Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:19])[CH:8]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CC(N(C)C)=O>[CH2:17]([N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH:29]([CH3:28])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:20])[CH2:11]1)[CH3:18]
Reactant: CCOC(=O)CCCCBr
Reactant: CCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCC(C)Oc1ccc2c(c1)C(N(CC)S(C)(=O)=O)CC(C)(C)O2
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1.5 g (5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-ethylmethane-sulfonamide (Example 1g) were stirred at 80° C. for 30 min with 0.7 g of powdered potassium carbonate in 75 ml of DMA. 0.8 ml (5 mmol) of ethyl 5-bromovalerate was then added and the mixture was stirred at 120° C. for 120 min. After reaction was complete (TLC), the mixture was concentrated in vac., treated with ice water and aqueous hydrochloric acid and a crystalline crude product was obtained, which was chromatographed on silica gel using n-heptane/EA (2:1). Appropriate fractions were crystallized using petroleum ether, 1.5 g, m.p. 65-67° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[NH:13][C:14](=[O:25])[C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a Parr shaker bottle was added 10% Pd/C (0.346 g) then ethyl acetate (50 mL) followed by 2-(4-tert-butyl-benzoylamino)-4-nitro-benzoic acid methyl ester (3.041 g, 8.53 mmol) as a solution in ethyl acetate (200 mL). The reaction was hydrogenated overnight, filtered through celite and silica washing with ethyl acetate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80) to afford 4-amino-2-(4-tert-butyl-benzoylamino)-benzoic acid methyl ester (2.122 g, 76%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[N:30]=[CH:29]4)([OH:25])[C:21]([F:24])([F:23])[F:22])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH2:42]([Sn](CCCC)(CCCC)C=C)[CH2:43]CC>C1(C)C=CC=CC=1>[F:24][C:21]([F:22])([F:23])[C:20]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[N:30]=[CH:29]2)([C:6]1[C:5]2[C:9](=[CH:10][C:2]([CH:42]=[CH2:43])=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH:7]=1)[OH:25]
Reactant: COc1ccc(Cn2cc(C(O)(c3ccc4c(cnn4-c4ccc(F)cc4)c3)C(F)(F)F)c3ccc(Br)cc32)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(C(O)(c3ccc4c(cnn4-c4ccc(F)cc4)c3)C(F)(F)F)cn(Cc3ccc(OC)cc3)c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
To a room temperature solution of 0.25 g (0.4 mmol) of 1-[6-bromo-1-(4-methoxybenzyl)-1H-indol-3-yl]-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol in toluene was added 0.13 g (0.4 mmol) of tri-n-butyl(vinyl)tin. After 15 minutes, 3.0 mg of dichlorobis(triphenylphosphine)Pd (II) was added and the reaction was warmed to 100° C. and stirred overnight. The mixture was then cooled to room temperature, filtered through a pad of CELITE® filter aid, and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate-hexanes (5-20% gradient) to afford 0.1 g (44%) of the title compound. MS m/z 572.6 (MH+).
Reaction SMILES: C[NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50]([O:52]C)=O)=[N:46]2)=[CH:31][CH:30]=1.N>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50]([NH2:2])=[O:52])=[N:46]2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: N
Product: NC(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate and ammonia. 1H-NMR (D6-DMSO, 400 MHZ, d) 8.60 (d, J=6.9 Hz, 1H), 8.41 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.65 (d, J=9.1 Hz, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.35 (t, J=7.9 Hz, 1H), 7.00 (t, J=6.8 Hz, 1H), 6.32 (s, 2H) ppm; m/e 353, 355.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=O)=O)=CC=1.[F:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([OH:25])=[CH:20][C:19]=1[N:26]1[C:30](=[O:31])[C:29]2[CH2:32][CH2:33][CH2:34][CH2:35][C:28]=2[C:27]1=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[F:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:20][C:19]=1[N:26]1[C:30](=[O:31])[C:29]2[CH2:32][CH2:33][CH2:34][CH2:35][C:28]=2[C:27]1=[O:36]
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
