Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[CH:27]=[C:26](Br)[CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:7].[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([NH:16][C:17]([C:19]1[S:20][C:21]3[CH:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:25]=[CH:24][C:22]=3[CH:23]=1)=[O:18])[CH2:9]2
Reactant: OB(O)c1ccccc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccccc3)cc2s1
Temperature: 80 °C

Procedure:
0.15 ml of 2 M aqueous sodium carbonate solution and 4.1 mg (0.005 mmol) of PdCl2(dppf) are added to a mixture of 40 mg (0.10 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A) and 12.1 mg (0.10 mmol) of phenylboronic acid in 1 ml of DMF. The reaction mixture is heated at 80° C. for 14 h, filtered through kieselguhr and evaporated to dryness. Purification of the crude product by preparative HPLC, subsequent addition of 1N hydrochloric acid and drying under high vacuum result in 14.5 mg (37% of theory) of the title compound.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:1]([Cl:4])=[O:2])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1ccc(CO)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Reaction time: 18 h

Procedure:
To a solution of phosgene in toluene (20% w/w, 2.2 mL, 4.2 mmol), cooled in an ice bath, was added dropwise a solution of 60 (321 mg, 1.9 mmol) in 2 mL of toluene. The mixture was stirred in the same bath, which was left to come to room temperature on its own. After 18 h, the mixture was concentrated in vacuo to give 61, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H), 5.28 (s, 2H), 7.13 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)O1.Br[C:20]1[CH:21]=[C:22]2[C:28]([C:29]([C:31]3[C:32]([F:50])=[C:33]([NH:38][S:39]([C:42]4[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=4[F:49])(=[O:41])=[O:40])[CH:34]=[CH:35][C:36]=3[F:37])=[O:30])=[CH:27][NH:26][C:23]2=[N:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.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>[F:50][C:32]1[C:31]([C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][N:13]=[CH:12]5)[CH:21]=3)[NH:26][CH:27]=2)=[O:30])=[C:36]([F:37])[CH:35]=[CH:34][C:33]=1[NH:38][S:39]([C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[F:49])(=[O:40])=[O:41]
Reactant: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F)c1c[nH]c2ncc(Br)cc12
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)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: [K+]
Solvent: CC#N
Product: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F)c1c[nH]c2ncc(-c3ccc4[nH]ncc4c3)cc12
Temperature: 140 °C
Yield: 55 %

Procedure:
Into a microwave vial, 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (12, 28 mg, 0.11 mmol) is combined with N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (26, 50 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium(0) (2.2 mg, 0.0019 mmol), and potassium carbonate (1.0 mL, 1.0 M in water) in 3 mL of acetonitrile. The reaction is heated at 140° C. for 50 minutes in a microwave, the solvents removed under vacuum, and the residue purified by silica gel column chromatography, eluting with dichloromethane and methanol. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a white solid (P-0002, 28 mg, 50%). MS (ESI) [M+H+]+=565.85.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Li+].[Cl-].[NH4+]>O1CCCC1.O>[N:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CCN1CCN(c2ccncc2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCN1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6 g (0.02 Mol) of methyl 3-[4(4-pyridyl)piperazin-1-yl]propionate dihydrochloride in 80 ml of tetrahydrofuran and 100 ml of water is added a solution of 4.2 g (0.1 Mol) of lithium hydroxide in 100 ml of water and the mixture is stirred for two hours at ambient temperature. It is then evaporated to dryness in vacuo and the residue remaining is taken up in absolute ethanol. 5.3 g (0.1 Mol) of ammonium chloride are added, the inorganic salts precipitated are suction filtered and the solution remaining is evaporated to dryness. The residue is triturated with ether and suction filtered.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:24])[NH:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1)(C)(C)C.[ClH:26]>CO.CC(O)C>[ClH:26].[ClH:26].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:24])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)NCCN2CCCC2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: NCc1ccc(C(=O)NCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of [4-(2-Pyrrolidin-1-yl-ethylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (400 mg, 1.15 mmol) in MeOH (30 mL) was added 6M HCl in IPA (25 mL). The mixture was stirred at ambient temperature for 5 h. After this time a precipitate had formed and was filtered and dried to yield the title compound. m/z (M+1) 248.34.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[CH:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:35]([NH:37][C@H:38]([C:44](OC2C=CC([N+]([O-])=O)=CC=2)=[O:45])[CH2:39][CH2:40][C:41]([NH2:43])=[O:42])=[O:36])=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C)C=O>[NH:37]([C:35]([O:34][CH2:33][C:30]1[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=1)=[O:36])[C@H:38]([C:44]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:45])[CH2:39][CH2:40][C:41](=[O:42])[NH2:43]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1

