Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:53][C:54]1[CH:55]=[C:56]([CH2:64][C:65](O)=[O:66])[CH:57]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=1>CN(C=O)C.CO.C(Cl)Cl>[F:53][C:54]1[CH:55]=[C:56]([CH2:64][C:65]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:18]5[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=5[O:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:66])[CH:57]=[C:58]([C:60]([F:62])([F:63])[F:61])[CH:59]=1
Reactant: Nc1ncnc2occ(-c3ccc4c(c3)CCN4)c12
Reactant: O=C(O)Cc1cc(F)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)cc(C(F)(F)F)c3)c12
Temperature: 0 °C

Procedure:
To a stirred dark greenish solution of 5-(2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (500 mg, 1.98 mmol) and HATU (829 mg, 2.18 mmol, 1.1 equiv) in 5 mL of DMF was added DIEA (381 uL, 2.18 mmol, 1.1 equiv). To this mixture was added [3-fluoro-5-(trifluoromethyl)phenyl]acetic acid portionwise (440 mg total, 1.98 mmol, 1 equiv), about 110 mg at 30 min intervals. After a total of 2.5 hours, the mixture was poured into 50 mL of ice cold water to give a suspension, which was filtered. The cake was washed with water (2×15 mL) and dried under house vacuum at rt for 18 h to afford crude product (1.10 g), which was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an SF25-60 g silica gel cartridge using gradient elution of 1% A to 50% A in DCM (A was a mixture of 3200/800/80 DCM/MeOH/NHeOH). The desired product eluted impure from 25-30% A. These fractions were combined and concentrated in vacuo. the residue was re-dissolved in 10% MeOH in DCM and absorbed to dryload cartridge. A second purification was done on an SF25-80 g silica gel cartridge using gradient elution of 1% B to 100% B in EtOAc (B was a mixture of 2.5% MeOH in EtOAc). Note: the product was not very soluble in EtOAc. Two fractions were collected. The first fraction eluted from 8-12% B. The second fraction eluted from 33-100% B. Both were pure by TLC. They were combined and conc in vacuo. The residue was taken up in CHCl3 (3 mL) and MTBE (7 mL) as a suspension, which was filtered. The solids were washed with MTBE (2×3 mL) and hexane (3×4 mL), and dried under vacuum at 65° C. for 18 h to afford 5-(1-{[3-fluoro-5-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (445 mg) as beige solids. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (t, J=8.5 Hz, 2H), 4.08 (s, 2H), 4.28 (t, J=8.5 Hz, 2H), 7.31 (d, J=8.3 Hz, 1H), 7.40 (s, 1H), 7.51 (d, J=9.9 Hz, 1H), 7.57 (s, 1H), 7.60 (d, J=8.1 Hz), 7.93 (s, 1H), 8.14 (d, J=8.1 Hz, 1H), 8.25 (s, 1H), NH2 protons not visible.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[OH:27][N:3]1[C:4]([CH3:17])([CH3:16])[CH2:5][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:7][C:2]1([CH3:18])[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1O
Temperature: 25 °C

Procedure:
To a solution of 25.4 g (0.1 mole) of the lactam compound prepared in Example 1 in 200 ml of chloroform is added portionwise 38 g (0.22 mole) of m-chloroperbenzoic acid over a one-hour period. The reaction mixture is stirred for an eighteen-hour period at ambient temperature. The mixture is then filtered to remove the m-chlorobenzoic acid formed. The filtrate is washed successively with 1N sulfuric acid, with water and with 10% aqueous sodium bicarbonate and then dried. The solvent is removed in vacuo and the residue recrystallized from tolueneheptane to give the above-named compound as an orange solid melting at 158°-164° C.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:33][C:34]([F:45])([F:44])[CH2:35]OS(C(F)(F)F)(=O)=O>C1COCC1>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:35][C:34]([F:45])([F:44])[F:33])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1csc(C2CCN(CC(F)(F)F)CC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reaction time: 2 h
Yield: 68.9 %

