Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1.Cl[C:15]([O:17][C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])=[O:16].O>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][N:2]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1)[C:15]([O:17][C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])=[O:16]
Reactant: CCOC(=O)Cc1csc(NC)n1
Reactant: CCC(C)(C)OC(=O)Cl
Agent: CCOC(=O)Cc1csc(=NC)[nH]1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1csc(N(C)C(=O)OC(C)(C)CC)n1

Procedure:
To a solution of ethyl 2-(2-methylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (8 g.) in a mixture of pyridine (80 ml.) and methylene chloride (40 ml.) was dropwise added tert-pentyl chloroformate over 2 hours at -25° to -20° C. with stirring, and the mixture was stirred for 30 minutes at the same temperature. After the reaction, the reaction mixture was poured into water (200 ml.), the mixture was extracted with ethyl acetate (300 ml.), and then the organic layer was separated. The organic layer was washed with 2 N hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water in turn. The organic layer was dried over magnesium sulfate and then concentrated to give oil of ethyl 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)-1,3-thiazol-4-yl]acetate (14.5 g.).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH3:40])=[N:6][C:7]=2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)C.[Pd]>[CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH3:40])=[N:6][C:7]=2[N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A suspension of tert-butyl 4-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methylene)piperidine-1-carboxylate (0.39 g, 0.729 mmol) and Pd/C (10 wt %, 0.1 g) in ethanol (15 mL) was stirred under a hydrogen atmosphere (balloon) at room temperature for 18 hours. The reaction mixture was then filtered through celite and concentrated. The crude product was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (0.36 g, 90%). LCMS m/z: 547.2 (MH+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=1)=[O:14]>>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:17]=1[Br:22])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc(O)c(Br)c1)c1cccs1
Product: CCOC(=O)COc1ccc(C(=O)c2cccs2)cc1Br
Yield: 95 %

Procedure:
This ester was prepared with 95% yield by reaction of ethylbromoacetate with (3-bromo-4-hydroxyphenyl) (2-thienyl) ketone. The product was an oil.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:38])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:36])(=[O:35])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=3[CH3:34])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:37])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:33][C:29]1[C:28]([CH3:34])=[C:27]([NH:26][S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:37])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:38])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)Nc3cccc(Cl)c3C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1NS(=O)(=O)c1ccc(-c2c(C)c(CC(=O)O)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Lithium hydroxide monohydrate (0.017 g, 0.39 mmol) was added to a stirred solution of {4-[4-(3-chloro-2-methyl-phenylsulfamoyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.050 g, 0.10 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {4-[4-(3-chloro-2-methyl-phenylsulfamoyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.039 g, 80%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s, 1 H), 9.95 (br. s, 1 H), 8.01 (dd, J=8.80, 6.40 Hz, 1 H), 7.90 (s, 1 H), 7.77 (d, J=7.80 Hz, 2 H), 7.32-7.46 (m, 4 H), 7.18 (t, J=7.80 Hz, 1 H), 7.03 (d, J=7.80 Hz, 1 H), 6.63 (dd, J=11.00, 2.40 Hz, 1 H), 3.85 (s, 2 H), 2.07 (s, 3 H), 2.06 (s, 3 H). MS calcd. for C26H20ClFNO4S [(M−H)−] 496, obsd. 496.3.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([CH3:20])=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:12]=1.C1COCC1.[OH-].[Na+]>CCO>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[O:9][C:10]=1[CH3:20]
Reactant: COC(=O)CCCCc1nc(-c2ccccc2O)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(CCCCC(=O)O)nc1-c1ccccc1O

Procedure:
Combine 5-[4-(2-hydroxy-phenyl)-5-methyl-oxazol-2-yl]-pentanoic acid methyl ester (2.9 g, 10.0 mmol) with THF (3 mL), EtOH (3 mL) and 2N NaOH (20 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 2.0-3.0 with aq HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 5-[4-(2-hydroxy-phenyl)-5-methyl-oxazol-2-yl]-pentanoic acid (2.14 g, 78%). MS (ES): (M+1)+ 276.2 m/z.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][NH:17][C:9]1[C:8]2[C:7](=[O:23])[C:6]3[C:15](=[C:2]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COCCN
Reactant: CN(C)CCNc1cccc2c1C(=O)c1cccc(Cl)c1C2=O
Product: COCCNc1cccc2c1C(=O)c1cccc(NCCN(C)C)c1C2=O

