Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1([CH2:11][NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].N12CCCN=C1CCCCC2>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1([CH2:11][N:12]2[C:13](=[O:21])[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:23]2=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)CC1(CNC(=O)c2ccccc2N)CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)CC1(Cn2c(=O)[nH]c3ccccc3c2=O)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of {1-[(2-amino-benzoylamino)-methyl]-cyclohexyl}-acetic acid methyl ester (620 mg, 2.04 mmol) and 1,1′-carbonyldiimidazole (660 mg, 4.07 mmol) in THF (25 mL) is added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL, 4.01 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, and is concentrated to afford the desired [1-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexyl]-acetic acid methyl ester (670 mg, 99%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]([S:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:11])[CH3:10].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.O.C(Cl)Cl.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>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:18]2[CH:17]=[CH:16][C:15]([S:12]([CH:9]([CH3:11])[CH3:10])(=[O:14])=[O:13])=[CH:20][CH:19]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
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: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cncc(Cl)n2)cc1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
A mixture of 2,6-dichloropyrazine (653.1 mg, 4.384 mmol), (4-isopropylsulfonylphenyl)boronic acid (500 mg, 2.192 mmol), Pd(PPh3)4 (126.6 mg, 0.1096 mmol) and Na2CO3 (2.192 mL of 2 M, 4.384 mmol) in ethanol (500.0 μL) and toluene (7.500 mL) was heated at reflux for 72 hours. The reaction mixture was cooled to ambient temperature and diluted with water and DCM. The layers were separated and the aqueous layer was extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 0 to 40% EtOAc/Petroleum Ether) to give the sub-title product as a white solid (321 mg, 49% Yield). 1H NMR (400.0 MHz, DMSO) δ 9.41 (s, 1H), 8.88 (s, 1H), 8.41 (d, 2H), 8.03 (d, 2H), 3.54-3.49 (m, 1H) and 1.19 (d, 6H) ppm; MS (ES+) 297.1
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[CH3:22][N:21]([CH3:23])[C:19](=[O:20])[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:34]4[CH:33]=[N:32][C:31]([CH3:30])=[CH:36][CH:35]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN(C)C(=O)CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(CC(=O)N(C)C)CC4)cc3n2)cn1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-acetamide (Example 80) was reacted with 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine in General Procedure A. Purification on silica yielded 174. (400 MHz CDCl3): 2.54 (8H, m, CH2), 2.55 (3H, s, CH3), 2.87 (3H, s, CH3), 3.00 (3H, s, CH3), 3.12 (2H, s, CH2), 3.76 (2H, s, CH2), 3.81-3.83 (4H, m, CH2), 3.96-3.99 (4H, m, CH2), 7.16 (1H, m, ar), 7.23 (1H, s, ar), 8.48 (1 h, dd (J=8.06, 2.23), ar), 9.43 (1H, d (J=1.87), ar). MH+ 496.37
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12](OC)=[O:13].[H-].C([Al+]CC(C)C)C(C)C.CO>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][OH:13]
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)c(CO)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37.6 %

Procedure:
To a −78° C. solution of dimethyl 4-bromoisophthalate (21.0 g, 77 mmol)(commercially available from Maybridge) in THF (100 mL) was slowly added diisobutylaluminum hydride (269 mL, 269 mol, 1.0 M solution in hexane, commercially available from Sigma-Aldrich, St. Louis, Mo., USA) over 20 minutes. After stirring at −78° C. for 3 hours, the resulting mixture was treated with MeOH. Organic solvents were removed under reduced pressure and the residue was redissolved in EtOAc and washed with 1.0 N HCl. After removal of organic solvents under reduced pressure, purification of the residue through silica gel chromatography with 0-35% EtOAc in hexanes as eluents afforded 132.1 (7.1 g, 38%).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[N:5][N:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC>O1CCCC1>[CH3:13][C:9]1[N:8]=[C:7]([C:6]2[C:2]([B:17]([OH:22])[OH:18])=[C:3]3[CH2:16][CH2:15][CH2:14][N:4]3[N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cccc(-c2nn3c(c2Br)CCC3)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2nn3c(c2B(O)O)CCC3)n1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 72.3 %