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-159) (0.072 g, 0.21 mmol) was dissolved in dry THF (5 mL) and DIPEA (0.66 mmol) was added followed by 2,2,2-trifluoroethyltrifluoromethanesulphonate (0.26 mmol) and the resulting mixture stirred for 2 hours. 2,2,2-Trifluoroethyltrifluoromethanesulphonate (0.26 mmol) was added and the mixture refluxed overnight. The solvent was evaporated and the resulting gum was purified by HPLC eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.06 g). LCMS m/z 415.13 [M+H]+ RT=12.16 min (Analytical Method 2).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[CH2:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:27]=2)[NH:22][N:21]=1)[CH3:19].[CH:33]1(Br)[CH2:37][CH2:36][CH2:35][CH2:34]1>C(OCC)(=O)C.CN(C=O)C>[CH:33]1([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:24]=3)[C:20]([CH2:18][CH3:19])=[N:21]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Reactant: BrC1CCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing 337 mg (8.4 mmol) of NaH (60% in mineral oil), 1.7 mL (8.4 mmol) of 15-crown-5 and 42 mL of DMF was added 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. This mixture was stirred at room temperature for 3 hours and then 1.35 mL (12.6 mmol) of cyclopentyl bromide was added and the reaction was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in 40 mL ethyl acetate, washed with 30 mL of water and 30 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography over SiO2 using a step gradient of 10% ethyl acetate in hexanes until the first compound eluted and then 50% ethyl acetate in hexanes to provide 662 mg (2.4 mmol) of methyl 1-cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxylate as a clear oil along with 144 mg (0.53 mmol) methyl 2-(cyclopentyl-3-ethyl)-2H-indazol-6-yl-carboxylate as a yellow oil. 1H-NMR (CDCl3) δ 8.17 (s, 1H), 7.71 (dd, J1=8.4 Hz, J2=6.7 Hz, 2H), 5.0 (p, J=7.5 Hz, 1H), 3.97 (s, 3H), 3.00 (q, J=7.5 Hz, 2H), 2.16 (m, 4H), 1.92 (m, 2H), 1.74 (m, 2H), 1.39 (t, J=7.6 Hz, 3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]([B:15]([CH2:18][CH3:19])OC)[CH3:14]>CCOCC.O1CCCC1.C(OC(=O)C)C>[CH2:13]([B:15]([CH2:18][CH3:19])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:14]
Reactant: Brc1cccnc1
Reactant: CCB(CC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCB(CC)c1cccnc1
Temperature: -40 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (25.6 ml of a 2.5M solution in hexanes, 64 mmol) was added as a rapid stream of droplets to a solution of 3-bromopyridine (10.04 g, 64 mmol) in ether (200 ml) at -40° C., under nitrogen. The addition was carried out over 5 minutes and the reaction temperature was maintained below -40° C. throughout. The reaction was stirred at -40° C. for 20 minutes and then cooled to -70° C. whereupon diethylmethoxyborane in tetrahydrofuran (64.0 ml of a 1M solution, 64 mmol) was added as a rapid stream of droplets over 5 minutes. The reaction temperature was maintained below -63° C. throughout this addiition. The reaction was then allowed to warm slowly to room temperature whereupon it was diluted with ethylacetate and washed with brine. The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure to give the crude product. This was purified by column chromatography on silica gel, eluting with dichloromethane to afford, after combination and evaporation of the appropriate fractions, the title compound as a yellow crystalline solid (7.3 g). Found: C,73.40; H,9.53; N,8.92; C9H14NB requires: C,73.52; H,9.60; N,9.53%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][N:3]=1.[CH3:21][C:22]1[CH:45]=[CH:44][C:25]2[CH:26]([C:36]3[C:37](=[O:43])[NH:38][C:39](=[O:42])[NH:40][CH:41]=3)[C:27]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:28]=3[CH:29]=[CH:30][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:21][C:22]1[CH:45]=[CH:44][C:25]2[CH:26]([C:36]3[C:37](=[O:43])[NH:38][C:39](=[O:42])[N:40]([C:2]4[N:7]=[C:6]([NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([C:17]([O:19][CH3:20])=[O:18])=[CH:4][N:3]=4)[CH:41]=3)[C:27]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:28]=3[CH:29]=[CH:30][C:24]=2[CH:23]=1
Reactant: COC(=O)c1cnc(Cl)nc1NCC(=O)OC(C)(C)C
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-n2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=O)[nH]c2=O)nc1NCC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
A mixture of the product of step (ii) (0.52 g), the product of example 8 step (i) (0.5 g) and cesium carbonate (0.49 g) in dimethylformamide (15 ml) was heated at 70° C. After 3 hours, the reaction mixture was partitioned between 1M HCl and ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 3% methanol in chloroform. Yield 0.47 g.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:16])=[N:9][C:10]3[N:11]([N:12]=[C:13]([CH3:15])[CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>>[CH3:15][C:13]1[CH:14]=[C:10]2[N:9]=[C:8]([CH3:16])[C:7]3[C:2]([NH:26][CH:22]([CH3:23])[CH2:24][CH3:25])=[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:4]=[N:5][C:6]=3[N:11]2[N:12]=1
Reactant: CCC(C)N
Reactant: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1Cl
Product: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1NC(C)CC
Reaction time: 1 h

