Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2>O1CCOCC1>[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]2
Reactant: O=C1CCc2cc(F)ccc2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=c1ccc2cc(F)ccc2[nH]1
Yield: 31.2 %

Procedure:
DDQ (0.38 g, 1.7 mmol) was added to a solution of 6-fluoro-3,4-dihydro-1H-quinolin-2-one (0.18 g, 1.1 mmol) in dioxane (25 mL) and the resulting solution was refluxed for 16 h. The mixture was concentrated, and sat aqueous Na2CO3 (25 mL) was added followed by extraction into an organic mixture (MeOH:CH2Cl2; 1:10, 3×50 mL). The combined organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash CC (SiO2; CH2Cl2/MeOH 20:1) to give the title compound (0.056 g, 31%). 1H NMR (DMSO-D6) δ 11.8 (brs, 1H), 7.85 (d, J=9.4 Hz), 7.50 (dd, J=2.8, 9.2 Hz), 7.43-7.37 (m, 1H), 7.37-7.25 (m, 1H), 6.54 (d, J=9.4 Hz).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:17][Si](C(C)(C)C)(C)C)=[C:6]2[C:10](=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14])[CH2:9][O:8][C:7]2=[O:16])[CH:2]=[CH2:3].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C>[C:25]([O:17][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[C:12]([O:13][CH3:14])[C:11]([CH3:15])=[C:10]2[C:6]=1[C:7](=[O:16])[O:8][CH2:9]2)(=[O:27])[CH3:26]
Reactant: C=CCc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=CCc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Temperature: 0 °C

Procedure:
A solution of 5-allyl-4-tert-butyldimethylsilyloxy-1,3-dihydro -6-methoxy-7-methyl-3-oxoisobenzofuran [(J. W. Patterson and G. Huang, Chemical Communications, 1579 (1991)] (7.5 g) in acetic acid (95 ml) and acetic anhydride (95 ml) was refluxed for 18 hours, then cooled and poured into ice water. The solution was extracted with ethyl acetate, and the extract washed with dilute aqueous sodium bicarbonate, followed by water, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 7:3 hexane:ethyl acetate, to give 4-acetoxy-5-allyl -1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran, mp 101°-102° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:4]([C@@H:5]([OH:30])[CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH2:3]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[S:32]([OH:34])(=[O:1])(=[O:33])[CH3:31].[S:32]([OH:34])(=[O:1])(=[O:33])[CH3:31].[OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:4]([C@@H:5]([OH:30])[CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 3α,6α-dihydroxy-5β-cholestan-24-one (168 mg) in pyridine (5 ml) was added methanesulfonyl chloride (0.5 ml) under cooling in an ice bath and the mixture was continuously stirred for one hour. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of hydrochloric acid and then with water, dried over magnesium sulfate and evaporated to give an oily product, 3α,6α-dihydroxy-5β-cholestan-24-one dimesylate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16]>C1COCC1.[O-2].[O-2].[Mn+4]>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=2)[N:1]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Mg]Cl
Reactant: COC(=O)c1ccc2ncccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(C(C)(C)C)ccc2c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a THF (20 ml) solution of methyl quinoline-6-carboxylate (984 mg, 5.26 mmol, J. O. C., 2002, 67, 7890) was added t-butylmagnesium chloride in THF (15.8 ml, 1M solution) dropwise at −78° C. over 30 min. The mixture was stirred at −78° C. for 30 minutes and at −40° C. for 30 minutes, then at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution (100 ml) and extracted with ethyl acetate (100 ml×2) which was dried over sodium sulfate. Then, filtration and evaporation gave a yellow oil, which was dissolved in THF (50 ml) and manganese dioxide (1.83 g 15.8 mmol) was added. After the mixture was stirred at room temperature for 2.5 hours, the precipitate was removed through a pad of celite and washed with ethyl acetate. The filtrate was concentrated and purified through silica gel column chromatography, eluting with Hexane/Ethyl acetate (20:1), to furnish the title compound (348 mg, 27% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.48 (9H, s), 3.99 (3H, s), 7.59 (1H, d, J=8.8 Hz), 8.08 (1H, d, J=8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.26 (1H, dd, J=2.2, 8.8 Hz), 8.55 (1H, d, J=2.2 Hz). MS (ESI): m/z 244 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH:11]1[C:23]2[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>O1CCOCC1.[Cu]I.NCC(N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([N:22]2[C:23]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:7]=1
Reactant: COc1ccc(F)cc1Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]I
Agent: CC(N)CN
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-n1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 260.9 %