Cyclopentyl p-toluenesulfonate (1.90 g, 8.11 mmol) was added to a solution of N-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.0 g, 6.76 mmol) and potassium carbonate (0.60 g, 4.34 mmol) in acetonitrile (50 ml), followed by stirring for 2 hours at 80° C. After completion of the reaction, 1N hydrochloric acid (20 ml) was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (20 ml×3 times). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (5 ml) was added to the resulting pale yellow oily substance, and the precipitated N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (0.77 g 2.12 mmol, 31.4% yield) was isolated by filtration. The spectral data and the like are as described in Example 1.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:27][CH2:28][CH2:29]Cl)[O:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][O:20]2)=[CH:15][CH:14]=1.O>CN(C)C=O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH2:27][CH2:28][CH2:29][O:3][C:4]3[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=3)[C:7]#[N:8])[O:20][CH2:21][C:22]([CH3:25])([CH3:26])[CH2:23][O:24]2)=[CH:17][CH:18]=1
Reactant: CC1(C)COC(CCCCl)(c2ccc(Br)cc2)OC1
Reactant: N#Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)COC(CCCOc2cccc(C#N)c2)(c2ccc(Br)cc2)OC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
236 mg (5.9 mmol) of sodium hydride (oily, 60%) was stirred in dimethylformamide. 691 mg (5.8 mmol) of 3-hydroxybenzonitrile was added thereto under cooling with ice. After stirring at room temperature for 30 minutes, a solution of 2 g (5.75 mmol) of 2-(4-bromophenyl)-2-(3-chloropropyl)-5,5-dimethyl-1,3-dioxane in dimethylformamide was added to the reaction mixture, and they were stirred at 100° C. overnight. Water was added to the mixture. After the extraction with ethyl acetate, the organic layer was washed with 1 N aqueous sodium hydroxide solution and saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([S:18](Cl)(=[O:20])=[O:19])=[CH:10][CH:9]=1)=[O:6].[N:28]([CH:31]([CH3:33])C)=[C:29]=[O:30]>C(N(CC)CC)C>[C:29]([N:28]1[CH2:31][CH2:33][CH:5]([NH:7][S:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=3[C:2]([F:27])([F:26])[F:1])=[CH:9][CH:10]=2)(=[O:20])=[O:19])[CH2:4][CH2:3]1)(=[O:30])[CH2:9][CH2:8][CH3:17]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C(F)(F)F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-trifluoromethyl-benzoylamino)-naphthalene-1-sulfonyl chloride and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.91 (s, 1H), 8.68 (d, 1H), 8.25 (m, 2H), 8.11 (d, 1H), 7.85 (m, 4H), 7.76 (m, 3H), 4.06 (m, 1H), 4.01 (m, 1H), 3.62 (d, 1H), 2.94 (t, 1H), 2.59 (t, 2H), 1.48 (m, 2H), 1.41 (m, 2H), 1.19 (m, 2H), 0.82 (t, 3H); LC/MS m/z 546 (M−H)−, 548 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:37])[C@@H:26]([N:28](C)[C:29](=O)OC(C)(C)C)[CH3:27])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:37])[C@@H:26]([NH:28][CH3:29])[CH3:27])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCNC(=O)[C@H](C)NC
Reaction time: 2 h
Yield: 113.4 %

Procedure:
To a solution of (S)-tert-butyl (1-((5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (F5, 103 mg) in 1,4-dioxane (2 mL), a 4.0 mol/L solution of hydrochloric acid in 1,4-dioxane (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The solvent was evaporated under reduced pressure. The obtained solid matter was washed with ethyl acetate, and then dried under reduced pressure to obtain (S)—N-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)-2-(methylamino)propanamide (F6) dihydrochloride (94 mg) as white solid.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH:5]=[CH2:6].[F:8][C:9]([F:19])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1>O1CCCC1.C(OCC)(=O)C>[F:8][C:9]([F:19])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([C:2]([OH:7])([CH2:3][CH2:4][CH:5]=[CH2:6])[CH3:1])=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Reactant: C=CCCC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCC(C)(O)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of hex-5-en-2-one (1.00 g, 10.2 mmol) in tetrahydrofuran (3 mL) was added to [4-(trifluoromethyl)phenyl]magnesium bromide (0.26 M solution in tetrahydrofuran, 50 mL, 13 mmol) at 0° C. After 15 minutes at 0° C., the reaction mixture was heated at 70° C. for 18 hours, then cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous ammonium chloride solution, with water, and with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 10% to 30% ethyl acetate in heptane) afforded the product as a dark gold oil. Yield: 1.86 g, 7.61 mmol, 75%. 1H NMR of crude product (400 MHz, CDCl3), characteristic peaks: δ 7.59 (br AB quartet, JAB=8 Hz, ΔνAB=19 Hz, 4H), 5.74-5.85 (m, 1H), 4.93-5.01 (m, 2H), 1.59 (s, 3H).