Procedure:
3.0 g. of 6-chloro-2,5-dimethylpyrazolo[1,5-a]-pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester of Example 1c (0.01 mol.) are dissolved in 20 ml. of alcohol. 2.1 g. of sec. butylamine (0.03 mol.) are added and the mixture is refluxed with stirring for 1 hour. The solvent and excess amine is removed in vacuo and the crystalline residue is treated with water and filtered off to obtain 2,5-dimethyl-6-[(1-methylpropyl)amino]pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester, yield 3.1 g. (91%), m.p. 113°-115° (ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[C:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1>>[C:22]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH:23]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: Nc1cccc(-c2ccccc2)c1
Product: O=C(O)CCc1ccc(OCc2cccc(Nc3cccc(-c4ccccc4)c3)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 298 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and biphenyl-3-ylamine. colorless crystals (yield 6%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:17]([CH2:29][CH3:30])=[N:18][C:19]3[C:24]([C:25]=2[C:26]([OH:28])=[O:27])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=1)#[N:2].[CH2:31](I)[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CC(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[C:17]([CH2:29][CH3:30])=[N:18][C:19]3[C:24]([C:25]=2[C:26]([O:28][CH2:31][CH3:32])=[O:27])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:14]=1)#[N:2]
Reactant: CCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2C#N)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1c(Oc2ccc(-c3ccccc3C#N)cc2)c(CC)nc2ccccc12
Temperature: 25 °C
Reaction time: 9 h
Yield: 93 %

Procedure:
A mixture containing the title C compound of Example 2, 3-[(2'-cyano[1,1'-biphenyl]-4-yl)oxy]-2-ethyl-4-quinolinecarboxylic acid (707 mg, 1.79 mmol), ethyl iodide (559 mg, 3.58 mmol), and cesium carbonate (1.46 g, 4.48 mmol) in dimethylformamide (4 mL) was stirred at room temperature for nine hours, then diluted with a mixture of acetone and ethyl acetate and filtered. The filtrate was concentrated in vacuo and the product extracted into ethyl acetate. The organic extract was rinsed with water and brine, dried (magnesium sulfate), and concentrated in vacuo to afford a crude product (720 mg). Flash chromatography on Merck silica gel (30 g) eluted with 1:1 hexanes:ethyl acetate afforded the title compound (703 mg, 93% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>COCCO>[CH2:14]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:15]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCC(CC)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCCCC(CC)COc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
86.5 g (0.5 mol) of 4-bromophenol in 500 ml of Methylcellosolve are placed in a 1 l sulfonating flask fitted with stirrer, condenser, dropping funnel and internal thermometer. This mixture is heated to 60 C., and then 70.0 g of 30% NaOH (0.53 mol) are run in slowly. The mixture is stirred for 15 minutes and then 116.8 g (0.575 mol) of 3-bromomethylheptane are added dropwise over the course of 45 minutes. The reaction is continued at 100 C. overnight. The thin-layer chromatogram indicates virtually quantitative conversion. Solvent and excess bromide are removed in vacuo and the residue (an oil) is taken up in 600 ml of toluene. The mixture is subjected three times to extraction by shaking with water and the extracts are dried over sodium sulfate and evaporated to dryness, to give 119.3 g (84% of theory) of 4-(2-ethylhexyloxy)bromobenzene as a light yellow oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[CH:17][C:16]=1[OH:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](F)[N:26]=1>C(#N)C>[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[CH:17][C:16]=1[O:23][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[N:26]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCc1ccc(O)c(OCc2ccccc2)c1
Reactant: Fc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1ccc(Oc2cccc(F)n2)c(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of K2CO3 (0.25 mmol; 35 mg) in anhydrous acetonitrile (2 mL) under argon, was added 2-Benzyloxy-4-ethyl-phenol (48 mg; 0.21 mmol) followed by 2,6-difluoropyridine (100 μL; 1.10 mmol). The reaction mixture was stirred at 80° C. overnight.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[O:13]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:24]1[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1Cc1cccc(Oc2ccccc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-phenoxy-benzylamine (0.106 mL, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(3-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.064 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.26 (s, 2H), 4.82 (s, 2H), 6.90-7.56 (m, 12H), 7.89 (d, 1H). GC-MS: m/z 315 (M)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1C
Yield: 73.8 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 2,4-dimethylphenylboronic acid (0.075 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.073 g (74%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[N:26]1([CH2:32][CH2:33][CH2:34][S:35]([NH2:38])(=[O:37])=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23]([NH:38][S:35]([CH2:34][CH2:33][CH2:32][N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)(=[O:36])=[O:37])=[O:24])[O:20][C:21]=3[CH3:22])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: NS(=O)(=O)CCCN1CCOCC1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)CCCN4CCOCC4)oc3C)cc2)cc1