Procedure:
Place tetrahydrofuran (28.0 mL) in a 100 mL round-bottom flask equipped with a temperature probe, a magnetic stirrer, and a septum and put under a nitrogen atmosphere. Add 3-bromo-2-[6-methyl-(pyridin-2-yl)]-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (1.44 g, 5.18 mmol) and triisopropyl borate (3.10 mL, 13.5 mmol). Cool the mixture to −78° C. using a dry ice/acetone bath. Add 1.4M n-butyllithium in hexanes (8.80 mL, 12.4 mmol) dropwise via a syringe pump over 10 min keeping the temperature below −40° C. Remove the dry ice/acetone bath and allow the reaction mixture to warm to room temperature. Add saturated aqueous ammonium chloride (10 mL) and extract with chloroform (2×100 mL). Combine the organic layers, dry over solid sodium chloride, and remove the solvent under reduced pressure to afford an oil. Purify the oil by normal phase flash chromatography (120 g Biotage KP-Sil 40L: 100% ethyl acetate in hexanes for 25 min, 0-10% methanol in ethyl acetate in ramp over 15 min, then 10% methanol in ethyl acetate) to yield 910 mg (73%) of the title compound. MS ES+ m/e 244 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1I.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][N:12]=1.C(N(CC)CC)C>CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: Cc1nccc(Cl)c1I
Reactant: C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nccc(Cl)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 1.0 g (4.0 mmol) 4-chloro-3-iodo-2-methyl-pyridine and 513 mg (4.3 mmol) 2-amino-5-ethynyl-pyridine using 75 mg (0.40 mmol) CuI, 276 mg (0.40 mmol) PdCl2(PPh3)2 and 5.4 mL (39.5 mmol) triethylamine in 40 mL dry DMF. After completion of the reaction the solvent is removed under vacuum and the product is purified by chromatography on silica gel using a DCM/MeOH gradient (100:0 to 90:10). Yield: 617 mg (64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:37]=[CH:36][C:35](Br)=[CH:34][N:33]=2)=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.C(Cl)Cl>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:37]=[CH:36][C:35]([NH:18][C:15]3[N:16]=[N:17][C:12]4[CH:11]=[C:10]([C:3]5[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=5[Cl:1])[CH:20]=[C:19]([CH3:21])[C:13]=4[N:14]=3)=[CH:34][N:33]=2)=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(NCCN1CCCC1)c1ccc(Br)cn1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(C(=O)NCCN5CCCC5)nc4)nnc3c2)c1
Yield: 54.9 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.090 g, 0.299 mmol, 1 equiv), 5-bromo-pyridine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (0.134 g, 0.449 mmol, 1.5 equiv), cesium carbonate (0.293 g, 0.899 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.035 g, 0.059 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.027 g, 0.0299 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (8 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 24 hours, then sonicated and slowly diluted with water. The resulting orange precipitate was filtered and dried. Column chromatography (1:5 MeOH/DCM) provided desired product as a yellow solid (0.085 g, 55% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)=[C:4]([O:45]C)[CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].N>ClCCl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)=[C:4]([OH:45])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccc(F)cc5O)c34)n(-c3ccccc3)c(=O)c12
Reaction time: 8 h
Yield: 54.5 %

Procedure:
(S)-2-(1-((5-(4-Fluoro-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (65 mg, 0.10 mmol) was dissolved in 1.3 ml dichloromethane and the reaction mixture was cooled at 0aC. Boron tribromide (1M in dichloromethane, 1 mL, 1.02 mmol) was added dropwise and the reaction mixture was stirred overnight. The reaction mixture was poured into a 4% sodium bicarbonate solution and extracted twice with dichloromethane. The organics were combined, dried, filtered and concentrated under reduced pressure. The white solid formed was re-dissolved in 650 μl anhydrous methanol and ammonia solution (7M in methanol, 1.3 ml, 9.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then concentrated to dryness, suspended in water and extracted twice with ethyl acetate. The organics were combined, dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude was purified using SP1® Purification System (0% to 10%, hexane-ethyl acetate) to obtain 27 mg (53% yield) of the title compound as a white solid. Purity 96%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][Si](C)(C)C)=[CH:6][CH2:5][C:4]([CH3:14])([CH3:13])[C:3]=1[CH:15]=[CH:16][C:17]([O:21][CH3:22])([CH3:20])[CH:18]=[CH2:19].C(=O)([O-])[OH:24].[Na+].O.O.O.S([O-])([O-])(=O)=O.[Mg+2].C(OO)(=O)C.Cl>CO.C(OCC)C>[OH:24][CH:6]1[CH2:5][C:4]([CH3:14])([CH3:13])[C:3]([CH:15]=[CH:16][C:17]([O:21][CH3:22])([CH3:20])[CH:18]=[CH2:19])=[C:2]([CH3:1])[C:7]1=[O:8]
