Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][C@@H:9]2[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: C[C@H]1CNCCN1c1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: C[C@H]1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 17.6 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-(S)-methyl-piperazine (0.56 g, 2.6 mmol) in isopropanol (20 mL) was added 2,6-lutidine (0.305 mL, 2.6 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and then treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.64 g, 1.7 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 20 h. The reaction was concentrated in vacuo and purified by flash chromatography (100% dichloromethane to 2% methanol/dichloromethane) to yield the title compound (0.151 g, 18%). 1H-NMR (CDCl3) δ: 1.0 (3H, d), 1.57 (6H, s), 1.79 (s, 1H), 2.25–2.52 (7H, m), 2.66–2.69 (1H, m), 2.98–3.12 (2H, m), 3.68–3.73 (1H, m), 5.32 (2H, br s), 6.17 (1H, t), 6.82 (3H, d), 7.18–7.31 (4H, m), 7.44 (1H, d), 7.56–7.60 (1H, m), 8.50 (1H, dd). ESI-MS m/z: 504 (M), UV retention time: 1.49 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)[S:13][CH:14]=1)=[O:7].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:16][CH:17]([O:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:18]2)[S:13][CH:14]=1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCc1csc(N2CC(O)C2)n1)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]-3-hydroxyazetidine (426 mg, 1.72 mmol) (obtained as described in Reference Example 67(2)) in methylene chloride (20 ml) were added methanesulfonyl chloride (0.16 ml, 2.07 mmol) and triethylamine (0.29 ml, 2.07 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (20:1) as the eluant to afford 1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (481 mg, yield 78%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([CH:6]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].[Cl:19][CH:20]([SiH3:22])[Cl:21]>C1CC=CCCC=C1.Cl[Pt]Cl.C1(C)C=CC=CC=1>[F:14][C:13]([F:15])([F:16])[S:10]([CH:6]([S:3]([C:2]([F:17])([F:1])[F:18])(=[O:4])=[O:5])[CH2:7][CH2:8][CH2:9][SiH2:22][CH:20]([Cl:21])[Cl:19])(=[O:12])=[O:11]
Reactant: C=CCC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F
Reactant: [SiH3]C(Cl)Cl
Agent: Cl[Pt]Cl
Agent: C1=C\CC/C=C\CC/1
Solvent: C1=CCCC=CCC1
Solvent: Cc1ccccc1
Product: O=S(=O)(C(CCC[SiH2]C(Cl)Cl)S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 110 °C
Reaction time: 0.05 h
Yield: 95.3 %

Procedure:
Under nitrogen atmosphere, a three-neck flask equipped with a reflux condenser and having a volume of 100 ml was charged with each of 126.7 g (0.393 mol) of 1,1-bis(trifluoromethanesulfonyl)-3-butene, 68.7 g of toluene, 15.2 mg (0.0002 parts by mass relative to BTSB) of dichloro(1,5-cyclooctadiene)platinum(II) (made by Tokyo Chemical Industry Co., Ltd.), and 50.0 g (0.4 parts by mass relative to BTSB) of dichloromethylsilane (made by Tokyo Chemical Industry Co., Ltd.). Continuously, under nitrogen atmosphere, stirring was conducted for three minutes for mixing. After that, while this flask was heated by immersion in an oil bath adjusted to 50° C., an addition reaction was conducted for 30 minutes. After termination of the addition reaction, toluene was distilled out under reduced pressure and recovered. Then, a distillation under reduced pressure was conducted. Under a reduced pressure of 533 Pa (4 mmHg), it was distilled out by heating at 105-115° C., thereby obtaining 163.0 g of 4,4-bis(trifluoromethanesulfonyl)butyldichloromethylsilane (in the following, it may be abbreviated as BTSB-DCMS) as a perfluoromethidization agent.
Reaction SMILES: [C:1]1([C:7]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]([CH3:10])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O.O>[N:17]([CH:9]([CH3:10])[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:8])=[N+:18]=[N-:19]
Reactant: CC1OC1(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C(O)(c1ccccc1)c1ccccc1
Yield: 69.7 %