Procedure:
550 mg of H-Asp(OtBu)-Phe-OCH3.HCl together with 574 mg of Z-Gln-ONP are dissolved in 2.5 ml of absolute N,N-dimethylformamide and stirred with 0.20 ml of triethylamine for 15 hours at 30°-33° C. bath temperature. Thereafter the product is extracted by shaking with a large amount of ethyl acetate as described under 19 and the solution is dried and evaporated.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([N:22](/C=C/C)/C=C/C)=[N:20][N:21]=3)[CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)CO[C:33](=[O:51])[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[NH2:22][C:19]1[N:17]2[CH:18]=[C:13]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH:1][C:33]([NH:34][C:35]4[N:36]([C:44]5[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=5)[N:37]=[C:38]([C:40]([CH3:42])([CH3:41])[CH3:43])[CH:39]=4)=[O:51])[CH2:3][CH2:4]3)[CH:14]=[CH:15][C:16]2=[N:21][N:20]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: C/C=C/N(/C=C/C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N)n4c3)c3ccccc32)cc1
Yield: 39 %

Procedure:
A mixture of Intermediate 101c (1.33 g, 3.54 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (for reference procedure see Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 2.0 g, 4.96 mmol) and DIPEA (1.82, 14.16 mmol) in DMF (20 mL) was stirred at RT for 20 h. The reaction mixture was diluted with MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The product containing fractions were concentrated in vacuo and the resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, followed by recrystallization from 5% MeOH in DCM (few drops of cyclohexane added to start recrystallization), to give the title compound (760 mg, 39%) as an off white dust. LCMS (Method 5): Rt 3.81 min, m/z 551 [MH+]. 1H NMR (400 MHz, CD3OD): 1.34 (9H, s), 1.86-2.08 (2H, m), 2.09-2.19 (1H, m), 2.22-2.34 (1H, m), 2.42 (3H, s), 4.89-4.96 (1H, m), 5.32 (1H, t, J=4.4 Hz), 6.37 (1H, s), 7.05 (1H, dd, J=10.0, 2.1 Hz), 7.23-7.44 (9H, m), 7.83 (1H, d, J=2.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][C:19](=[CH2:21])[CH3:20]>C1COCC1.S(=O)(=O)(O)O>[C:19]([O:16][C:15]([C:10]1([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:17])([CH3:21])([CH3:20])[CH3:18]
Reactant: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-(4-nitro-phenyl)-cyclopentanecarboxylic acid (as prepared in the previous step) in THF at −78° C. in a pressure bottle is treated with 2 drops of concentrated sulfuric acid, and isobutylene gas is condensed into the mixture. The mixture is stirred 24 h at RT, cooled to −78° C. and quenched with satd aq NaHCO3. The mixture is warmed to RT and extracted with EtOAc. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with an appropriate solvent to afford the title compound.
Reaction SMILES: C(#N)C.C([O:7][C@@H:8]1[CH:13]=[CH:12][C@@:11]([OH:20])([C:14]#[C:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][O:9]1)(=O)C>O>[OH:9][CH2:10][C:11]1([C:14]#[C:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[O:20][C@@H:8]([OH:7])[CH:13]=[CH:12]1
Reactant: CC(=O)O[C@@H]1C=C[C@@](O)(C#C[Si](C)(C)C)CO1
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)C#CC1(CO)C=C[C@H](O)O1
Temperature: 40 °C
Reaction time: 15 h
Yield: 93.3 %