Reactant: C=CC(C)(C=CC1=C(C)C(O[Si](C)(C)C)=CCC1(C)C)OC
Reactant: O=C([O-])O
Agent: CC(=O)OO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: C=CC(C)(C=CC1=C(C)C(=O)C(O)CC1(C)C)OC
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 32.0 g of 1-[2,6,6-trimethyl-3-(trimethylsiloxy)-1,3-cyclohexadien-1-yl]-3-methoxy-3-methyl-1,4-pentadiene, 10.0 g of sodium hydrogen carbonate, 10.0 g of magnesium sulphate trihydrate and 500 ml of diethyl ether was stirred well at 2°-5° C., then treated dropwise with 26.45 g of 40% peracetic acid and left to warm to room temperature. The mixture was subsequently cooled to 0° C., treated dropwise with 90 ml of a mixture of methanol and 1N hydrochloric acid (vol. 1:1) and extracted with diethyl ether. The organic phase was washed twice with cold semi-concentrated sodium pyrosulphite solution, once with ice-water, twice with ice-water to which had been added a small amount of saturated sodium hydrogen carbonate solution and a further twice with ice-water. After drying over sodium sulphate and concentration under a water-jet vacuum at 35° C., there were obtained 26.4 g of crude 1-(4-hydroxy-3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)- 3-methoxy-3-methyl-1,4-pentadiene (purity 91.5%) which still contained 7.07% of 1-(3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methoxy-3-methyl-1,4-pentadiene.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@H:26](OC(=O)C)[NH:25][C:24]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:32]([O:39][CH2:40][CH:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[OH:42])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@@H:26]([O:42][CH:41]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:40][O:39][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[NH:25][C:24]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)CCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC(O[C@H]1NC(=O)[C@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)CCc1ccccc1)c1ccccc1
Yield: 7 %

Procedure:
A mixture of (3S,4S)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-acetoxy-azetidin-2-one (4.36 g, 10.30 mmole), 2-(tert-butyldimethylsilyl)oxy-1-phenylethanol (2.6 g, 10.30 mmole), and zinc acetate dihydrate (2.26 g, 10.30 mmole) in a mixture of benzene (70 ml) and toluene (70 ml) was refluxed overnight using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (4:3) as eluent and (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-{2-(tert-butyidimethylsilyl)oxy-1-phenyl ethoxy}-azetidin-2-one was obtained (440 mg, 7% yield).
Reaction SMILES: [CH:1]1([CH:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1>ClCCl>[CH:19]1([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C@@H:11]2[C@H:18]3[C@H:14]([CH2:15][N:16]([S:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:32])([F:44])[F:45])[CH:35]=4)(=[O:42])=[O:41])[CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2-Dicyclohexyl-N-((3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl)acetamide from Example 53 (101 mg, 0.304 mmol), triethylamine (0.042 mL, 0.304 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.049 mL, 0.304 mmol) were combined in dichloromethane (2 mL). A catalytic amount of N,N-dimethylaminopyridine was added. The reaction was stirred at room temperature for 1 hour and 1 cms showed product, and tlc showed no more starting material. The reaction was quenched with aqueous sodium bicarbonate and the aqueous layer was separated. The organic layers was concentrated to give a precipitate. The precipitate was washed with water and ether and dried under a stream of nitrogen to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.49 (d, J=6.3, 1H), 8.34 (s, 1H), 8.19 (d, J=7.9, 1H), 7.93 (d, J=7.8, 1H), 7.73 (t, J=7.8, 1H), 4.46-4.38 (m, 1H), 3.73 (dd, J=3.4, 9.3, 1H), 3.17 (dd, J=2.8, 9.7, 1H), 3.07 (ddd, J=6.4, 12.0, 23.6, 3H), 2.49 (dd, J=8.0, 15.9, 1H), 2.12 (t, J=7.2, 1H), 2.02-1.77 (m, 8H), 1.73 (dd, J=5.3, 9.0, 4H), 1.68-1.58 (m, 3H), 1.52 (ddd, J=3.2, 12.5, 14.7, 1H), 1.43 (ddd, J=3.1, 12.6, 15.0, 1H), 1.37-1.03 (m, 9H); MS (ESI+) m/z 541 (M+H)+.