Procedure:
A solution of 9.35 g (44.5 mmol) 2,2-diphenyl-3-methyloxirane and 9.00 g (138 mmol) NaN3 in 100 ml of 2:1 N,N-dimethylformamide-water was heated at reflux for 72 hours. The solution was concentrated and the residue was partitioned between ether and water. The ether layer was washed with NaHCO3, then water, dried over Na2SO4 and concentrated. HPLC (5% EtOAc-hexane) afforded 7.86 g (70%) of 2-azido-1,1-diphenylpropanol as a clean oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7].[Cl:23]C(OCC(C)C)=O.[C:31]([C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36])(=[O:33])[NH2:32].Cl.Cl.C(O)C>CN(C=O)C.C(N(CC)CC)C>[OH2:2].[ClH:23].[C:31]([C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH:36][C:15](=[O:17])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:12]1)(=[O:33])[NH2:32]
Reactant: NC(=O)c1ccccc1N
Reactant: COc1ccc(C(=O)N2CCN(CC(=O)O)CC2)cc1OC
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(CC(=O)Nc3ccccc3C(N)=O)CC2)cc1OC
Product: O

Procedure:
2.77 Grams of [4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-acetic acid was dissolved in 30 ml of DMF, then to this solution was added 1.2 g of triethylamine. Under ice-cooled condition with stirring, 1.4 g of isobutyl chloroformate was added dropwise thereto and stirred for 30 minutes. Further, the reaction mixture was stirred at a room temperature, a DMF solution of 1.46 g of o-carbamoylaniline was added dropwise to the mixture and was stirred for 6 hours. The reaction mixture obtained was concentrated to dryness, the residue was extracted with chloroform and 1N-sodium hydroxide aqueous solution. The chloroform layer was washed with water, dried then chloroform was removed by distillation. The residue obtained was purified by a silica gel column chromatography and the product obtained was converted into a hydrochloride by adding hydrochloric acid-ethanol, then recrystallized from water-acetone to obtain 0.7 g of o-carbamoyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloride monohydrate in the form of colorless needle-like crystals. Melting point: 122.0°-125.0° C. (decomposed).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])O)[CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([NH2:37])=[O:36].O>CN(C=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:22][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[N:8]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=[O:10])=[O:11])[CH2:34][C:35]([NH2:37])=[O:36]
Reactant: NC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(C)cc2C(O)c2ccccc2Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CC(N)=O)c2ccc(C)cc2Cc2ccccc2Cl)cc1OC
Reaction time: 18 h
Yield: 78 %

Procedure:
To 0.47 g of N-{4-methyl-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenzenesulfonamide dissolved in 5.7 ml of DMF is added, at 0° C., 0.048 g of sodium hydride. After 1 hour at this temperature, 0.166 g of 2-bromoacetamide is introduced and the mixture is left for 18 hours at room temperature. The medium is poured into water and then extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate mixture to give 0.4 g of the expected product.
Reaction SMILES: [C:1]1(=[O:13])[C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.[CH:14]1([CH:20]=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[K+].[H][H]>[Pd].C(O)C>[CH:14]1([CH2:20][CH:2]2[CH2:3][C:4]3[C:12](=[CH:11][C:10]4[CH2:9][CH2:8][CH2:7][C:6]=4[CH:5]=3)[C:1]2=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CC1CCCCC1
Reactant: O=C1CCc2cc3c(cc21)CCC3
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2cc3c(cc2CC1CC1CCCCC1)CCC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In argon atmosphere, a 250 ml Berghof stainless steel autoclave with PTFE leaner was charged with 25.0 g (0.145 mol) of 3,5,6,7-tetrahydro-s-indacen-1(2H)-one, 20.0 g (0.178 mmol) of cyclohexanecarbaldehyde, 2.0 g (0.036 mol) of potassium hydroxide, 2.0 g of 10% Pd on charcoal and 150 ml of 96% ethanol. This reactor was flashed by hydrogen, and then hydrogen was fed to a pressure of 3 atm. This mixture was stirred for 3 h at room temperature. The resulting mixture was filtered through glass frit (G3), and the precipitate was additionally washed by 50 ml of ethanol. The filtrate was evaporated to dryness, and 500 ml was added to the residue. The crude product was extracted by 3×200 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane). Yield 36.5 g (94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][C@@H:23]([C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[C:24](N3[C@H]4C5C=CC=CC=5C[C@H]4OC3=O)=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:46]O.[Li+].[OH-].Cl>O.C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][C@@H:23]([C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[C:24]([OH:46])=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: COc1ccc(-n2nc(C[C@H](C(=O)N3C(=O)O[C@@H]4Cc5ccccc5[C@@H]43)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(C[C@H](C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a stirred THF/toluene solution containing 3-{3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionyl}-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one (Example 520, 9.45 kg, 14.8 mol) at 0-10° C. was added H2O (5.25 L) and 30% hydrogen peroxide (4.35 L, 42.6 mol) followed by 19% aq. LiOH (9.40, 42.6 mol). The reaction mixture was stirred between 0-10° C. for 2 h. When HPLC analysis indicated the disappearance of the starting material, the reaction was quenched between 0-10° C. with 1.5 N sodium meta-bisulfite solution (8.0 L) maintaining the pH at 9-10. The quenched reaction mixture was then acidified to pH 1-2 using 6 N HCl (8.4 L). After removing the aqueous layer, ˜60.0 L of the organic phase was removed under reduced pressure, and EtOAc (8.5 L) was added. The resultant suspension was filtered and washed. The filtrate, containing the desired acid, was used directly in the next synthetic step without isolation. Chemical characterization data obtained herein for the title compound is not duplicated in this Example in light of the same data given in Example 1, Step H.
Reaction SMILES: Br[C:2]1[C:3]([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[N:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29](B(O)O)[CH:30]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[C:3]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[N:4][C:5]([CH3:18])=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])=[CH:29][CH:30]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1nc(OCC2CC2)c(Br)cc1C(=O)N[C@@H]1CCCC[C@H]1O
Product: Cc1nc(OCC2CC2)c(-c2ccc(Cl)cc2)cc1C(=O)N[C@@H]1CCCC[C@H]1O