Procedure:
570 mL of an acetonitrile solution containing 190 g of Compound 5 was heated to 40° C., to which 760 mL of an aqueous solution containing 19 g Lipase PS Amano SD was added and the resultant was agitated for 15 hours while maintaining the temperature at 40° C. After confirming the end of the reaction by thin-layer chromatography, the resultant was left to cool at room temperature, added with water and subjected to extraction with ethyl acetate. The organic layer was concentrated to obtain 148 g of a mixture of Compounds 9 and 10 as a clear brown oily product (crude yield: 93.8%).
Reaction SMILES: C[O:2][C:3]1[S:4][C:5]([CH:10]=[O:11])=[C:6]([O:8]C)[N:7]=1.ClCCl.P(Br)(Br)Br>CCOCC>[CH:10]([CH:5]1[S:4][C:3](=[O:2])[NH:7][C:6]1=[O:8])=[O:11]
Reactant: COc1nc(OC)c(C=O)s1
Agent: BrP(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC1SC(=O)NC1=O

Procedure:
To a stirred solution of 2,4-dimethoxythiazole-5-carboxaldehyde (0.01 mol), which may be prepared as described in Step (b) above, in a solvent such as dichloromethane is added phosphorous tribromide or another suitable ether cleaving reagent, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the corresponding 2,4-thiazolidindione-5-carboxaldehyde is formed, the reaction is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated. The residue is dissolved in THF, and 1 mol equivalent of a suitable non-nucleophilic base as described above in Example 17 is added, followed by 1 mol equivalent of methyl iodide. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the corresponding 2-methoxy-4,5-dihydro-thiazolin-4-one-5-carboxaldehyde is formed, the mixture is partitioned and worked up as described above. The resulting residue is dissolved in THF, and 1 mol equivalent of a suitable non-nucleophilic base as described above in Example 17 is added, followed by 1 mol equivalent of 2,2-difluoro-hex-5-ynoyl chloride, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the reaction is partitioned and worked up as described above to give (E)-5-(2,2-difluoro-hex-5-ynoyloxymethylene)-2-methoxy-4,5-dihydro-thiazolin-4-one, which may be purified, if needed or desired, by chromatography on silica gel or crystallization. Also formed is (Z)-5-(2,2-difluoro-hex-5-ynoyloxymethylene)-2-methoxy-4,5-dihydro-thiazolin-4-one, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][N:23]4[N:26]=[C:27]([CH2:29][O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:28]=[C:22]4[C:21]3=[O:37])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][N:23]4[N:26]=[C:27]([CH2:29][O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:28]=[C:22]4[C:21]3=[O:37])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(N3CCn4nc(COc5ccccc5)cc4C3=O)n2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(N3CCn4nc(COc5ccccc5)cc4C3=O)n2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
10% Palladium on charcoal (11 mg, 0.01 mmol) was added to a stirred suspension of 6-(4-oxo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (51 mg, 0.10 mmol) and ammonium formate (38 mg, 0.61 mmol) in MeOH (0.5 mL) in a sealed tube and under nitrogen. The mixture was stirred at 80° C. for 30 minutes. The mixture was filtered through a pad of diatomaceous earth and washed with DCM. The filtrate was treated with brine and extracted with more DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 6-(4-oxo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (44 mg, 86% yield) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Li+].[OH-]>CO>[CH3:15][O:14][C:12]([NH:11][C:4](=[C:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[C:3]([OH:16])=[O:2])=[O:13]
Reactant: COC(=O)NC(C(=O)OC)=C1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)NC(C(=O)O)=C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid methyl ester (141 mg, 0.62 mmol) in methanol (1.8 mL) was added an aqueous LiOH solution (1M, 1.8 mL, 1.8 mmol). The resulting solution was stirred at room temperature for 16 hours and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCl. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated to give methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid. To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid (23 mg, 0.11 mmol) in dimethylformamide (0.6 mL) was added HATU (41 mg, 0.11 mmol). After stirring for 5 minutes, a solution of {2-methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloride (50 mg, 0.068 mmol) in dimethylformamide (0.6 mL) was added to the reaction, followed immediately by diisopropylethylamine (85 μL, 0.49 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3 solution, water and brine, dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield {1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (28 mg, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH:11]3[C:13](=[O:14])[CH:8]([CH2:9][CH2:10]3)[CH2:7][C:6]=2[CH:15]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH:11]3[C:13](=[O:14])[CH:8]([CH2:9][CH2:10]3)[CH2:7][C:6]=2[CH:15]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C2CCC1Cc1cc(O)ccc1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C2CCC1Cc1cc(OCc3ccccc3)ccc1C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-hydroxy-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-one (15 g; J. Org. Chem 1982, 47, 4329), K2CO3 (20.5 g) and benzyl bromide (10.6 ml) in DMF (100 ml) was stirred for 48 hrs at room temperature. The reaction was diluted with water (500 ml) and extracted with EtOAc (3×150 ml). The combined organic phases were washed with water (2×300 ml), brine (150 ml), dried and concentrated to give a gummy oil which crystallized on standing and after trituration with ether the title benzyl ether (19.5 g, 90%) as a white solid (360 MHz 1H, δ-CDCl3) 1.32 (2H, m), 1.85 (2H, m), 2.57 (2H, m), 2.87 (4H, m), 5.05 (2H, s), 6.82 (2H, m), 7.11 (1H, d, J=8.2), 7.37 (5H, m).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:18]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccccc1
Reactant: O=C(Cl)C1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C2CCCC2)cc1