Procedure:
2-Bromo-4-fluoroanisole (20 g, 10 mmol, 1 equiv) and carbazole (18.4 g, 11 mmol, 1.1 equiv) were dissolved in 1,4-dioxane (200 mL). Potassium phosphate tribasic hydrate (46 g, 20 mmol, 2 equiv), copper(I) iodide (1 g, 0.5 mmol, 0.05 equiv) and 1,2-diaminopropane (1 mL, 1.3 mmol, 0.13 equiv) were added and the reaction was refluxed for 18 hours. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified over silica gel (250 g), eluting with gradient of 0 to 10% ethyl acetate in heptanes to give compound 1 (7.6 g, 26% yield) as an off white solid that was contaminated with carbazole. This material was used subsequently.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:10][CH2:11][CH:12]([OH:13])[CH2:14][O:5]1
Reactant: O=Cc1ccccc1F
Reactant: OCC(O)CO
Product: OC1COC(c2ccccc2F)OC1

Procedure:
Using the method of Example 5g, except no solvent was necessary, 24.8 g 2-fluorobenzaldehyde and 18.4 g glycerol were reacted to form 2-(2-fluorophenyl)-5-hydroxy-1,3-dioxane. The product was cooled and dissolved in 100 ml ether. The ether solution was washed with an aqueous potassium carbonate solution, dried with magnesium sulfate, filtered and evaporated under reduced pressure. The resultant oil was distilled, and that fraction distilling at 140°-145° C/10-5 mm contained 2-(2-fluorophenyl)-5-hydroxy-1,3-dioxane.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30]([C:35]2[N:44]=[C:43](O)[C:42]3[C:37](=[C:38]([CH3:48])[C:39]([O:46][CH3:47])=[CH:40][CH:41]=3)[N:36]=2)[CH:31]=[C:32]([F:34])[CH:33]=1>>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:43]2[C:42]3[C:37](=[C:38]([CH3:48])[C:39]([O:46][CH3:47])=[CH:40][CH:41]=3)[N:36]=[C:35]([C:30]3[CH:31]=[C:32]([F:34])[CH:33]=[C:28]([F:27])[CH:29]=3)[N:44]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: COc1ccc2c(O)nc(-c3cc(F)cc(F)c3)nc2c1C
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cc(F)cc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC

Procedure:
The alcohol 15 and the quinazolinol 128 was reacted according to same procedure described in example 155 which gave the title compound as a white solid slightly contaminated by triphenyl phosphine oxide (1.245 g, >100%), LRMS (M+H) 652.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[CH3:16][O:17][C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]2[C:31]3[CH:30]=[C:29](Br)[N:28]=[CH:27][C:26]=3[N:25]=[CH:24]2)=[CH:20][CH:19]=1>CN(C=O)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[C:31]3[CH:30]=[C:29]([NH:1][C:2]4[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=4)[N:28]=[CH:27][C:26]=3[N:25]=[CH:24]2)=[CH:33][CH:34]=1
Reactant: COc1ccc(Cn2cnc3cnc(Br)cc32)cc1
Reactant: N#Cc1cnc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cnc3cnc(Nc4cnc(C#N)cn4)cc32)cc1
Temperature: 150 °C
Yield: 39.2 %

