Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[O:22]([CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]Cl)[CH2:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:38][CH2:37][CH2:36][N:33]1[CH2:32][CH2:31][CH:30]([CH2:29][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:35][CH2:34]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: ClCCCN1CCC(COc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2c1ncn2CCCN1CCC(COc2ccccc2)CC1
Temperature: 40 °C
Yield: 42 %

Procedure:
A mixture of 15.4 g (0.1 mole) of 6-chloropurine, 75 ml of N,N-dimethyl formamide, 13.8 g (0.1 mole) of potassium carbonate and 26.8 g (0.1 mole) of 3-(4-phenoxymethylpiperidino)-propyl chloride is heated to 40° C for 6 hours, while stirring. The reaction mixture is then mixed with water extracted with ethyl acetate and the extract is dried and evaporated. The residue obtained is recrystallized from ethyl acetate/ligroin. There are obtained 16.2 g (42% of theory) of 6-chloro-9-[3-(4-phenoxymethylpiperidino)-propyl]-purine; m.p. 95° - 96° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([I:18])=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([I:18])=[CH:16][N:17]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[C:12]2=[CH:11][CH:10]=1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]cc(I)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-(2,6-difluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (657 mg, 1.845 mmol) in THF (18 mL) was treated with 4-toluenesulfonyl chloride (387 mg, 2.029 mmol, Aldrich) and solid NaOH (89 mg, 2.214 mmol, VWR). The reaction was stirred at 23° C. under N2. After 45 min, the solution was diluted with EtOAc (200 ml) and washed with brine (150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 10-30% EtOAc/hexane), affording 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3C=C(OC4C=CC=C(C(F)(F)F)C=4)N=C[N:30]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1(C2C=CC(N)=C(C3C=C(O[C:66]4[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:75])([F:74])[F:73])[CH:67]=4)N=CN=3)C=2)CCCCC1>>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:29]=[C:9]([CH2:10][NH:13][CH2:14][C:66]4[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:73])([F:74])[F:75])[CH:67]=4)[CH:8]=[CH:7][N:30]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(Oc3cccc(C(F)(F)F)c3)ncn2)c1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(Oc2cccc(C(F)(F)F)c2)ncn1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(CNCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared using the procedure described for the preparation of 3-((3-((4-(piperidin-1-yl)-2-(6-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 3.9 from 4-(piperidin-1-yl)-2-(6-(3-(trifluoromethyl)phenoxy)pyrimidin-4-yl)aniline 3.9b. MS (ES, m/z) 662.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([Cl:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+].O>CO.[Fe]>[NH2:12][C:11]1[C:2]([Br:1])=[C:3]([CH:8]=[C:9]([Cl:15])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Cl)cc(N)c1Br
Temperature: 70 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
To a solution of methyl 2-bromo-5-chloro-3-nitrobenzoate (4.0 g, 14 mmol) in methanol (130 ml) at room temperature was added ammonium chloride (7.13 g, 136 mmol) followed by deionized water (65 ml). The mixture was heated to 70° C. in air before the addition of iron (4.55 g, 81.5 mmol). The reaction was stirred at 70° C. for 3 hours, allowed to cool to room temperature and filtered through Kieselgel. The filter pad was washed with MeOH (65 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3 (50 ml) and EtOAc (100 ml). The phases were separated and the organic phase was washed with saturated NaHCO3(aq) (3×50 ml) before being dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 1.92 g (48%) of the title compound as a colourless oil. LC-MS 92%, m/z=268.8/265.8/267.6, 1H NMR (500 MHz, Chloroform-d) δ 7.08 (1H, d, J=2.36 Hz), 6.86 (1H, d, J=2.36 Hz), 4.34-4.49 (2H, m), 3.93 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC.CN(C)C=O.Cl>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][C:12]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:30])[CH3:29]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1C(C)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2E)-3-[4-(benzyloxy)-2-bromophenyl]prop-2-enoate (950 mg, 2.63 mmol, 1.00 equiv), tributyl(1-ethoxyethenyl)stannane (1.434 g, 3.97 mmol, 1.51 equiv), Pd(PPh3)2Cl2 (184.8 mg, 0.26 mmol, 0.1 equiv), N,N-dimethylformamide (15 mL). The resulting solution was stirred overnight at 