Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4]Br.[H-].[Na+].[CH3:13][N:14]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH3:15]>CN(C)C=O>[CH3:13][N:14]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:4][C:3]1[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][C:2]=1[F:1])[CH3:15]
Reactant: CN(C)CCCCO
Reactant: Fc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCCOCc1cc(Br)ccc1F

Procedure:
In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl bromide (967 mg, 3.61 mmol) was dissolved in N,N-dimethylformamide (3.5 ml). To this solution sodium hydride (60%, 245 mg, 6.14 mmol) was added and the resulting mixture was stirred for ten minutes. To the reaction mixture 4-(N,N-dimethylamino)butanol (633 mg, 5.41 mmol) was added and the rsulting mixture was stirred for six hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[C:10](#[N:13])[CH:11]=[CH2:12]>CO>[C:10]([CH2:11][CH2:12][NH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])#[N:13]
Reactant: C=CC#N
Reactant: COC(=O)C(C)(C)CN
Solvent: CO
Product: COC(=O)C(C)(C)CNCCC#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
A mixture of methyl 3-amino-2,2-dimethylpropanoate (1.0 g, 7.63 mmol) and acrylonitrile (2 eq., 1 mL, 15.26 mmol) in methanol (50 mL) was stirred at room temperature for about 18 hours. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel, using cyclohexane-ethyl acetate 1:1 as eluant, to give the title compound as colourless oil (0.7 g, 70% yield).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:5][CH2:6]2.[ClH:16]>O1CCOCC1.O>[OH:1][C@H:2]1[C@H:7]([Cl:16])[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:3]1
Reactant: Cl
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC2OC2C1
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@@H](Cl)[C@H](O)C1
Reaction time: 15 h

Procedure:
5.0 g (0.018 mol) of 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-piperidine are dissolved in 50 ml of dioxane and the solution is treated with 60 ml of 6 N hydrochloric acid. The slightly exothermic reaction is kept at room temperature by means of a water bath, and the reaction mixture is stirred for 15 hours, then diluted with water and extracted with 3 times 100 ml of methylene chloride. The organic phase is washed with 0.1 N sodium hydroxide solution and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and then evaporated to dryness, first under a water pump vacuum and then under a high vacuum, whereupon trans-3-hydroxy-4-chloro-1-(β,β,β-trichloroethoxycarbonyl)-piperidine is obtained in the form of a slightly yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)sc1-c1ccnc(C2(C#N)CCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.7 %

Procedure:
A mixture of {5-[2-(1-cyano-cyclobutyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 19.2) (300 mg), DCM (5 mL) and TFA (1 mL) is stirred for 4 h at rt, quenched by addition of a saturated solution of NaHCO3 (50 mL), and extracted with DCM (3×75 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 1:0→96:4) to afford 181 mg of the title compound as a yellow solid: ESI-MS: 271.1 [M+H]+; tR=2.48 min (System 1); TLC: Rf=0.45 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[F:12].C([Li])CCC.[CH3:18][C:19]([CH3:21])=[O:20].O>O1CCCC1>[F:12][C:6]1[CH:7]=[C:8]([C:19]([OH:20])([CH3:21])[CH3:18])[CH:9]=[CH:10][C:5]=1[CH:4]=[CH:3][O:2][CH3:1]
Reactant: COC=Cc1ccc(Br)cc1F
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC=Cc1ccc(C(C)(C)O)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of compound 2-(4-bromo-2-fluorophenyl)vinyl methyl ether (115.5 g, 0.5 mol) in tetrahydrofuran (666 mL) at −78° C. was added n-butyllithium (240 mL of 2.5M in hexanes, 0.6 mol), and the resulting mixture was stirred at −78° C. for 1 hour. A solution of acetone (37.7 g, 0.65 mol) in tetrahydrofuran (280 mL) was added dropwise to the reaction mixture. Then the reaction solution was slowly warmed to 0° C., stirred for 30 minutes, and then at room temperature for 30 minutes. Water (300 mL) was added to quench the reaction. The biphasic mixture was extracted with ethyl acetate (2×). The combined organics were dried and concentrated in vacuo. Purification via flash chromatography afforded the title compound.
Reaction SMILES: C([CH:5]([O:27][C:28]1[CH:29]=[N:30][NH:31][C:32](=[O:35])[C:33]=1[Cl:34])[C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH2:12][CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:8][CH:7]=1)(C)(C)C.[F-:36].[K+]>C(#N)C>[C:6]([N:31]1[C:32](=[O:35])[C:33]([Cl:34])=[C:28]([O:27][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][F:36])=[CH:25][CH:26]=2)[CH:29]=[N:30]1)([CH3:26])([CH3:7])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc(C(Oc3cn[nH]c(=O)c3Cl)C(C)(C)C)cc2)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)n1ncc(OCc2ccc(OCCCF)cc2)c(Cl)c1=O
Reaction time: 0.67 h
Yield: 50.2 %