Procedure:
Palladium (II) acetate (3.5 mg, 16 μmol) was added to (±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (59 mg, 94 μmol) in DMF/toluene (1:2) and the resulting mixture was degassed under a stream of nitrogen gas for 10 minutes. 2-Amino-5-cyanopyrazine (19 mg, 0.16 mmol), sodium tert-butoxide (45 mg, 0.47 mmol) and 1-(4-methoxybenzyl)-6-bromo-1H-imidazo[4,5-c]pyridine (50 mg, 0.16 mmol) were added and the mixture was degassed for a further 5 minutes before heating at 150° C. for 30 minutes using microwave irradiation. The reaction mixture was partitioned between water and dichloromethane. The aqueous phase extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The residue was dissolved in methanol, passed through a PS-Thiol column and concentrated. The product was purified using preparative HPLC to give the title compound (22.4 mg, 40%). 1H NMR (d6-DMSO, 400 MHz) δ 10.84 (br s, 1H), 8.77 (d, 1H, J=1.3 Hz), 8.74 (m, 2H), 8.49 (s, 1H), 8.17 (s, 1H), 7.34 (m, 2H), 5.41 (s, 2H), 3.72 (s, 3H). LCMS (2) Rt=2.32 min; m/z (ESI+) 358 (MH+), (ESI−) 356 (M−H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]([O:22]CC)=[O:21])=[O:18])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(O)C.[OH-].[K+].Cl>C1COCC1.O>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]([OH:22])=[O:21])=[O:18])=[CH:12][CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)Nc1ccc(CP(=O)(OCC)OCC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)C(Cc2ccccc2)C(=O)O)cc1)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 94.2 %

Procedure:
To an ice-cooled and stirred solution of ethyl 2-(p-diethoxyphosphorylmethylphenylaminocarbonyl)-3-phenylpropionate (6.0 g) in THF (30 ml)-ethanol (10 ml) was added dropwise a solution of KOH (0.9 g) in water (10 ml). After stirring at 4° C.-room temperature for 15 hours, the reaction mixture was acidified with 1N HCl, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried (MgSO4). The_organic solvent was evaporated off to yield 2-(p-diethoxyphosphorylmethylphenylaminocarbonyl)-3-phenylpropionic acid (5.3 g, 94%) as crystals. Recrystallization from ethyl acetate-hexane gave pale yellow needles having melting point of 160 to 161° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH:8]=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:11][Mg]Br.CCOCC>C1COCC1>[Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH:8]([OH:9])[CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cncc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottom flask is added 5-bromo-4-chloro-pyridine-3-carbaldehyde (490 mg, 2.22 mmol) in 10 ml of THF at 0° C., followed by the addition of methylmagnesium bromide, 3M in ether (0.89 ml, 2.67 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated. The residue is diluted with EtOAc/saturated NH4Cl. The organic layer is separated, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 287 mg of 1-(5-bromo-4-chloro-pyridin-3-yl)-ethanol.
Reaction SMILES: Cl.C1(NC2C(C)=C(C)N=C([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)N=2)CCCCC1.Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:29]([CH2:40][CH3:41])=[C:28]([CH3:42])[N:27]=1>>[CH2:40]([C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[N:31][C:26]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:27][C:28]=1[CH3:42])[CH3:41]
Reactant: CCc1c(C)nc(Cl)nc1Nc1ccc(F)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: CCc1c(C)nc(NCc2ccccn2)nc1Nc1ccc(F)cc1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using 2-chloro-5-ethyl-N-(4-fluorophenyl)-6-methylpyrimidin-4-amine (Step A) instead of 2-chloro-N-cyclohexyl-5,6-dimethylpyrimidin-4-amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.09-1.20 (m, 3H), 2.25-2.35 (m, 3H), 2.52-2.62 (m, 2H), 4.57 (bs, 2H), 6.80-6.88 (m, 2H), 7.20-7.36 (m, 4H) 7.65-7.76 (m, 1H) 8.50 (bm, 1H); MS (ESI) m/z 338.8 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17]CC3C=CC(OC)=CC=3)[CH:12]=2)[N:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:7]1=[O:34])#[N:2].Br.C(O)(=O)C>>[NH2:17][C:13]1[CH:12]=[C:11]([C:9]2[N:8]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:7](=[O:34])[N:6]([CH2:5][C:4]3[CH:35]=[CH:36][CH:37]=[CH:38][C:3]=3[C:1]#[N:2])[CH:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1ccc(CNc2cc(-c3cn(Cc4ccccc4C#N)c(=O)n3-c3ccc(F)cc3)ccn2)cc1
Agent: Br
Solvent: CC(=O)O
Product: N#Cc1ccccc1Cn1cc(-c2ccnc(N)c2)n(-c2ccc(F)cc2)c1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To 1.5 g of 1-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-[2-(4-methoxybenzylamino)pyridin-4-yl]-4-imidazolin-2-one (Compound of Example 5) was added 3 ml of 25% hydrogen bromide-acetic acid solution, and the mixture was stirred at 70° C. for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was made alkali with an aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 572 mg of the title compound as colorless crystal. Melting point: 182-183° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(O[N:20]1N=N[C:22]2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C.CO>O.CN(C=O)C>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:21][CH3:22])=[O:6]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCNC(=O)c1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.1 %