Reaction SMILES: [CH:1]([CH:3]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][C:4]1([CH3:11])[CH3:10])=[O:2].CC(C)=[O:14].OS(O)(=O)=O.O=[Cr](=O)=O.O.C(OCC)(=O)C>CC(C)=O.C(O)(C)C>[CH3:8][C:7]1([CH3:9])[CH2:6][CH2:5][C:4]([CH3:11])([CH3:10])[CH:3]1[C:1]([OH:14])=[O:2]
Reactant: CC(C)=O
Reactant: CC1(C)CCC(C)(C)C1C=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)C1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
2.47 g of 1-formyl-2,2,5,5-tetramethylcyclopentane was dissolved in 26 ml of acetone, and 5.2 ml of Jones' reagent was added thereto with ice cooling After stirring at room temperature for 4 hours, 26 ml of water, 26 ml of ethyl acetate and 2.6 ml of isopropyl alcohol were added thereto, and the mixture was stirred at room temperature for 30 minutes, and the resulting layers were separated. The organic layer was washed with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and subjected to filtration. The filtrate was concentrated under reduced pressure, whereby 2.51 g of 2,2,5,5-tetramethylcyclopentanecarboxylic acid was obtained. Yield 92%.
Reaction SMILES: C12CC(CC1)C=C2B(O)O.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]=1[C:21]1[N:26]=[C:25]([CH2:27][NH:28][C@H:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][OH:31])[C:24]([F:35])=[CH:23][CH:22]=1>[Pd].CC(C)CCO>[F:35][C:24]1[C:25]([CH2:27][NH:28][C@H:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][OH:31])=[N:26][C:21]([CH:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)=[CH:22][CH:23]=1
Reactant: CC(C)[C@H](CO)NCc1nc(C2=Cc3ccccc3CC2)ccc1F
Agent: [Pd]
Agent: OB(O)C1=CC2CCC1C2
Solvent: CC(C)CCO
Product: CC(C)[C@H](CO)NCc1nc(C2CCc3ccccc3C2)ccc1F

Procedure:
(R)-2-4(6-(3,4-dihydronaphthalen-2-yl)-3-fluoropyridin-2-yl)methyl)amino)-3-methylbutan-1-ol was prepared according to Example 199, substituting 3,4-dihydronaphthalen-2-ylboronic acid for bicyclo[2.2.1]hept-2-en-2-ylboronic acid. (R)-2-(((6-(3,4-dihydronaphthalen-2-yl)-3-fluoropyridin-2-yl)methyl)amino)-3-methylbutan-1-ol was subjected to hydrogenation (H2 atmosphere, Pd/C catalyst) to provide the title compound. MS (ESI+) m/z 343 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:16])C(=O)C1>CC#N.CCOC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:16])=[CH:4][N:3]=1
Reactant: Nc1ncccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-3-fluoro-pyridine (9.4 g, 83.1 mmol, 1 eq.) in MeCN (470 mL) under argon at 0° C. was added NBS (7.4 g, 41.5 mmol, 0.5 eq.). The reaction mixture was stirred at r.t. for 1 h then cooled to 0° C. before introducing additional NBS (7.39 g, 41.5 mmol, 0.5 eq.). The reaction mixture was stirred at r.t. for 1 h then diluted in EtOAc. The organic layer was washed with a saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was diluted in DCM, washed with a 1N NaOH solution. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford Intermediate Gen-1-a (2-amino-5-bromo-3-fluoropyridine).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Li]CCCC.CCCCCC.[CH2:20]([O:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)[CH2:21][CH2:22][CH2:23][CH3:24]>CN(P(N(C)C)(N(C)C)=O)C.O>[OH:33][CH:32]([CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:36][CH:35]=1)[CH2:34][C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: C#CCCCC(=O)O
Reactant: CCCCCOc1ccc(OCC2CO2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCOc1ccc(OCC(O)CC#CCCCC(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A dry flask equipped with an addition funnel and a mechanical stirrer under Ar was charged with 100 ml of HMPA and 9.7 g of 5-hexynoic acid. The flask was cooled in an ice water bath and a solution of n-BuLi in hexane (118 ml, 0.189 mole) was added dropwise. The resulting reaction mixture was stirred for 1.5 hr and then a solution of 24.5 g of 2-(4-pentoxyphenoxymethyl)oxirane, the product of Example 14a, in 20 ml of HMPA was added and stirring was continued for 2 days. The reaction mixture was poured into water and extracted with Et2O three times. The ether solution was washed with aqueous NH4OH twice. The aqueous solution was acidified with HCl and extracted with Et2O. The ether solution was washed with saturated NaCl solution, dried over MgSO4. Solvent was removed to give the crude product which was recrystallized in cyclohexane to give the title compound, mp 58.0°-60.0°.