Procedure:
To a scintillation vial containing a suspension of Example 4F (4.5 mg, 8.64×10−3 mmol) in anhydrous acetonitrile (0.25 mL) was added a solution of potassium fluoride (1.6 mg, 4.07×10−2 mmol) and kryptofix (15.0 mg, 4.07×10−2 mmol) in anhydrous acetonitrile (0.25 mL). The vial was capped and lowered into a 90° C. oil bath. The reaction was allowed to stir for 40 minutes. The reaction was cooled and concentrated under reduced pressure. Preparatory thin layer chromatography [silica gel; eluent pentane-ethyl acetate (3:2)] provided the desired product (0.8 mg, 25%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][N:20]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: Nc1ncc(B(O)O)cn1
Product: Cc1c2n(c3c(-c4cnc(N)nc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (20 mg, 26%), MS (ISP) m/z=312.5 [(M+H)+], mp 310° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2-amino-pyrimidin-5-ylboronic acid (45.1 mg, 0.325 mmol).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].CS(O[CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)(=O)=O>CN(C=O)C>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][CH:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[C:6]1=[O:15]
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Reactant: NC1Cc2ccccc2NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN2C(=O)C(N)Cc3ccccc32)O1
Temperature: 80 °C
Yield: 52.6 %

Procedure:
Sodium hydride (60% in oil, 191 mg, 4.70 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28, 1985; 1511–16,450 mg, 2.27 mmol), in anhydrous DMF (6 mL) at 0° C. over a period of 5 min keeping the internal temperature at <10° C. The reaction was stirred for a further 30 min before addition of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (J. Med. Chem. 35, 1992, 1650–62; 528 mg, 2.50 mmol) and the reaction has then heated to 80° C. for a period of 5 h. The reaction was then cooled and evaporated before addition of sat. aqueous NaHCO3 (20 mL) and EtOAc (50 mL). The organic layer was then dried (MgSO4), filtered and evaporated and the residue was purified by column chromatography (MeOH:DCM 1:19) to afford the title compound (330 mg, 53%) as colourless oil.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH2:27][CH3:28]>C(#N)C>[C:32]1([CH3:35])[CH:33]=[CH:34][C:29]([CH:26]([CH2:27][CH3:28])[C:5]#[N:6])=[CH:30][CH:31]=1
Reactant: CCC(Br)c1ccc(C)cc1
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CCC(C#N)c1ccc(C)cc1
Reaction time: 0.08 h

Procedure:
7.36 g (74.4 mmol) Trimethylsilyl cyanide was added to a solution of 74.4 ml (1.0 M in THF, 74.4 mmol) tetrabutylammonium flouride in 300 ml acetonitrile and the mixture was stirred for 5 minutes. 5.28 g (24.8 mmol) rac-1-(1-Bromo-propyl)-4-methylbenzene were added and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the viscous residue obtained was partitioned between water and dichloromethane. The dichloromethane was separated, then washed with water, dried over MgSO4 and evaporated to dryness. Purification of the residue by column chromatography on silica gel with a gradient of heptane to 9:1 heptane/ethyl acetate afforded rac-2-p-tolyl-butyronitrile as a colourless oil. NMR (CDCl3, ppm): 0.95 (3H, t), 1.77 (2H, m), 2.21 (3H, s), 3.58 (1H, t), 7.07 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:17][CH:18]=2)=[O:23])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Yield: 63.5 %