Procedure:
This procedure was carried out as described previously in step (a) of Example 15, using Compound 17 (0.25 g, 0.76 mmol) and 2-methoxyethylamin (0.66 mL, 7.6 mmol). This product was used in the next step without any purification. The structure of Compound 23 is given below:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:10])[CH:16]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: COc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-c2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Nitrogen was bubbled through a mixture of 1-bromo-4-methoxybenzene (5.0 g, 26.8 mmol), 3-hydroxyphenylboronic acid (6.8 g, 49.6 mmol), aqueous potassium carbonate (2 M, 20 mL, 40 mmol), acetone (170 mL) and H2O (300 mL) for 5 minutes. Pd(OAc)2 (800 mg, 3.55 mmol) was added and the mixture was stirred under a nitrogen atmosphere at room temperature for 20 minutes, after which time LC-MS analysis showed the reaction to be complete. The reaction mixture was concentrated under vacuum then diluted with ethyl acetate (200 mL). The resulting suspension was filtered through a pad of celite, and the aqueous phase was then separated and extracted with EtOAc (2×100 mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness under vacuum. The crude product was loaded onto a 340 g Biotage silica cartridge and purified by Biotage chromatography (eluting with iso-hexane/EtOAc, gradient 0 to 50%). The target compound 4′-methoxy-[1,1′-biphenyl]-3-ol was isolated as a white solid (5.66 g, 78% yield).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17]O)[CH2:3][CH2:2]1.P(Br)(Br)[Br:20]>ClCCl>[Br:20][CH2:17][C:5]1[C:6]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a 0° C. solution of (5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-yl)-methanol (0.124 g, 0.44 mmol) in dichloromethane (4 mL) is added phosphorous tribromide (0.261 g, 0.963 mmol). The ice bath is removed after 20 minutes and the reaction is allowed to stir for an additional twenty minutes at room temperature. The reaction mixture is quenched with pH 7 buffer and extracted with dichloromethane several times. The organic layers are combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (0.124 g, 82%). 1H-NMR (400 MHz CDCl3) δ 7.45-7.33 (m, 3H), 4.20 (s, 2H), 2.09 (m, 1H), 1.27 (m, 2H), 1.16 (m, 2H).
Reaction SMILES: [C:1]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].CCCCC.[CH3:16][Si:17]([CH2:20][Li])([CH3:19])[CH3:18].[Cl-].[NH4+]>C1COCC1>[C:1]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: [Li]C[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)P(C[Si](C)(C)C)C(C)(C)C
Temperature: 25 °C

Procedure:
50.00 g (0.277 mol) of Di-t-butylchlorophosphine, 304 ml of 1.0 M pentane solution of (trimethylsilylmethyl)lithium and 150 ml of THF) were refluxed under argon for 3 days. The reaction mixture was allowed to cool off to RT and an aqueous solution of ammonium chloride was added slowly. The organic phase was separated, and dried with magnesium sulfate. After removal of the solvent, the product was purified by distillation in vacuum. The yield of di-tert-butyl-trimethylsilanylmethyl-phosphane was 55.32 g (86%) with b.p. 50-52° C./0.5 mm. 31P NMR (C6D6)+20.05 ppm. 1H NMR (C6D6) 0.01 (s, 9H, SiMe3), 0.23 (d, 2H, 2JPH=5.34 Hz, P—CH2—SiMe3), 0.91 (s, 9H, Me3C), 0.93 (s, 9H, Me3C). Anal. Calcd. for C12H29PSi: C, 62.01; H, 12.58; P, 13.33. Found: C, 61.89; H, 12.53; P, 13.25.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:28][CH3:29])[N:21]=3)[CH2:16][CH:15]2[C:30](=[O:39])[N:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=C)[CH3:32])=[O:13])[CH2:8][CH:7]1[CH:9]=C)=[O:5])[CH3:2]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:37][CH2:36][CH2:35][CH2:34][CH2:33][N:31]([CH3:32])[C:30](=[O:39])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:28][CH3:29])[N:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2cc(OC)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(OC)nc(OC)n3)CC1C(=O)N2
Yield: 49.1 %