90° C. in an oil bath. The mixture was cooled to 0° C. before 2N hydrogen chloride (10 mL) was carefully added dropwise. The resulting solution was stirred for an additional 1.0 h at 15° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:4). The solution was then diluted with 10 mL of H2O. The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic layers combined. The combined extracts were washed with 1×20 mL of water and 1×20 mL of aqueous saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 800 mg (89%) of ethyl (2E)-3-[2-acetyl-4-(benzyloxy)phenyl]prop-2-enoate as light yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[CH2:13]([N:15](CC)[CH2:16]C)C.CNC>C(#N)C>[CH3:13][N:15]([CH3:16])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(CCBr)c1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: CC#N
Product: CN(C)CCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a 250 mL round bottom flask was charged 1-(2-bromoethyl)-3-nitrobenzene (10 g, 43.5 mmol) and acetonitrile (36 mL). The suspension was treated with triethylamine (18.1 mL, 130 mmol) and dimethylamine (2 M in tetrahydrofuran, 65.2 mL, 130 mmol). The resulting solution was stirred at ambient temperature for 48 hours. The reaction was concentrated. The residual solid was partitioned between ethyl acetate (130 mL) and 60 ml saturated aqueous sodium bicarbonate. The aqueous layer was washed with ethyl acetate (75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The concentrate was purified by flash chromatography on an 80 g silica gel column using an AnaLogix IntelliFlash 280 system eluting with a gradient of from 0% to 7% methanol in CH2Cl2 to provide the title compound. MS (DCI+) m/e 195.1 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH:10]([O:12]C(C)(C)C)[CH2:9][NH:8]1)(C)(C)C.C(OC(=O)[C@@H]1CCCN1)(C)(C)C.[C:30]([S:33][CH2:34][CH2:35][C:36](Cl)=[O:37])(=[O:32])[CH3:31].C(SCC(C)C(Cl)=O)(=O)C>>[C:30]([S:33][CH2:34][CH2:35][C:36]([N:8]1[CH2:9][CH:10]([OH:12])[CH:11]=[C:7]1[C:6]([OH:5])=[O:17])=[O:37])(=[O:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(OC(C)(C)C)CN1
Reactant: CC(=O)SCCC(=O)Cl
Agent: CC(=O)SCC(C)C(=O)Cl
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Product: CC(=O)SCCC(=O)N1CC(O)C=C1C(=O)O

Procedure:
By substituting 4-tert-butoxy-L-proline tertbutyl ester for the L-proline tert-butyl ester and 3-acetylthiopropanoyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1, 1-(3-acetylthio-1-oxopropyl)-4,5-dihydro-4-hydroxy-1H-pyrrole-2-carboxylic acid is obtained.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C([Li:23])CCC>C1C=CC=CC=1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([Li:23])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(Br)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: [Li]c1ccc(CCCCC)cc1
Temperature: 25 °C

Procedure:
18.35g (0.081mol) of 4-pentylbromobenzene was dissolved in 30ml of benzene and the solution was stirred at room temperature in a stream of nitrogen. To the resulting solution was added drop-wise 50ml (0.081mol) of hexane solution including 15% butyllithium for 30 minutes and the solution was stirred for 2 hours. Then the produced precipitate gathered by the filtration in a stream of nitrogen was dried under reduced pressure to yield 9.2g of 4-pentylphenyllithium.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[N+:20]([O-:22])=[O:21])=[N:8][N:7]=[N:6]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[N+:20]([C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[S:10][C:9]1[N:5]([CH2:4][CH2:3][NH:2][S:24]([CH3:23])(=[O:26])=[O:25])[N:6]=[N:7][N:8]=1)([O-:22])=[O:21]
Reactant: NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
To a suspension of 4.9 g (14.1 mmol) of 1-(2-aminoethyl)-5-(2,4-dinitrophenylthio)tetrazole hydrochloride in 100 ml of pyridine was added 1.5 ml (2.2 g, 19.2 mmol) of methanesulfonyl chloride. The mixture was stirred for 1.5 hours, then an additional 0.5 ml of methanesulfonyl chloride was added and the mixture was stirred another hour. The pyridine was removed by evaporation and the residue was dissolved in a small volume of dimethylformamide. Water was added to the solution and the resulting precipitate was collected by filtration, washed with watr and air dried. The precipitate was dissolved in a minimum amount of dimethylformamide and the solution was diluted with ethyl acetate and treated with Darco G-60. The mixture was filtered and evaporated to dryness to give a syrupy residue which was crystallized from ethyl acetate to give 5-(2,4-dinitrophenylthio)-1-(2-methanesulfonamidoethyl)tetrazole.
