CH3:23])[C:7]=1[CH2:24][CH3:25])[CH2:10][O:11][C:12]2=[O:22])[CH2:2][P:35](=[O:34])([OH:38])[OH:36])[CH3:27]
Reactant: CCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CBr
Reactant: COP(OC)OC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: CCC(=CCc1c(O)c2c(c(C)c1CC)COC2=O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of 6-(3-bromomethyl-pent-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (32 mg, 0.070 mmol) in trimethylphosphite (0.8 mL) was heated at 110° C. After 2 hrs the reaction was complete. The reaction was cooled to room temperature and the excess trimethylphosphite was removed in vacuo. The crude material was used in the next step without further purification. The crude product of the Arbuzov reaction was dissolved in MeCN (0.8 mL). Trimethylsilyl bromide (108.0 mg, 0.706 mmol) was added and the reaction was stirred at room temperature. After 2 hrs a second batch of trimethysilyl bromide (108.0 mg, 0.706 mmol) was added. After 3 hrs the reaction was quenched with MeOH (2 mL). The solvents were evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN). The product-containing fractions were combined and lyophilized to yield 15.7 mg (63%) of the product. 1H NMR (300 MHz, DMSO-d6): δ=0.98-1.09 (m, 6H), 2.10 (s, 3H), 2.30 (m, 2H), 2.64 (q, J=7.5 Hz, 2H), 3.38 (m, 4H), 5.03 (m, 1H), 5.25 (s, 2H) ppm; 31P NMR (121 MHz, DMSO-d6): δ=22.26 ppm; MS=355 [M++1].
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH:20]4[CH2:24][CH2:23][CH2:22][O:21]4)=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1.CO>[OH-].[OH-].[Pd+2].C(O)(=O)C>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)=[O:19])[CH2:16][CH2:17]2)[CH2:9]1
Reactant: O=C(C1CCCO1)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(C1CCCO1)N1CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Palladium hydroxide on carbon (0.15 g) was placed in a 5 mL tube and then a solution of 1-[1-(diphenylmethyl)azetidin-3-yl]-4-(tetrahydrofuran-2-ylcarbonyl)piperazine (0.66 g, 1.6 mmol), methanol (4 mL) and acetic acid (0.3 mL) was added. The mixture was stirred under hydrogen (1.6 bar) at RT for 60 h and then the catalyst was filtered off by means of Celite®. The solvent was removed by evaporation and the crude product was used in the next step without quantification. LCMS: m/z 240 (M+1)+.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[Cl:25])(=[O:16])=[O:15])[CH2:11][N:10]2[C:26]([C:28]2([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=3)[CH2:31][NH:30][CH2:29]2)=[O:27])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:39]I>CO>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[Cl:25])(=[O:15])=[O:16])[CH2:11][N:10]2[C:26]([C:28]2([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=3)[CH2:31][N:30]([CH3:39])[CH2:29]2)=[O:27])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CI
Reactant: COc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(C(=O)C3(c4ccc(Cl)cn4)CNC3)C2)c(Cl)c1
Solvent: CO
Product: COc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(C(=O)C3(c4ccc(Cl)cn4)CN(C)C3)C2)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of example 2 (0.05 g, 86.4 μmol, Eq: 1.00) in refluxing methanol (1 ml) was added methyl iodide (9.2 mg, 4.05 μl, 64.8 μmol, Eq: 0.75). After complete addition the mixture was stirred at 80° C. for 2 h. Additional methyl iodide (9.2 mg, 4.05 μl, 64.8 μmol, Eq: 0.75) was added and the mixture was stirred at 80° C. for 2 h, then at 20° C. over night. The mixture was purified by preparative HPLC to yield a colorless solid (3 mg; 6%). m/z=592.2 [M+H]+.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([C:4]1[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=1)=[O:13]
Reactant: Cc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1ccc(C(=O)CCCCl)cc1
Reaction time: 1 h

Procedure:
To a solution of 100 g (1.1 mole) of toluene and 146 ml (1.3 mole) of 4-chlorobutyryl chloride in 470 ml of carbon disulfide at 10° C. under N2, is added in portions, 180 g (1.4 mole) of aluminum chloride. Stir 1 hr. at 0° C., then discontinue the stirring and allow the reaction mixture to settle for 1/2 hr. Decant the top carbon disulfide layer and pour the lower layer into concentrated HCl/ice. Extract with two 600 ml portions of methylene chloride. The combined extracts are washed with 1 L of 10% potassium bicarbonate, dried over sodium sulfate and concentrated in vacuo to provide the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[NH:17][CH:16]=[CH:15][C:12]3=[N:13][CH:14]=2)O1.[NH2:19][C:20]1[C:29]2[C:24](=[C:25](Br)[C:26]([CH3:30])=[CH:27][CH:28]=2)[N:23]=[N:22][C:21]=1[C:32]([NH2:34])=[O:33]>>[NH2:19][C:20]1[C:29]2[C:24](=[C:25]([C:9]3[CH:10]=[C:11]4[NH:17][CH:16]=[CH:15][C:12]4=[N:13][CH:14]=3)[C:26]([CH3:30])=[CH:27][CH:28]=2)[N:23]=[N:22][C:21]=1[C:32]([NH2:34])=[O:33]
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: CC1(C)OB(c2cnc3cc[nH]c3c2)OC1(C)C
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1cnc2cc[nH]c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H), 6.84 (br s, 1 H), 6.93 (br s, 1 H), 7.85 (d, J=8.59 Hz, 1 H), 8.15 (br s, 1 H), 8.27-8.30 (m, 1 H), 8.35 (s, 1 H), 8.54 (d, J=8.59 Hz, 1 H), 8.58 (s, 1 H), 8.71 (br s, 1 H), 8.76 (s, 1 H); ESI-MS m/z [M+H]+ 319.2.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.C(N(C(C)C)CC)(C)C.[N:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[N+:20]=[N-:21]>CC(C)=O>[N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=NCCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NCCCNc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To a solution of cyanuric chloride (18.42 g, 0.10 mol) in acetone (180 mL) in an ice-water bath was added diisopropylethylamine (DIPEA) (12.92 g, 0.10 mol). 1-azido-3-aminopropane (5.00 g, 0.050 mol) in acetone (50 mL) was added slowly over 2 hours. The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, washed with water, dried (Na2SO4) and rotary evaporated. The resulting residue was purified by column chromatography on silica gel (eluent CH2Cl2) to give 1 as a white solid (5.62 g, 45%): ESI-MS m/z 248.1 (M+H+) calculated for C6H8Cl2N7 248.0.
Reaction SMILES: [CH2:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3].Cl.C[CH2:14][O:15]CC>[C-]#N.[Zn+2].[C-]#N>[OH:11][C:10]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([OH:6])[CH:7]=[CH:8][C:9]=1[CH:14]=[O:15]
Reactant: CCCc1c(O)cccc1O
Reactant: CCOCC
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Product: CCCc1c(O)ccc(C=O)c1O
Reaction time: 0.5 h

Procedure:
Zinc cyanide (24 g) was added to a stirred suspension of 2-propylresorcinol (32.4 g) in dry ether (150 ml) and the resulting mixture saturated with hydrogen chloride. After being left to stand at room temperature for 30 minutes the ether was decanted and the remaining solid heated on the steam bath with water for 30 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:38](COCC[Si](C)(C)C)[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]5[CH2:36][CH2:35]5)=[O:32])=[C:26]([Cl:37])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:38][C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]5[CH2:36][CH2:35]5)=[O:32])=[C:26]([Cl:37])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(OCc5ccccc5)cc4)cc23)cc1Cl)NC1CC1
Yield: 85.4 %

Procedure:
After dissolving 38 mg of 1-{4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}-3-cyclopropylurea in 0.8 ml of tetrahydrofuran, 0.2 ml of tetrabutylammonium fluoride (1 M tetrahydrofuran solution) was added dropwise and the mixture was refluxed for 2 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with ethyl acetate and tetrahydrofuran. The organic layer was washed with water and saturated saline, concentrated and dried under reduced pressure to obtain 26 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C>C(OCC)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)[C:6]#[N:7]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(C#N)ccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C#N)ccc1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A solution of 4-bromo-3-methoxybenzonitrile (Combi-Blocks, San Diego, Calif., 2.500 g, 11.79 mmol) in 100 mL of diethyl ether was cooled to −78° C. and was treated with n-butyllithium (4.95 ml, 12.38 mmol). After stirring for 10 minutes, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.07 ml, 16.51 mmol) was added, and the cooling bath was removed. After stirring for an additional 2 hours, LC/MS showed mostly product, so the reaction mixture was quenched with saturated NH4Cl solution. After stirring for 20 minutes, the reaction mixture was poured into a separatory funnel charged with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.62 g, 6.25 mmol, 53.0% yield) with minor impurities. m/z (ESI) 260.1 (M+H)+
