Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:11].O=P(Cl)(Cl)Cl.Cl.[OH-].[Na+]>O>[Cl:11][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1cc[n+]([O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccncc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound was prepared by a modified procedure based on the method of J. Rokach and Y. Girard, J. Heterocycl. Chem. 1978, 15, 683–684. 4-Cyanopyridine-N-oxide (250 g, 2.08 mol) was added portionwise to a stirred suspension of PCl5 (599.94 g, 2.88 mol) and POCl3 (800 mL, 8.71 mol) at 20° C. under nitrogen, in a reactor fitted with a reflux condensor. During the addition the temperature rose to 41° C. The mixture was stirred at 100° C. for 3 h then cooled to 95° C. and transferred to a mixture of 6M HCl (200 mL) and a 6:4 mixture of ice and water (5994 g) at such a rate that the temperature stayed below 15° C. (about 35 min). The resulting brown solution was cooled to below 5° C. and taken to pH 4.15 by adding 33% aqueous NaOH (about 4.5 L), keeping the temperature below 5° C. The resulting beige precipitate was filtered and washed thoroughly with water (4×500 mL), sucking as dry as possible. The residue was suspended in water (1.5 L) and n-heptane (7 L) and stirred at 30° C. for 1 h. The aqueous phase was separated and extracted further with n-heptane (2×2 L), stirring for 30 min each time at 30° C. The combined heptane layers were combined, dried (Na2SO4, 136 g), filtered and the resulting solution was concentrated under reduced pressure to a weight of 1.9 kg (about 3 L), at which point the product began to crystallise. The mixture was cooled to 0° C., stirred for 1.5 h then the product was filtered, washed with cold n-heptane (2×125 mL) and dried at room temperature in a circulating air drier to give the product (129.08 g, 44.8%) as a crystalline solid; m.p. 73.4° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:50][C:51]([F:57])([F:56])[C:52]1([NH2:55])[CH2:54][CH2:53]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:55][C:52]4([C:51]([F:57])([F:56])[F:50])[CH2:54][CH2:53]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: NC1(C(F)(F)F)CC1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1(C(F)(F)F)CC1)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a DMF (0.4 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 50 mg, 0.15 mmol) and HATU (87 mg, 0.23 mmol) was charged 1-(trifluoromethyl)cyclopropanamine hydrochloride (37 mg, 0.23 mmol), followed by drop-wise addition of DIEA (0.080 mL, 0.46 mmol). After stirring first at ambient temperature for 15 minutes and then at 85° C. overnight, the reaction was cooled and directly purified by reverse-phase chromatography (5 to 60% acetonitrile/water) to yield the final product as off-white solid (15 mg, 23%). LCMS (apci) m/z=435.0 (M+H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(O)C=CC=CC=1.C(O)CC/C=C/CCCCC.[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCCCCC)=[CH:36][CH:35]=1>CCOCC>[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]/[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCC/C=C/CCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CCCCC/C=C/CCCOc1ccc(C(=O)OC)cc1
Yield: 80 %