Reaction SMILES: [C:1]([CH:6]1[NH:9][C:8](=[O:10])[CH:7]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.[F:24][C:25]([F:29])([F:28])[S:26]Cl>C(Cl)Cl.CCOCC>[C:1]([CH:6]1[N:9]([S:26][C:25]([F:29])([F:28])[F:24])[C:8](=[O:10])[CH:7]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: FC(F)(F)SCl
Reactant: CCOC(=O)C1NC(=O)C1c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1C(c2ccccc2)C(=O)N1SC(F)(F)F

Procedure:
To a mixture of 1.2 g of 4-carboethoxy3-phenylazetidin-2-one and 1.2 ml of triethylamine in 25 ml of methylene chloride at 0° was added dropwise over 10 minutes 11.25 ml of a 10% solution of trifluoromethanesulfenyl chloride in ether. After stirring for several hours the solution was washed with water, dried over sodium sulfate, filtered and evaporated. The crude residue was chromatographed to yield pure 4-carboethoxy-3-phenyl-1-trifluoromethanesulfenylazetidin-2-one as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[C:30](=[O:31])[CH2:29][NH:28][C:27]4=[O:32])=[CH:22][C:21]=3[F:33])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.CN(C=O)C>[CH2:36]([N:28]1[CH2:29][C:30](=[O:31])[N:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][C:13]3[C:12]4[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[C:10]([O:34][CH3:35])[CH:11]=4)[N:16]=[CH:15][CH:14]=3)=[C:21]([F:33])[CH:22]=2)[C:27]1=[O:32])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(Oc3ccc(N4C(=O)CNC4=O)cc3F)ccnc2cc1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(N4C(=O)CN(Cc5ccccc5)C4=O)cc3F)ccnc2cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a stirring suspension of 3-(4-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)imidazolidine-2,4-dione (Example 50, 200 mg, 0.42 mmol) and benzyl bromide (0.06 mL, 0.51 mmol) in THF (2 mL) and DMF (1 mL) was added 1 M LiHMDS in THF (0.51 mL). After 3 h at RT, the solvents were removed under reduced pressure and the residue was purified on a silica gel to afford the title compound. Calc'd Mass for C33H26FN3O5, 563, MS (M+1) 564.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].[CH2:39]([OH:42])[C:40]#[CH:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(#N)C>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:41]#[C:40][CH2:39][OH:42])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(Br)c2)c2cccnc21
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCO)c2)c2cccnc21
Yield: 3 %

Procedure:
A mixture of N-[1-butyl-4-(3-bromophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (575 mg, 1 mmol), propargyl alcohol (168 mg, 3 mmol), copper (I) iodide (38 mg, 0.2 mmol), triphenylphosphine (52 mg, 0.2 mmol), bis(triphenylphosphine)palladium (II) chloride (14 mg, 0.02 mmol), triethylamine (5 ml) and acetonitrile (5 ml) was heated under reflux for five hours. After allowed to stand for cooling, the mixture was diluted with a mixture of tetrahydrofuran and ethyl acetate, and the mixture was filtered through a cerite pad. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The resultant was washed with 0.1N aqueous hydrochloric acid solution, washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3~5:5), and further purified by thin layer chromatography (hexane:ethyl acetate=5:5) to give the title compound (16 mg, 0.03 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:18][NH2:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:19][CH2:18][C:17]3[CH:16]=[C:15]([Cl:14])[CH:22]=[C:21]([Cl:23])[CH:20]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cc(Cl)cc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cc(Cl)cc(Cl)c3)ccc12
Yield: 2.3 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (97 mg, 0.374 mmol), 3,5-dichlorobenzylamine (0.057 mL, 0.424 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), rac-BINAP (70 mg, 0.112 mmol) and NaOtBu (104 mg, 1.08 mmol) in DMA (5 mL) was heated at 80° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3,5-dichloro-benzylamino)-2H-phthalazin-1-one (3 mg) as a white solid, 1H (400 MHz, CDCl3) δ: 4.40 (s, 2H), 6.84 (m, 1H), 6.99 (m, 1H), 7.22 (m, 3H), 8.14 (m, 1H), 10.80 (s, 1H) ppm; m/z (M+1) 353.83.