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31c, using 5-bromo-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-2-methyl-nicotinamide and 5-chlorophenyl-boronic acid as starting materials, MS (ISP): 415.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:6][CH:5]=1.[CH2:19]([O:21][C:22](=[O:35])[C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][C:28]=1[CH3:34])([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:35])[C:23]([CH3:25])([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:16][CH:14]([CH3:15])[CH2:13][CH2:12][C:11]#[C:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:17])([F:18])[F:1])=[CH:9][CH:8]=2)=[CH:29][C:28]=1[CH3:34])[CH3:24])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: CC(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(C)CCC#Cc2ccc(OC(F)(F)F)cc2)cc1C

Procedure:
In analogy to the procedure described in example 24A], rac-6-(4-trifluoromethoxy-phenyl)-hex-5-yn-2-ol (example 31E]) and 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) yielded the title compound as yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:6]=1[OH:25])[CH3:4].S([O-])(=O)(=O)C.[CH3:31][C:32]1([CH3:39])[O:36][CH:35]([CH2:37]O)[CH2:34][O:33]1>CN(C)C=O>[CH2:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]=[CH:7][C:6]=1[O:25][CH2:37][CH:35]1[CH2:34][O:33][C:32]([CH3:39])([CH3:31])[O:36]1)[CH3:4]
Reactant: CCCCCCCCCCCCCCc1ccc(O)c(CC)c1
Reactant: CC1(C)OCC(CO)O1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(OCC2COC(C)(C)O2)c(CC)c1
Temperature: 80 °C

Procedure:
To a suspension of 2.53 g of prewashed 50% sodium hydride in 130 ml of dimethylformamide was added dropwise a solution of 11.99 g of 2-ethyl-4-tetradecylphenol in dimethylformamide. The resulting suspension was heated at 80° C. for 1/2 hour, then allowed to cool and 10.29 g the mesylate of solketal was added. The mixture was heated at reflux for 3 hours, then cooled quenched slowly with water and extracted several times with ether. The ether extracts were combined, washed with brine, dried and the solvents evaporated, giving 16.1 g of the desired compound, mp 34°-38° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]#[N:12])=[N:7][C:8]=1[CH2:9]Br.[CH3:13][Si:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][O:17][CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C:20]1=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:28]=[C:20]1[N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:30])([CH3:29])[CH3:13])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]21[CH2:9][C:8]1=[N:7][C:6]([C:11]#[N:12])=[CH:5][CH:4]=[C:3]1[CH2:2]2
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: N#Cc1ccc(CBr)c(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(C#N)nc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 5,6-bis(bromomethyl)pyridine-2-carbonitrile from Step C (1.80 g, 6.21 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.64 g, 6.21 mmol, described in Intermediate 1) in DMF (207 mL) was added cesium carbonate (6.07 g, 18.6 mmol), portionwise, over 5 min. After 18 h, the mixture was partitioned between CH2Cl2 (100 mL), saturated aqueous NaHCO3 (100 mL) and brine (200 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 10:90, to give the title compound. MS: m/z=393 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25].C(O)(=O)C.Cl.C(O)(=O)CCCC>O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: COC(=O)CCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: Cl
Solvent: O
Solvent: CCCCC(=O)O
Solvent: CC(=O)O
Product: CC1(C2CCCC2)Cc2cc(OCCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
A mixture of methyl 5-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]pentanoate (14 g., 0.0339 mole), acetic acid (100 ml) and 6N hydrochloric acid (50 ml) is stirred and refluxed for 6 hours. The mixture is poured into water (400 ml) and the product which solidifies upon standing is removed by filtration and dried. The product is recrystallized from a mixture of tetrahydrofuran, ether and petroleum ether (50/100/200 ml) to give 12.5 g, of 5-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)]pentanoic acid, m.p. 106°-108° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[NH:4][N:3]=1.Cl[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:13][C:5]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([CH3:1])[N:3]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=2)[N:4]=1
Reactant: Cc1n[nH]c(C)c1-c1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2nc(C)c(-c3ccccc3)c2C)nc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 52.1 %