Reaction SMILES: C([O:8][C:9](=O)[C@@H:10]([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[C:21]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].[H-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C>[C:15]([O:14][C:12]([N:11]1[CH:10]([CH3:19])[C:9](=[O:8])[CH:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:22]1[C:21]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: O=C(/C=C/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1C(=O)C(C(=O)OCc2ccccc2)C(C(=O)OCc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5.59 g (20.0 mmol) of (R)—N-tert-butoxycarbonylalanine benzyl ester and 5.92 g (20.0 mmol) of dibenzyl fumarate in 60 mL of toluene was added 1.60 g (40 mmol) of 60% NaH in mineral oil. The reaction was stirred at ambient temperature under N2 for 24 h, then diluted with 300 mL of diethyl ether. The solution was extracted with 1M HCl(aq.) (1×50 mL), saturated NaHCO3(aq.) (3×50 mL), and brine (1×50 mL), dried over MgSO4, filtered, and concentrated to provide the titled compound as an oil.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH:17]=[O:18].[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>>[CH:17]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:2]=1[C:26]1[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=1)=[O:18]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=Cc1nc2c(N3CCOCC3)ccnn2c1Br
Product: COC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1

Procedure:
Compound 14b (3.0 g, 11 mmol) was subjected to Suzuki coupling conditions with [4-(methoxycarbonyl)phenyl]boronic acid using the procedure described in Example 38, Step A to obtain compound 58c as a gray solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C19H18N4O4: 367.1 (M+H). Found: 367.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C=C(C)C=C(C)C=1.[C-]#N.[Na+].[CH3:26][NH:27]CCNC>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:26]#[N:27])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1cc(C)cc(C)c1
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Example 1) (99.1% purity, 5.0 g, 0.02 mol) and 1,3,5-trimethylbenzene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and powdered sodium cyanide (powdered just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57g, 0.003 mol) and N,N′-dimethylethylenediamine (1.51 g, 0.017 mol) were added. The reaction mixture was heated to between about 138 and 140° C. for 3 h, then heated to reflux (about 155° C.), and then cooled to 23° C., and water (20 mL) was added over 5 minutes. The mixture was stirred for 30 minutes and then filtered. The solid collected was washed with water (2×10 mL), chlorobenzene (10 mL), and then dried to constant a weight in a vacuum-oven at 50° C. to give the title compound (3.3 g) as an off-white solid melting at 202-203° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:22])[N:7]2[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[N:7]1[C:8]2[C:3](=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=3[F:30])[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=2)[CH2:4][CH2:5][C:6]1=[O:22]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
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: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reaction time: 3.5 h

Procedure:
A A mixture of 24 mg of 5-bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 1), 28 mg of 2,4-difluorophenylboronic acid, 3 mg of Pd(Ph3P)4, and 0.15 mL of a 1M aqueous Na2CO3 solution in 2 mL of toluene and 0.2 mL of EtOH in a 10 mL flask equipped with a reflux condenser was evacuated and purged three times with Ar. The mixture was heated to reflux and stirred at this temperature for 3.5 h, then cooled and diluted with 15 mL EtOAc and 10 mL of saturated aqueous NaHCO3. The phases were separated and the organic phase was dried over MgSO4 and concentrated. The resulting residue was purified by preparative thin-layer chromatography, eluting with 3:1 hexanes-EtOAc, to yield 1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone. Mass spectrum (ESI) 434.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.50 (d, J=8.0 Hz, 2H); 7.35 (t, J=8.0 Hz, 1H), 7.32 (m, 1H); 6.96, (m, 2H); 6.52 (d, J=2.5 Hz, 1H); 5.89 (d, J=2.5 Hz, 1H); 3.69 (s, 3H); 2.64-3.00 (m, 4H).
Reaction SMILES: I[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3].[NH:22]([CH3:24])[CH3:23]>C(Cl)Cl.CCO>[CH3:23][N:22]([CH3:24])[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:3]
Reactant: CC(I)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: CNC
Solvent: CCO
Solvent: ClCCl
Product: CC(c1cccc2c1ccn2S(=O)(=O)c1ccccc1)N(C)C

Procedure:
A solution of 4-(1-iodoethyl)-1-(phenylsulfonyl)-1H-indole (40 mg, 97.3 μmol; Intermediate 99) in CH2Cl2 (1.5 mL) was treated with Me2NH (174 μL of a 5.6 M solution in EtOH, 973 μmol) at rt for 1 h. The reaction mixture was concentrated in vacuo, the obtained residue taken up with MeOH/THF and purified by prep. HPLC (System B, 30-60% MeCN, 50 mM NH4HCO3) to yield the title compound as a white, waxy solid (10.6 mg, 11% over two steps). MS (ESI+) for C18H20N2O2S m/z 329 (M+H)+.