Procedure:
A mixture of 2-amino-3-bromo-benzoic acid (2 g, 9.26 mmol), HATU (3.84 g, 10.10 mmol, Sigma Aldrich), DMF (42.1 mL), 2.0 M ethylamine in MeOH (4.21 mL, 8.42 mmol, Sigma Aldrich), and TEA (1.8 mL, 12.62 mmol) was set stirring at RT for 18 h. It was diluted with water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. It was diluted with DCM, adsorbed onto silica, and purified on 40 g SiO2 (eluent: 0-100% EtOAc/hexanes over 25 min, RediSep Gold). The product fractions were combined and concentrated to give the product as a yellow oil (2.5 g, 122%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (1H, br. s.) 7.47-7.54 (2H, m) 6.52 (1H, t, J=7.82 Hz) 6.44 (2H, br. s.) 3.19-3.29 (2H, m) 1.11 (3H, t, J=7.24 Hz). m/z (ESI, +ve) 242.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[O:20]C.[Br-].[Br-].[Br-].B.O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[OH:20]
Reactant: COc1ccc(C2(c3ccccc3)CCCCC2)cc1F
Agent: B
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1F
Reaction time: 3 h

Procedure:
A solution of the crude 2-fluoro-1-methoxy-4-(1-phenyl-cyclohexyl)-benzene in dichloromethane (100 mg, 0.25 mmol, 2 mL) was added to a solution of borane tribromide in dichloromethane (1 M, 0.25 ml, 025 mmol) at −78° C. under an argon atmosphere and stirred at r.t for 3 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (2×10 mL). The combined organic phase was dried (Na2SO4) and concentrated to a syrup. Work-up by flash-chromatography (eluent: 30→80% dichloromethane in heptane) gave the title product in a yield of 50 mg.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][CH:10]([CH2:11]3)[N:9]3[C:5](=[N:6][C:7]([C:17]([NH2:19])=[O:18])=[CH:8]3)[C:4]=2[CH:3]=1.[C:20]([C:22]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23]1)#[CH:21]>>[OH:27][C:22]1([C:20]#[C:21][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[CH:12]2[CH2:16][CH:10]([CH2:11]2)[N:9]2[C:5]3=[N:6][C:7]([C:17]([NH2:19])=[O:18])=[CH:8]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C#CC1(O)CCCC1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1C1CC2C1
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CCCC3)ccc1C1CC2C1