Procedure:
The diolefin 18e (0.73 g, 1.34 mmol) was reacted with Hoveyda Grubbs 2nd generation catalyst (100 mg) in DCE (700 ml) according to the procedure described in Example 13 step d. Purification by column chromatography on silica gel gave the title compound, (0.34 g, 49%), (M+H)+517.
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:30]C)=[C:25]([NH:27][CH2:28][CH3:29])[CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([OH:30])=[C:25]([NH:27][CH2:28][CH3:29])[CH:26]=3)=[N:12][N:11]=2)=[CH:32][CH:33]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNc1cc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cnc1OC
Solvent: ClC(Cl)Cl
Product: CCNc1cc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cnc1O

Procedure:
In analogy to Ex. 3, treatment of a solution of 1-(4-tert-butyl-anilino)-4-[5-ethylamino-6-methoxy-(pyridin-3-yl)-methyl]phthalazine in CHCl3 with Me3Sil, followed by hydrolysis gives the title compound. ES-MS: (M+H)+=428; HPLC(Grad20-100) tRet=11.9.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH2:19]([O:21][C:22](=[O:29])[C:23]([NH2:28])([CH2:26][CH3:27])[CH2:24][CH3:25])C>>[CH3:19][O:21][C:22](=[O:29])[C:23]([NH:28][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CCOC(=O)C(N)(CC)CC
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)OC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-2-ethyl-butanoic acid ethyl ester hydrochloride (1:1) (CAN 70974-26-4) as starting materials, LC-MS (UV peak area/ESI) 100%, 361.2120 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33]C)=[O:32])=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>O1CCOCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([OH:33])=[O:32])=[CH:23][CH:24]=2)[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:9]([Cl:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(-c3ccccc3C(=O)OC)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCc1nc(Cl)c(CC(=O)O)c(Cc2ccc(-c3ccccc3C(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.2 %

Procedure:
175 mg of the product of Example 7 were introduced into 1.75 ml of dioxane and 1.6 ml of N sodium hydroxide and after stirring at ambient temperature for 3 days, followed by dilution with 10 ml of water, neutralization with 1.6 ml of 1N hydrochloric acid, extraction 5 times with 10 ml of methylene chloride and evaporation to dryness under reduced pressure, the residue was taken up in 2 ml of hexane, stirred for 1 hour and separated to obtain 152 mg of the expected product melting at approx 100°-110° C.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([C@H:44]3[CH2:49][CH2:48][C@H:47]([CH:50]=O)[CH2:46][CH2:45]3)[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)=[O:31].O>C1COCC1>[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:39][CH2:40][C@H:41]([C@H:44]3[CH2:49][CH2:48][C@H:47]([CH:50]=[CH2:2])[CH2:46][CH2:45]3)[CH2:42][CH2:43]2)[CH2:34][CH2:33]1)=[O:31]
Reactant: COC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)CC1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](C(=O)OC)CC3)CC2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 30.2 g (74.7 mmol) of methyltriphenylphosphonium iodide and 400 ml of THF was cooled to -50° C. To this mixture was added 9.23 g (82.2 mmol) of t-BuOK and the resulting mixture was stirred for one hour. To this mixture was added dropwise a solution of 20.0 g (59.8 mmol) of trans-4-(trans-4-(trans-4-formylcyclohexyl)cyclohexyl)cyclohexane carboxylic acid methyl ester in 500 ml of THF, while maintaining a temperature at below -50° C. After the dropwise addition, the reaction temperature was gradually allowed to rise up to room temperature. After 300 ml of water was added to the reaction mixture, the reaction mixture was extracted with 1000 ml of toluene. The organic layer was washed three times with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to a silica gel column chromatography (a developing solvent: heptane) to give 9.90 g of crude trans-4-(trans-4-(trans-4-ethenylcyclohexyl)cyclohexyl)-cyclohexane carboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH3:12])[CH2:11][C:4]=2[CH:3]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][N:10]1[C:9](=[O:13])[CH2:8][CH2:7][NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:18]=[CH:17]/[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][C:4]=2[CH2:11]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN1Cc2cc(Br)cnc2NCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NCCC1=O
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-bromo-5-methyl-2,3,5,6-tetrahydropyrido[2,3-b][1,5]diazocin-4(1H)-one (670 mg, 2.48 mmol), tert-butyl acrylate (1.8 mL, 12.4 mmol) and (i-Pr)2EtN (1.3 mL, 7.44 mmol) in 30 mL of DMF:Propionitriole (4:1) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (19.4 mg, 0.09 mmol) and P(o-tol)3 (51.7 mg, 0.18 mmol) then heated to 110° C. for 16 h. The hot mixture was filtered through a pad of celite. The filtrate was diluted with 100 mL H2O then extracted with 2×100 mL ethyl acetate. The resulting brown solid was triturated with a solution of hexanes:ethyl acetate (4:1) followed by filtration to yield the brown solid product. Yield 391 mg (50%); 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.51 (s, 1H), 7.49 (d, J=16.4 Hz, 1H), 6.26 (d, J=16.0 Hz, 1H), 5.22 (bm, 1H), 4.55 (s, 2H), 3.66 (q, J=7.2 Hz, 2H), 3.07 (t, J=7.2 Hz, 2H), 2.81 (s, 3H), 1.55 (s, 9H); ESI MS m/z 318 [C17H23N3O3+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(NC(=O)c4ccccc4)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Yield: 99.9 %