Procedure:
DEAD (641 mg, 3.68 mmol), phenol 34 (487 mg, 3.2 mmol), alcohol 26i (500 mg, 3.2 mmol), and TPP (966 mg, 3.68 mmol) in 16 ml anhydrous ether were reacted according to the procedure for compound 35a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5 to 90/10 (v/v, Hex/EtOAc). Evaporation of the solvent yielded 748 mg (80%) of colorless liquid.
Reaction SMILES: [Na].[CH:2]1C2C(=CC=CC=2)C=CC=1.C1(S([NH:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)(=O)=O)C=CC=CC=1.Cl>COCCOC.O>[NH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:2])=[O:36])=[CH:32][CH:33]=1
Reactant: COC(=O)Cc1ccc(C[C@@H]2CCC[C@H]2NS(=O)(=O)c2ccccc2)cc1
Reactant: c1ccc2ccccc2c1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(C[C@@H]2CCC[C@H]2N)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
0.5 g (21 mmoles) of sodium is added to a mixture of 2.6 g (21 mmoles) of naphthalene and 20 ml of 1,2-dimethoxyethane, under a flow of nitrogen. After stirring 1 hour at 20° C., a solution of 2 g (5.2 mmoles) of methyl trans-4-[[2-[[(phenyl)sulfonyl]amino]cyclopentyl]methyl]benzeneacetate in 20 ml of 1,2-dimethoxyethane is added dropwise during 1 hour, at room temperature. After stirring 1 hour at 20° C., 40 ml of water are added dropwise, before washing with ethyl acetate. The aqueous phase acidified with diluted HCl is washed with ethyl acetate, before being concentrated to dryness under reduced pressure. The residue is captured by 50 ml of absolute ethanol and the white suspension obtained is saturated at 0° C. with gaseous HCl. After stirring 16 h at 20° C., the reaction mixture is concentrated under reduced pressure, captured with H2O, made basic with NH4OH and extracted with ethyl acetate. This organic phase after washing with H2O saturated with NaCl is dried over Na2SO4, concentrated, to give 0.5 g (yield=39.3%) of a partially crystallized brown oil, which is used without any other purification.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F. substituting the product of Example 62A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.02 (d, J=8.48 Hz, 1H) 7.76 (d, J=1.36 Hz, 1H) 7.45 (d, J=7.80 Hz, 1H) 7.40 (dd, J=8.31, 1.86 Hz, 1H) 7.07 (d, J=7.80 Hz, 1H) 3.95-4.07 (m, 1H) 3.25-3.45 (m, 1H) 2.59 (s, 3H) 2.50 (s, 3H) 2.43-2.78 (m, 6H) 1.77-2.00 (m, 4H) 1.47-1.68 (m, 2H). MS: (M+H)+=364.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:15])[NH:5][C:4](=[O:16])[CH:3]=1.[Br:17]Br.N#N>C(O)(=O)C>[CH3:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:15])[NH:5][C:4](=[O:16])[C:3]=1[Br:17]
Reactant: BrBr
Reactant: Cc1cc(=O)[nH]c(C)c1Cc1ccccc1
Agent: N#N
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(Br)c(C)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a solution of 4,6-dimethyl-5-benzyl-1H-pyridin-2-one (2.21 g, 10.4 mmol) in anhydrous acetic acid (10 mL) was added bromine (3.3 g, 1.06 mL, 20.7 mL). It was stirred at room temperature for one hour. Then the reaction vessel was blew N2 to remove bromine and evaporation removed volatiles. The residue was partitioned between CH2Cl2/sat. NaHCO3/saline (100/50/50 mL). The organic layer was dried over Na2SO4 and evaporation gave the brominated compound as a yellow solid (3.17 g, 100%). 1H NMR (CDCl3) δ 2.07 (s, 3H), 2.37 (s, 3H), 3.81 (s, 2H), 7.00–7.40 (m, 5H); MS (CI) m/z 293, 295 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](SC)[C:5]([C:12]#[N:13])=[C:4]([S:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[S:19][CH:20]=2)[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[Cl-].[NH4+].C(OCC)(=O)C>CC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:5]([C:12]#[N:13])=[C:4]([S:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[S:19][CH:20]=2)[N:3]=1
Reactant: CSc1c(C#N)c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c1C#N
Reactant: C1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1