Reaction SMILES: [C-]#N.[K+].[C:4]([NH2:7])(=O)C.[Cl-].C[N+](C)(C)[C:11]1[N:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([O:19][CH3:20])[N:12]=1>O>[C:4]([C:11]1[N:12]=[C:13]([O:19][CH3:20])[N:14]=[C:15]([O:17][CH3:18])[N:16]=1)#[N:7]
Reactant: CC(N)=O
Reactant: COc1nc(OC)nc([N+](C)(C)C)n1
Agent: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: COc1nc(C#N)nc(OC)n1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A mixture of 26 g of potassium cyanide and 60 g of oven-dried acetamide was heated to 85°-90° C. To this melt was added 24 g of the product from Example 2 in portions over a period of 15-20 minutes. The resulting brown reaction solution was heated to 90°-100° C. for an additional one hour. When the solution had cooled to room temperature, water was added and the aqueous layer was extracted with ether and methylene chloride. The combined organic extracts were backwashed with several small portions of water, brine, and were then dried over magnesium sulfate and concentrated in vacuo to afford 6.5 g of 2-cyano-4,6-dimethoxy-1,3,5-triazine as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)O)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:32])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([F:32])[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=S(=O)(c1ccccc1)c1ccc(C(O)Cc2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc(C(F)Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Fluorophenyl)-1-[4-(phenylsulfonyl)phenyl]ethanol (Example 118, 100 mg, 0.28 mmol) was dissolved in dichloromethane (5 mL) and (diethylamino)sulfur trifluoride (0.05 mL, 0.32 mmol) added. The reaction was stirred at room temperature for 30 minutes. Saturated sodium hydrogencarbonate was added and the products extracted into ethyl acetate. The organic layer was dried over MgSO4 and evaporated. The residue was triturated with diethyl ether/isohexane to give the title compound as a beige solid. δH (360 MHz, CDCl3): 7.94-7.90 (4H, m), 7.58-7.48 (3H, m), 7.35 (2H, d, J=8.5 Hz), 7.08-7.00 (2H, m), 6.96-6.90 (2H, m), 5.69-5.53 (1H, m), 3.21-2.99 (2H, m).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][O:36][CH2:37][C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was dissolved in dimethylformamide (3 ml) and triethylamine (153 μl, 1.1 mmol) was added followed by methoxyacetic acid (31 μl, 0.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) and 1-hydroxybenzotriazole (54 mg, 0.40 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) and the product was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (112 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].O1CCCC1.[OH-].[Li+].Cl>CO>[C:9]([O:8][C:6]([NH:5][C@@H:4]([C:3]([OH:23])=[O:2])[CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)c(F)cc1F)C(=O)O

Procedure:
A solution of 2.41 g (7.5 mmol) of (R)-N-(tert-butoxycarbonyl)-2,4,5-trifluorophenylalanine methyl ester in approximately 200 mL of a mixture of tetrahydrofuran:methanol: 1N lithium hydroxide (3:1:1) was stirred at 50° C. for 4 h. The reaction was cooled, acidified with 5% hydrochloric acid (aqueous) and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound. LC-MS 220.9 (M+1-BOC).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8][CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[C@H:3]1[C:15]([OH:17])=[O:16].CC1(C)[C@@H](/C=C\C(=O)OCCOC)[C@H]1C(O[C@H:35]([CH3:49])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=1)=O.O(C1C=C(C(O)C)C=CC=1)C1C=CC=CC=1>>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8][CH2:9][C:10]([Cl:13])([Cl:11])[Cl:12])[C@H:3]1[C:15]([O:17][C@H:35]([CH3:49])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=1)=[O:16]
Reactant: COCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C)c2cccc(Oc3ccccc3)c2)C1(C)C
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Agent: CC(O)c1cccc(Oc2ccccc2)c1