Procedure:
To a solution of 4-((1R,2R)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (306 mg, 0.61 mmol) in CH2Cl2 (10 mL) and pyridine (1.5 mL) was added benzoylchloride (0.10 mL, 0.86 mmol) at room temperature. The resultant solution stirred for 24 hours and quenched with 2N aq. HCl (15 mL). The mixture was further partitioned between H2O (40 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (2×40 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil (367 mg, 100%): 1H NMR (400 MHz, δ in ppm) 9.84 (s 1H), 8.10-7.98 (m, 6H), 7.67-7.48 (m, 4H), 6.96 (d, J=8.6 Hz, 1H), 5.76 (d, J=9.0 Hz, 1H), 5.05 (dd, J=6.5, 9.0 Hz, 1H), 4.67 (pentet, J=6.3 Hz, 1H), 2.36 (s, 3H), 1.45 (d, J=6.3 Hz, 3H), 0.83 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[NH:13][N:12]=[CH:11][C:10]=2[NH:14][C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[N:22][C:21]=23)=[O:16])[CH:8]=1)#[N:2].[CH3:28][C:29]1([O:32][CH2:31]1)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:10]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:11][N:12]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[N:13]=2)[CH:8]=1)#[N:2]
Reactant: CC1(C)CO1
Reactant: COc1ccc(C#N)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C#N)cc1-c1nn(CC(C)(C)O)cc1NC(=O)c1cnn2cccnc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 11.3 %

Procedure:
To a solution of N-(5-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.557 mmol) in 20 mL DMF was added isobutylene oxide (0.20 mL, 2.2 mmol) and cesium carbonate (363 mg, 1.11 mmol). The reaction mixture was stirred at 80° C. for 6 hours, then diluted with ethyl acetate and filtered, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 27.2 mg (11%) of desired product. LCMS (ESI) m+H=431.9. 1H NMR (CDCl3, 400 MHz): 69.68 (s, 1H), 8.78 (dd, J=2.0, 6.8 Hz, 1H), 8.71 (s, 1H), 8.56 (q, J=1.6 Hz, 1H), 8.37 (s, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.72 (dd, J=2.0, 8.4 Hz, 1H), 7.1 (d, J=8.8 Hz, 1H), 7.01 (dd, J=4.4, 7.2 Hz, 1H), 4.11 (s, 2H), 3.91 (s, 3H), 1.23 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH2:4]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1
Reactant: COC1COc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2C1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Yield: 52.9 %

Procedure:
There were mixed 3.63 g of 2,3-dihydro-3-methoxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran4-one, 3.41 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 150 ml of dioxane. The mixture was refluxed for 48 hours. The reaction mixture was cooled. The resulting precipitate was removed by filtration. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 3 : 1 mixture of toluene and ethyl acetate) to obtain 1.91 g (yield: 52.9%) of 3-methoxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one [Compound No. 2].
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([N:22]1[CH2:23][CH2:24][N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccccc2)CC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and 1-phenylpiperazine as starting raw materials, to produce an intended compound.