Procedure:
Reaction of 4-aminobenzophenone (102 mg, 0.52 mmol) in THF (6 mL) with 4-biphenylcarbonyl chloride (143 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave biphenyl-4-carboxylic acid (4-benzoyl-phenyl)-amide (125 mg, 0.33 mmol, 63% yield) as a yellow powder after purification by crystallisation in DCM/EtOAc.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24]([O:27][CH:28](Cl)[CH3:29])(=[O:26])[CH3:25]>>[C:24]([O:27][CH:28]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:29])(=[O:26])[CH3:25]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CC(=O)OC(C)Cl
Product: CC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 5, piroxicam (2.00 g, 6.0 mmol) and alpha-chloroethyl acetate (2.22 g, 18.1 mmol) were converted to chromatographed title product, 1.17 g of yellow solid (2.8 mmol, 46.4%) which gave white crystals (1.08 g) upon crystallization from isopropyl alcohol: mp 161°-162° C.; IR (KBr) 1755, 1677 cm-1 ; 1H NMR (CDCl3) delta 1.72 (d, J=6 Hz, 3H), 1.95 (s, 3H), 3.13 (s, 3H), 6.39 (q, J=6 Hz, 1H), 7.07-7.18 (m, 1H), 7.65-7.96 (m, 5H), 8.30-8.42 (m, 2H), 9.52 (br s, 1H); precise mass calcd for C17H15N3O5S m/e (P+ --C2H4O) 373.0738, found 373.0678.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[N:4][C:5]([F:30])=[C:6]([Cl:29])[C:7]=1[CH:8](C(OCC1C=CC=CC=1)=O)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O>CS(C)=O>[Cl:29][C:6]1[C:5]([F:30])=[N:4][C:3]([F:31])=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1c(Cl)c(F)nc(F)c1Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(Cc1c(Cl)c(F)nc(F)c1Cl)OCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
3,5-dichloro-2,4,6-trifluoropyridine (25 g, 15.4 mL, 123.7 mmol) and dibenzyl malonate (35.8 g, 31.5 mL, 126 mmol, Aldrich) were dissolved in anhydrous DMF (240 mL) under nitrogen atmosphere. The mixture was then cooled in an ice bath. To a stirred mixture, was added 60% sodium hydride (10 g, 250 mmol) portionwise (2 g) for 2 hr. The mixture was then stirred in a water bath for ca. 17 hr. Glacial acetic acid was added and the mixture was partitioned between ether and water. Ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and dried in vacuo to give 62 g of dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate as a yellow oil. dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate (62 g) was then dissolved in dimethyl sulfoxide (DMSO) (120 mL) and stirred with water (10 mL) in an oil bath (130-140° C.) for 3 hr. After cooling to room temperature, water was added to the mixture and the product was extracted with ether (Sometimes addition of EA is necessary to dissolve product completely). The ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light yellow solid. The crude product was recrystallized from MC/Hexane three times to afford 30.9 g (75% for two steps) of benzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)acetate as a white solid. m.p. 98-101° C. 1H NMR (200 MHz, CDCl3) δ 4.11 (2H, s), 5.19 (2H, s), 7.30-7.38 (5H, m).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:28]([O:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1)[CH3:29]>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:28]([O:30][C:31](=[O:44])[C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:39][CH2:40][N:41]([C:2]3[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=4)=[CH:4][N:3]=3)[CH2:42][CH2:43]2)=[CH:36][CH:37]=1)[CH3:29]
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Temperature: 120 °C
Yield: 65 %