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:35])([CH3:34])[CH2:9][NH:10][CH:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[N:18][C:19]([Cl:33])=[CH:20][N:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:35])([CH3:34])[CH2:9][NH:10][CH:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[N:18][C:19]([Cl:33])=[CH:20][N:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(NCC(C)(C)NC(=O)OC(C)(C)C)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NCC(C)(C)N)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1

Procedure:
Formula 202 where R2 is H; R3 is Cl; R5 is Benzyl; R6 is Isopropyl; R6′ is H; Ra and Rb are Methyl; W and Z are —N═; X and Y are —C═: To a solution of (±)-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (1.63 g, 3.16 mmol) in dichloromethane (40 mL) is added trifluoroacetic acid (10 mL). The resultant solution is maintained at ambient temperature overnight and concentrated under reduced pressure. The residue is dissolved in dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate (40 mL). The aqueous layer is extracted with dichloromethane (50 mL) and the combined extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-pteridin-4-one which is used in the subsequent step without purification.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].[N+:20]([O-])([OH:22])=[O:21].[K+].[Br-]>C(O)(=O)C>[OH:1][CH:2]1[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Oc2ccsc2C(N2CCCCC2=O)C1O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(N2CCCCC2=O)C1O

Procedure:
The title compound was prepared as described in Example 5 starting with 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran (1.5 g, 5.33 mmol) and 90% nitric acid (2.5 mL) in acetic acid (25 mL) to give the product, 0.837 g (48%), as a yellow solid: mp 210°-211° C.; IR (KBr): 3231, 1613, 1515 and 1492 cm-1 ; MS: m/z 327 (MH+); 1H NMR (CDCl3): δ1.32(s, 3H), 1.51(s, 3H), 1.84(m, 4H), 2.55(m, 2H), 3.20(m, 2H), 3.84(d, J=9.5 Hz, 1H), 4.78(bs, 1H, exchanges with D2O), 5.86(d, J=9.5 Hz, 1H) and 7.40(s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[C:25](N)[C:24]=2[CH:33]([CH3:35])[CH3:34])=[O:21])[CH2:15][CH2:14]1.N([O-])=[O:37].[Na+].O.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[C:25]([OH:37])[C:24]=2[CH:33]([CH3:35])[CH3:34])=[O:21])[CH2:17][CH2:18]1
Reactant: O=N[O-]
Reactant: CC(C)c1ccc(N)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
2-[4-[2-(Benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(3-amino-2,6-diisopropylphenyl)acetamide (198 mg, 0.4 mmol) was dissolved in 6% aqueous solution of sulfuric acid (3.4 ml), an aqueous solution (0.8 ml) of sodium nitrite (35 mg, 0.5 mmol) was added thereto at 0° C. and the mixture was stirred at that temperature for 30 minutes. The reaction solution was slowly dropped into a boiling water (40 ml) which was heating and stirring at an external temperature of 140° C. After 10 minutes from the dropping, the reaction solution was allowed to cool, neutralized with sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by a preparative thin layer chromatography (developing solvent, chloroform:ammonia-saturated methanol=20:1) to provide 178 mg (yield 89%) of the desired compound, which was recrystallized from ethanol-hexane to provide colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:23]([Cu])#[N:24]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:23]#[N:24])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: N#Cc1cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2s1