Procedure:
In analogy to the procedure of Example I, the title compound is prepared from 31 g (0.287 mol) of anisole, 46 g (0.345 mol) of aluminium chloride and 40 g (0.302 mol) of cyclopentanecarbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=[O:11])=[CH:4][CH:3]=1.[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:10](=[O:11])[CH2:18][CH2:17][C:19](=[O:20])[CH3:21])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: C=CC(C)=O
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)CCC(=O)c1cccc(Oc2ccc(F)cc2)c1
Reaction time: 6 h
Yield: 66.5 %

Procedure:
To a stirred solution of 3-(4-fluorophenoxy)benzaldehyde (26.8 g; 0.124M) in ethanol (60 ml) was added methyl vinyl ketone (8.32 ml; 0.1M), 3-benzyl-5-(2-hydroxyethyl)-4-methylthizolium chloride (5.93 g; 0.022M), and triethylamine (27.88 ml; 0.2M) at room temperature. After stirring for 6 hrs, volatiles were removed. To the residue was added water (200 ml), and the whole was extracted with ethyl acetate (150 ml×2). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over MgSO4, and concentrated in vacuo. The residual oil was purified by flash column (SiO2) eluting with ethyl acetate-n-hexane (1:5) to give 19.03 g (yield 66.5%) of the subtitle compound [C] as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[N:14]=[C:13]([CH3:18])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:19][C:16]1[C:11]([NH:10][NH:9][CH2:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[N:12][C:13]([CH3:18])=[N:14][C:15]=1[NH2:17]
Reactant: Cc1nc(N)cc(NNCc2cncc(Br)c2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(N)c(Br)c(NNCc2cncc(Br)c2)n1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 29.7 %

Procedure:
To a mixture of N-[[(5-bromo-3-pyridinyl)methyl]amino]-2-methyl-4,6-pyrimidinediamine (1.00 g, 3.40 mmol) in carbon tetrachloride (50 mL) at 23° C. was added N-bromosuccinimide (0.61 g, 3.90 mmol). The mixture was stirred for 1.5 hours at 23° C. and then filtered. The isolated solid was purified by flash chromatography (silica gel, 1:1 EtOAc:CHCl3 then 20% MeOH in EtOAc as eluants) and two recrystallizations from methanol to provide the title compound (376 mg, 1.01 mmol, 30%): mp 221°-222° C., Rf 0.69 (20% MeOH in EtOAc); 1H NMR (DMSO-D6, 400 MHz)δ8.54 (d, J=2 Hz, 1H), 8.50 (d, J=2 Hz, 1H), 7.93 (m, 1H), 7.09 (t, J=6 Hz, 1H), 6.39 (s, 2H), 4.51 (d, J=6 Hz, 2H), 2.13 (s, 3H); IR (KBr) 3480, 3300 (NH), 2900-3150 (CH), 1650, 1600 (C=C, C=N) cm-1 ; mass spectrum m/e 375 (M+, 45%), 373 (M+, 84%), 371 (M+, 44%), 292 (C11H11BrN5, 54%), 185 (C6H6BrN2, 50%).