Procedure:
A solution of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (50 mg, 0.13 mmol), a catalytic amount of DMAP, diisopropylethyl amine (0.07 mL, 0.41 mmol), 4-(piperazin-1-yl)-benzoic acid ethyl ester (94 mg, 0.41 mmol) in 5 mL in dioxane was heated at 120° C. in a sealed tube for about 23 h. The reaction mixture was cooled, followed addition of another portion of 4-(piperazin-1-yl)-benzoic acid ethyl ester (94 mg, 0.41 mmol) and diisopropyl ethyl amine (0.07 mL, 0.41 mmol) and the mixture was re-heated at 120° C. for 3 more days. The reaction mixture was then cooled and partitioned between EtOAc and aq. saturated Na2CO3. The organic layer was then collected, dried over Na2SO4 filtered and concentrated. The residue was chromatographed with a silica gel column and 20-40% EtOAc in hexanes to afford the product (23 mg. Yield: 65%). HRMS m/z calcd for C26H27N4O3I [M+H]: 571.1201. Found: 571.1197.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][NH2:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][NH:31][CH3:30])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CN
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 10 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and methylamine (40% in water) to give the title compound in 10% yield; NMR Spectrum: 2.63 (s, 3H), 3.25 (t, 2H), 4.07 (t, 2H), 5.24 (s, 2H), 7.16 (d, 1H), 7.36 (t, 1H), 7.48 (d, 1H), 7.57 (d, 1H), 7.87 (t, 1H), 7.98 (s, 1H), 8.22 (s, 1H), 8.24 (br s, 1H), 8.58 (d, 1H); Mass Spectrum: 426 (MH+).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][N:28]2[CH2:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])[CH2:10]1)(C(C)(C)C)(C)C.Cl>CO>[O:34]=[C:29]1[NH:30][C:31](=[O:33])[CH2:32][N:28]1[CH2:27][C@@H:11]1[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN2CC(=O)NC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CO
Product: O=C1CN(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(2,4-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.78 g) in a mixture of methanol (100 ml) and conc. hydrochloric acid (1.62 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated in vacuo. The resulting residue was dissolved in toluene (30 ml) and the solution was concentrated under reduced pressure to give a residue. The residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (2:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-(2,4-dioxoimidazolidin-1-yl)methyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.27 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:11](Cl)([Cl:13])=[O:12]>C(Cl)Cl>[CH:1]1([C:11]([Cl:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C1NCCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (0.5 g, 3.76 mmol) was added to a cooled mixture of phosgene (5 ml of 20% phosgene in toluene solution, 9.4 mmol) in methylene chloride (5 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was evaporated in vacuo. The residue was suspended in ethyl ether, filtered and the eluents were condensed to give a pale pink oil. Purification by flash column chromatography (silica gel, 0-10% ethyl acetate/hexane) gave 0.586 g of the desired product. IR (film) 1735.3 cm−1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([C@H:40]2[CH2:45][CH2:44][C@H:43]([O:46][CH2:47][CH3:48])[CH2:42][CH2:41]2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:47]([O:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([C:32]2[CH:31]=[CH:30][C:29]([NH:28][C:21]3[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:11][CH:12]=4)[N:22]=3)=[C:37]3[C:33]=2[CH2:34][N:35]([CH3:39])[C:36]3=[O:38])[CH2:45][CH2:44]1)[CH3:48]
Reactant: CCO[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OCC)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (40.0 mg, 0.0944 mmol) and 7-amino-4-(trans-4-ethoxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 166B). 1H NMR (DMSO-d6, 400 MHz): δ=1.11 (t, J=6.95 Hz, 3H), 1.18 (t, J=6.95 Hz, 6H), 1.21-1.33 (m, 2H), 1.54-1.68 (m, 2H), 1.80 (d, J=12.63 Hz, 2H), 2.09 (dd, J=12.63, 3.28 Hz, 2H), 3.08 (s, 3H), 3.18-3.27 (m, 2H), 3.49 (q, J=6.99 Hz, 2H), 3.91-4.01 (m, 4H), 4.52 (s, 2H), 7.26 (dd, J=8.72, 1.89 Hz, 2H), 7.40 (d, J=8.59 Hz, 1H), 7.56 (br. s., 2H), 8.45 (s, 1H), 8.67 (s, 1H), 9.89 (s, 1H), 10.58 (br. s., 1H). MS (ES+): m/z=676.25 [MH+] (TOF, polar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](Br)[CH:3]=1.C([Li])CCC.[N:15]1[O:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][C:19]=12>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C@:19]23[CH2:20][O:21][CH2:22][CH2:23][C@H:18]2[CH2:17][O:16][NH:15]3)[CH:3]=1
Reactant: Fc1ccc(Br)cc1Br
Reactant: C1CC2CON=C2CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1ccc(Br)cc1[C@]12COCC[C@H]1CON2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1,3-Dibromo-4-fluorobenzene (837 mg) was dissolved in a toluene-THF (10:1) mixture (15 ml). The mixture was cooled to −78° C. and n-butyllithium (2.64 M, 1.19 ml) was added dropwise. After stirring at the same temperature for one hour, a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (200 mg) in toluene-THF (10:1) (5.0 ml) and a boron trifluoride-diethyl ether complex (394 μl) were added dropwise at the same time. After stirring at the same temperature for three hours, the reaction was terminated with an ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (365 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[N:4]=1.Br>O>[F:19][C:2]([F:1])([F:18])[C:3]1[N:4]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Agent: Br
Solvent: O
Product: Oc1ccc(Oc2cccc(C(F)(F)F)n2)cc1

Procedure:
A mixture comprising 127 grams of 2-trifluoromethyl-6-(4-methoxyphenoxy)pyridine, prepared above in Example V, and 250 milliliters of 48 percent hydrobromic acid was heated at reflux overnight. The mixture was cooled and diluted with water and thereafter extracted with methylene chloride. The extract was concentrated under reduced pressure leaving the 4-((6-trifluoromethyl-2-pyridyl)oxy)phenol, a white solid, as a residue. Recrystallization of this solid from a 3:1 mixture of benzene and hexane gave 69.1 grams (57 percent of theoretical) of the product as a white crystalline solid which melted at 94°-95° C.