Procedure:
9-Bromo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide (30 mg) was reacted with 1-ethynylcyclopentanol similar to as described in Procedure E to afford 8.9 mg of 9-[2-(1-hydroxycyclopentyl)ethynyl]-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide following reverse phase hplc purification. MS (Q1) 348 (M)+. 1H NMR (400 MHz, DMSO) δ 8.61 (d, J=11.1 Hz, 1H), 7.82 (s, 1H), 7.52 (s, 1H), 7.26 (s, 2H), 7.09 (s, 1H), 5.33 (s, 1H), 4.92 (q, J=4.5 Hz, 1H), 3.75-3.66 (m, 1H), 3.12-3.03 (m, 2H), 1.96-1.88 (m, 4H), 1.81-1.62 (m, 7H).
Reaction SMILES: O.[OH-].[Li+].OO.C([C@@H]1COC(=O)N1[C:19]([CH:21]1[CH2:25][C:24](=[O:26])[N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])[CH2:22]1)=[O:20])C1C=CC=CC=1.S([O-])(O)=[O:39].[Na+]>O.O1CCCC1>[CH3:37][O:36][C:29]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=1[CH2:27][N:23]1[C:24](=[O:26])[CH2:25][CH:21]([C:19]([OH:20])=[O:39])[CH2:22]1
Reactant: COc1ccc(CN2CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)CC2=O)c(OC)c1
Reactant: O=S([O-])O
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CC(C(=O)O)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a solution of lithium hydroxide monohydrate (3.29 g) in water (50 ml) was added dropwise 30 wt % aqueous solution of hydrogen peroxide (17.5 ml) under cooling with an ice-sodium chloride bath, and the mixture was stirred for 15 minutes. To this reaction solution was added tetrahydrofuran (30 ml), and then a solution of the low-polarity component of (R)-4-benzyl-3-[1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone (26.4 g) in tetrahydrofuran (150 ml) was added dropwise thereto, and the mixture was stirred for additional 1 hour. To this reaction solution was slowly added a solution of sodium hydrogen sulfite (18.7 g) in water (60 ml), and the mixture was warmed to room temperature by removing the bath, and then extracted with ethyl acetate (100 ml). The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/1 to 1/2, chloroform/methanol=5/1) to give the titled compound (14.3 g). An analysis of this solid by HPLC analysis condition 2 showed that an isomer with shorter retention time was a main product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:17]=[C:16]([CH2:18][CH:19]([N:25]=C(C2C=CC=CC=2)C2C=CC=CC=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[ClH:44]>C(OCC)(=O)C>[ClH:44].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:17]=[C:16]([CH2:18][CH:19]([NH2:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:15][N:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1

Procedure:
2-{5-[2-(Benzhydrylidene-amino)-2-ethoxycarbonyl-ethyl]-isoxazol-3-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 1.35 mmol) was stirred in a mixture of ethyl acetate (20 mL) and 1 N hydrochloric acid (100 mL) for 3 hours. The reaction was neutralized by the addition of saturated sodium bicarbonate. The aqueous portion was extracted with diethyl ether. The combined organics were dried over magnesium sulfate and the solvent removed in vacuo. The resulting oil (200 mg) was used directly in example 14C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[Cl:16]N1C2C=CC=CC=2N=N1>ClCCl>[Cl:16][C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12
Reactant: Cln1nnc2ccccc21
Reactant: c1cncc(-c2ccnc3ccnn23)c1
Solvent: ClCCl
Product: Clc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 3.92 g. of 7-(3-pyridyl)pyrazolo[1,5-a]-pyrimidine and 3.40 g. of N-chlorobenzotriazole in 100 ml. of dichloromethane is heated on a steam bath for 15 minutes. The mixture is poured into 100 ml. of ice cold 2.5 N sodium hydroxide and the dichloromethane layer is separated and dried over anhydrous sodium sulfate. The dichloromethane extract is passed through a column of hydrous magnesium silicate and the eluent is concentrated and diluted with hexane to give 2.75 g. of the product of the example, m.p. 225°-226° C.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]([C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1
Reactant: COC(=O)C(C)Oc1ccc(N(C)c2cnc3cc(Cl)ccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Oc1ccc(N(C)c2cnc3cc(Cl)ccc3n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl 2-{4-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate (1.0 g; compound no 26, Example 8) was suspended in ethanol (5 ml) and a solution of sodium hydroxide (0.11 g) in water (5 ml) was added over a period of 45 minutes. Further ethanol (6 ml) was added and the mixture was stirred at room temperature for a period of 48 hours. The ethanol was removed by distillation under reduced pressure, the residue was dissolved in water and the aqueous solution was acidified to pH 4 by the addition of aqueous 2 M hydrochloric acid. The precipitate was collected by filtration and dried to give the title compound, mp 204° C.