Procedure:
A mixture of 3,5-dimethyl-4-phenyl-1H-pyrazole (2.50 g, 14.5 mmol), ethyl 6-chloronicotinate (5.39 g, 29.0 mmol), potassium carbonate (8.02 g, 58.1 mmol) and dimethyl sulfoxide (100 mL) was stirred at 160° C. for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and toluene (2:1) and washed with water. The organic fraction was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with hexane/ethyl acetate (8:1) to afford 2.43 g (52%) of the title compound: MS (ESI) m/z 322 [M+H]+, 1H-NMR (CDCl3) δ 9.06-9.05 (1H, m), 8.39-8.36 (1H, m), 8.04-8.01 (1H, m), 7.48-7.29 (5H, m), 4.42 (2H, q, J=7.2 Hz), 2.67 (3H, s), 2.32 (3H, s), 1.43 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)N[C@@H]1CCCNC1
Product: COC(=O)c1cccc(N2CCC[C@@H](NC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 30.2 %

Procedure:
Using (R)—N-(piperidin-3-yl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (336 mg, 1.00 mmol) and 3-(methoxycarbonyl)phenylboric acid (360 mg, 2.00 mmol), the same procedure was followed as in Example 2 to give 142 mg (30%) of the desired compound as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2OCC#N)[C:5]([Cl:19])=[CH:4][N:3]=1.[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]>>[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH:36][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[CH2:6][CH2:5][C:4]#[N:3])[C:5]([Cl:19])=[CH:4][N:3]=3)[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: CC(=O)N1CCC(=O)NCc2cc(Nc3ncc(Cl)c(Nc4ccccc4CCC#N)n3)ccc21

Procedure:
Title compound was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one in an analogous manner to Example 1221d. (120° C., 40 min) Obtained 82 mg (55%) as a white foam. HPLC purity: 96%, LCMS 490.16 (M+H), 1H-NMR (CDCl3, 400 MHz) δ: 8.10 (s, 1H), 7.59 (s, 1H), 7.51-7.45 (m, 5H), 7.08-7.03 (m, 1H), 6.99-6.94 (m, 2H), 6.09 (bt, 1H), 4.81-4.76 (m, 1H), 4.22-4.18 (m, 1H), 3.45 3.41 (m, 1H), 3.01 (t, J=7.1 Hz, 2H), 3.00-2.97 (m, 1H), 2.72-2.63 (m, 3H), 2.58-2.53 (m, 1H), 1.76 (s, 3H).
Reaction SMILES: NC1C=CC(C(NC(C)C(N2CCCC2C(O)=O)=O)=O)=CC=1Cl.[O:24]=[C:25]1[O:29][CH:28]([O:30][CH2:31][CH2:32]C2C=CC=CC=2)[CH:27]([NH:39][C:40]([CH:42]2[CH2:46][CH2:45][CH2:44][N:43]2[C:47](=[O:61])[CH:48]([NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[C:54]([Cl:59])[CH:53]=2)[CH3:49])=[O:41])[CH2:26]1>>[CH2:31]([O:30][CH:28]1[CH:27]([NH:39][C:40]([CH:42]2[CH2:46][CH2:45][CH2:44][N:43]2[C:47](=[O:61])[CH:48]([NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[C:54]([Cl:59])[CH:53]=2)[CH3:49])=[O:41])[CH2:26][C:25](=[O:24])[O:29]1)[CH3:32]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1ccc(N)c(Cl)c1
Yield: 59 %

Procedure:
Prepared from anti-(2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97a following the method used for 98a to afford 175 mg of title compound (59%). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.10-1.28 (m, 3H), 1.42 (d, 0.6H), 1.46 (d, 2.4H), 1.75-2.45 (m, 4H), 2.45-2.70 (m, 1H), 2.80-3.05 (m, 1H), 3.50-3.95 (m, 4H), 4.20-4.75 (m, 3H), 4.75-4.90 (m, 1H), 5.32 (s, 0.8H), 5.38 (s, 0.2H), 6.80 (d, 1H), 7.55-7.84 (m, 2H). Analytical HPLC: 10.47 min. LC-MS (ES+): m/e=467.3 (MH+).