Procedure:
Compound (59) was prepared from compounds (4) and (58) by adapting the procedure of Example 2A. LC/MS System D; Rt=4.97 mins, m/z (ES+)=529 (M+H for C27H32N2O7S).
Reaction SMILES: [Mg].[CH3:2][CH2:3][O:4][C:5]([C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].O.Br[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30]>O1CCCC1>[C:16]([O:15][C:13]([NH:8][C@H:7]([CH2:11][CH2:10][C:9]([C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])=[O:12])[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc(F)c(Br)cc1F
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium (0.452 g) in tetrahydrofuran (20 mL), 1-bromo-2,4,5-trifluorobenzene (2.2 mL) was added dropwise at 55° C. over 15 minutes, and the reaction solution was stirred at room temperature for 30 minutes. This solution was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.0 g) in tetrahydrofuran (25 mL) at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 4.5 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[Li][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>CCOCC>[CH:6]1([C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: [Li]c1cccnc1
Reactant: CON(C)C(=O)C1CCCCCC1
Solvent: CCOCC
Product: O=C(c1cccnc1)C1CCCCCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of N-methoxy-N-methylcycloheptanecarboxamide (1.11 g, 6 mmol) in ether (10 ml) was added dropwise at −78° C. to a solution of 3-lithiopyridine (prepared by addition of BuLi (3.75 ml, 6 mmol) to 3-bromopyridine (0.58 ml, 6 mmol) in ether (25 ml) at −78° C.). The mixture was stirred for 2 hours at −78° C., quenched by addition of aqueous saturated NH4Cl, allowed to warm to room temperature and diluted with ether. The layers were separated and the aqueous phase was extracted 3 times with ether. Combined organic layers were washed with brine, dried over Na2SO4 and concentrated. After purification by chromatography on silica gel (CH2Cl2), the cycloheptyl(3-pyridinyl)methanone 18 was obtained as a slightly yellow oil (490 mg, 40%).
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[C:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[CH2:19][CH2:18]1)(=[O:16])[CH3:15]>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[CH2:19][CH2:18]2)([OH:16])[CH3:15])=[N:8][CH:9]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Agent: [Li]C(C)(C)C
Solvent: ClCCl
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ccc(Cl)cn2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
t-BuLi (0.950 mL, 1.52 mmol) was added dropwise to a cooled solution of 2-bromo-5-chloropyridine (225 mg, 1.17 mmol) in DCM (11 mL) at −78° C. over 2 minutes. The reaction mixture was stirred for 2 hours at −78° C. and a solution of butyl trans-4-acetylcyclohexanecarboxylate (291 mg, 1.286 mmol) in DCM (1 mL) was added dropwise at −78° C. The reaction mixture was slowly warmed to room temperature over a period of 16 hours. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford trans-butyl 4-(1-(5-chloropyridin-2-yl)-1-hydroxyethyl)cyclohexanecarboxylate as a brown oil. MS ESI calc'd for C18H27ClNO3 [M+H]+ 340. found 340.
Reaction SMILES: [O:1]1[CH2:4][CH2:3][CH2:2]1.[Br-:5].[CH3:6][N+:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][CH2:10][NH:11][CH3:12]>O>[Br-:5].[OH:1][CH2:2][CH2:3][CH2:4][N:11]([CH2:10][CH2:9][CH2:8][N+:7]([CH3:14])([CH3:13])[CH3:6])[CH3:12]
Reactant: CNCCC[N+](C)(C)C
Reactant: C1COC1
Agent: [Br-]
Solvent: O
Product: CN(CCCO)CCC[N+](C)(C)C

Procedure:
A mixture of 20 g. of oxetane (0.34 mole), 32.8 g. of N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide (0.156 mole) and 22 ml. water is heated in a sealed tube at 100° for 15 hours. The solution is evaporated in vacuo and the residue is dissolved in 50 ml. of acetonitrile and filtered. Upon evaporation the desired product crystallizes. The product may be recrystallized from acetonitrile.