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (Example No. 2) (0.500 g) in pyridine (5 mL) is added CuCN (0.201 g). The reaction is heated to reflux and stirred for 18 h. The reaction mixture is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale yellow solid which is recrystallized from methanol to yield 0.100 g (26%) of the title compound as an off-white solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([OH:20])[CH2:16][CH2:15]2)[CH2:10]1)=O)(C)(C)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[ClH:28].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:15][CH2:16][C:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)([OH:20])[CH2:18][CH2:19]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCC(O)(c3ccc(F)cc3)CC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1CCN(C2CCC(O)(c3ccc(F)cc3)CC2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
To a solution of 4-((3R)-3-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-1-(4-fluorophenyl) cyclohexanol (1.05 g, 2.8 mmol) in ethyl acetate (50 ml), cooled to 0° C. was added hydrogen chloride gas, bubbled in gently for 5-10 minutes. The reaction mixture was stirred for 20 minutes at 0° C. and the above procedure was repeated twice. Concentration and flushing with ethyl acetate three times gave 4-((3R)-3-aminopyrrolidin-1-yl)-1-(4-fluorophenyl) cyclohexanol dihydrochloride (0.87 g, 89%); 1H NMR (DMSO) δ 11.33 (bd, 1H)), 8.60 (bd, 3H), 7.52 (m, 2H), 7.14 (m,2H), 5.12 (bs, 1H), 3.35-4.04 (m, 6H), 1.76-2.27 (m, 10H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[O:18]=[C:19]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][N:20]1[CH2:36][C:37](O)=[O:38].C(N(C(C)C)CC)(C)C>ClCCl>[O:38]=[C:37]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[CH2:8][CH2:9]1)[CH2:36][N:20]1[CH2:21][CH2:22][C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:18]
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(3-(trifluoromethyl)benzyl)piperazine (0.090 g, 0.368 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.140 g, 0.368 mmol) and 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.099 g, 0.335 mmol) in dichloromethane (1.0 mL) was added diisopropylethylamine (0.088 mL, 0.502 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated and loaded onto silica gel. The product was eluted using a gradient of 5% to 100% ethyl acetate/hexanes giving incomplete purification. A second chromatography over silica gel using a gradient of 0.5% to 5% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.58 (m, 4H), 7.20-7.37 (m, 10H), 4.19 (s, 2H), 3.60 (t, J=4.8 Hz, 2H), 3.52 (t, J=6.5 Hz, 2H), 3.51 (s, 2H), 3.41 (t, J=4.8 Hz, 2H), 2.81 (t, J=6.5 Hz, 2H), 2.40 (t, J=4.9 Hz, 2H), 2.28 (t, J=4.8 Hz, 2H); MS (ESI−) m/z 520 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@:5]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[OH:6].CCN(CC)CC.Cl[C:42]([O:44][CH3:45])=[O:43]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:13][C:9]1[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[C:7]([C@:5]([C@@H:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)([OH:6])[CH2:4][CH2:3][CH2:2][NH:1][C:42]([O:44][CH3:45])=[O:43])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(-c2c(Cl)cccc2[C@](O)(CCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCC[C@@](O)(c1cccc(Cl)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (R)-tert-butyl 3-((S)-4-amino-1-(6-chloro-3′-methylbiphenyl-2-yl)-1-hydroxybutyl)piperidine-1-carboxylate (800 mg, 1.69 mmol) in anhydrous CH2Cl2 (15 mL) were added 4-dimethyaminopyridine (1.24 g, 10.17 mmol) and Et3N (2.35 mL, 16.95 mmol). The mixture was cooled with an ice bath and methyl chloroformate (0.65 mL, 8.47 mmol) in CH2Cl2 (5 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The solvent was removed in vacuo and the residue was purified by column chromatography to afford (R)-tert-butyl 3-((S)-1-(6-chloro-3′-methylbiphenyl-2-yl)-1-hydroxy-4-(methoxycarbonylamino)butyl)piperidine-1-carboxylate (700 mg, 78%). 1H NMR (400 MHz, CD3OD): 1.00-1.70 (m, 17H), 2.30-2.50 (d, 3H), 2.50-2.70 (s, 1H), 2.90-2.31 (m, 2H), 3.50-3.52 (m, 3H), 3.80-4.20 (m, 2H), 6.0-7.15 (m, 3H), 7.15-7.40 (m, 3H), 7.50-7.70 (m, 1H); MS (E/Z): 531 (M+H+)