Product: C[C@@H](OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step D of Example 9, 6 g of (IR,cis) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trichloroethoxy) -1-propynyl]-cyclopropane-carboxylic acid and 4.1 g of 1-(R) (3-phenoxy-phenyl)-ethanol were reacted to obtain after chromatography and elution with an 8-2 mixture of cyclohexane-ethyl acetate 4.38 g of (R)α-methoxy-3-phenoxy-benzyl (IR, cis) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trichloroethoxy)-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH:5]=[C:4]1[CH2:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[OH:32][N:31]=[N:13][CH2:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:3]2[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: NO
Reactant: CCn1c(CC[C@@H]2CCCN2C(=O)Cc2ccccc2)cc2ccc(C#N)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1c(CC[C@@H]2CCCN2C(=O)Cc2ccccc2)cc2ccc(CN=NO)cc21
Yield: 5.3 %

Procedure:
190 mg of 1-ethyl-2-[2-[(S)-1-(2-phenylacetyl)pyrrolidin-2-yl]ethyl]indole-6-carbonitrile obtained in Example 14-a) was dissolved in methanol. 103 mg of hydroxylamine hydrochloride and 210 mg of sodium carbonate were added and the reaction solution was refluxed overnight with stirring. After water was added, the reaction solution was extracted two times with dichloromethane. The extract was dried over MgSO4 and distilled under reduced pressure. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol (20:1)] to obtain 11 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.C(N(CC)CC)C.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>C1COCC1>[C:18]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1cc(=O)c(O)co1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(=O)c(OC(=O)c2cccnc2)co1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
Allomaltol (1.266 g, 10 mmol) was dissolved in 40 mL of anhydrous THF. The mixture was cooled to 0° C. Triethylamine (1.8 mL, 13 mmol) was added. Nicotinoyl chloride hydrochloride (1.988 g, 11 mmol) was added portionwise. Cold bath was removed and the mixture was stirred at room temperature overnight. The reaction was neutralized with ammonia hydroxide then extracted with EtOAc. The organic phase was washed with brine 2 times then dried over Na2SO4 and concentrated. The crude product was purified with flash chromatography using DCM/MeOH to give the desired product as an off-white solid (1.35 g, 58%). MP (148° C.). 1H NMR (CDCl3) δ (ppm): 2.27 (d, 3H, J=0.9 Hz), 6.26 (d, 1H, J=0.9 Hz), 7.42 (dd, 1H, J=4.8, 8.1 Hz), 7.95 (s, 1H), 8.37 (td, 1H, J=1.8, 7.8 Hz), 8.79 (br s, 1H), 9.28 (br s, 1H). 13C NMR (CDCl3) δ (ppm): 19.8, 115.3, 123.8, 124.7, 138.2, 140.8, 148.1, 151.3, 154.1, 162.4, 166.4, 172.4.
Reaction SMILES: C[Si](C)(C)CCO[CH2:6][N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([O:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:9]=1Br.[CH2:54]([Sn](CCCC)(CCCC)/C=C\OCC)CCC>O1CCOCC1.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>[C:23]1([C:20]2[N:19]=[CH:18][C:17]([C:16]3[CH:15]=[N:14][N:13]4[C:8]5[NH:7][CH:6]=[CH:54][C:9]=5[C:10]([O:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[N:11][C:12]=34)=[CH:22][CH:21]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(-c2ccc(-c3cnn4c3nc(OC3CCNCC3)c3cc[nH]c34)cn2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A degassed mixture of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate (Int-11c, 0.26 mmol, 216 mg), Pd(PPh3)4 (30 mg, 0.026 mmoL), (Z)-tributyl(2-ethoxyvinyl)stannane (142 mg, 0.39 mmoL) in Dioxane (6 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, filtered through 9:1 SiO2:KF plug and concentrated in vacuo. The crude (Z)-ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(2-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (Int-11d) was treated with 50% TFA in H2O (6 mL) and stirred overnight. The reaction mixture was concentrated in vacuo. Purification with prep-LC provided 3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yloxy)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (Int-11e): LCMS tR=2.71 Min (10 min run, UV254nm). Mass calculated for, M+410.1, observed m/z 411.1 (M+H).