Procedure:
5.00 g (11.63 mmol) of the compound from Example 44A and 57.50 ml (581.43 mmol) of piperidine were initially charged in 120 ml of acetone and heated at reflux for 8 h. After cooling, the mixture was poured into a solvent mixture of 50 ml of saturated aqueous ammonium chloride solution and 50 ml of ethyl acetate. The phases were separated. The organic phase was washed twice with in each case 20 ml of saturated aqueous sodium chloride solution and then dried over magnesium sulfate. After removal of the solvent, the residue was triturated with 100 ml of diethyl ether. The precipitate was filtered off with suction and dried under reduced pressure at 50° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH2:26][CH2:27][OH:28])[N:20]=3)=[CH:15][C:14]=2[O:31][CH3:32])[N:10]=1.[CH2:34]([P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:34]/[P:43](=[O:50])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[CH:22][N:21]([CH2:26][CH2:27][OH:28])[N:20]=3)=[CH:15][C:14]=2[O:31][CH3:32])[N:10]=1
Reactant: COc1cc(COc2nn(CCO)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(CCO)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 9.8 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(2-hydroxyethyl)-1H-pyrazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.30 g) and N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (100:1, v/v) to give diethyl (E)-2-[3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.06 g, yield 15%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18](=[O:19])[C:17]3[CH:16]=[CH:15][C:14]([OH:20])=[CH:13][C:12]=3[O:11][CH:10]=2)=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[CH:16]=[CH:15][C:14]([O:20][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:13][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2coc3cc(OC(=O)C(C)(C)C)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Formononetine (90 g; 335 mmol) was suspended in acetonitrile, K2CO3 was added and the mixture was stirred for about 20 minutes at r.t. Pivaloyl chloride (59.85 g; 496 mmol) was dropped into the mixture, then the reaction was stirred for further 15 minutes and quenched into water. The solid was filtered, washed with water, dissolved in CHCl3; the solution was dried and evaporated to dryness to obtain the title compound, which can be crystallised from hot toluene. 102 g of a white crystalline powder were obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[CH:12][C:13]2[O:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]=2[CH:20]=1)([O-:9])=[O:8].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:15]1[C:14]2[CH:20]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[CH:12][C:13]=2[O:19][CH2:18][CH2:17][CH2:16]1)[CH3:27]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCCO2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCOc2ccc([N+](=O)[O-])cc21
Temperature: 120 °C
Yield: 49.2 %

Procedure:
Powdered and flame dried potassium carbonate (1.52 g, 11 mmol, 1.1 eq.) was placed in a round bottom flask together with 60 mL of anhydrous dimethylformamide and kept under inert atmosphere. 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (1.942 g, 10 mmol, 1 eq.) was dissolved in 20 mL of anhydrous DMF and added to the reaction mixture. The reaction was heated to 120° C. under reflux condenser for 1 hour and then solution of ethyl bromoacetate (3.34 g, 2.22 mL, 20 mmol, 2 eq.) in 5 mL of dry DMF was added dropwise to the hot solution. The reaction mixture was then heated to 120° C. for an additional 12 hours. When cooled, the DMF was removed on the rotary evaporator, and diluted with 100 mL of water. The aqueous phase was washed (3×) with 50 mL portions of methylene chloride. The methylene chloride extracts were combined and washed with water and brine and dried over magnesium sulfate. Crude material (3.018 g) was chromatographed on a large Biotage column in 20% ethyl acetate/hexanes. 1.38 g (50% yield) of pure material (bright yellow crystalline powder) was collected. LC MS: AP+281, AP−280.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH:16]1[CH3:21])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH:16]1[CH3:21])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Reactant: Clc1ncccn1
Product: CC1CN(c2ncccn2)CCN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
100 mg 2-chloro-pyrimidine was added to 175 mg 2-Methyl-piperazine-1-carboxylic acid tert-butyl ester and this mixture was stirred for 2 h at 120° C. to give 240 mg of the desired compound. Rt: 1.31 min (method B), (M+H)+: 279
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][CH2:8][CH2:9][OH:10].F[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>C(#N)CC>[OH:10][CH2:9][CH2:8][S:7][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: O=Cc1ccccc1F
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC#N
Product: O=Cc1ccccc1SCCO
Temperature: 85 °C

Procedure:
To a slurry of potassium carbonate (362 g, 2.62 moles) in propionitrile (1000 ml) under nitrogen, was added 2-mercaptoethanol (184 ml, 2.618 moles) as a solution in propionitrile (750 ml). 2-Fluorobenzaldehyde (250 g, 2.014 moles) was added as a solution in propionitrile (750 ml) and heated at 85° C. for 18 hours. The reaction was cooled to 20° C. and sequentially washed with water (1500 ml), 1M sodium hydroxide solution (500 ml) and water (1000 ml). The final solution was dried by azeotropic distillation to leave the title compound as a clear, yellow solution in propionitrile (4250 ml). A small sample was concentrated for yield calculation (348.7 g, 95%).
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].[F:6][C:7]([F:23])([C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][OH:9]>CCN(C(C)C)C(C)C>[OH:3][C@H:2]([CH2:1][O:9][CH2:8][C:7]([F:23])([F:6])[C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])[CH2:4][OH:5]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OC[C@@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H](O)COCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 58.2 %

Procedure:
(S)-2-hydroxy-3-(2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyloxy)-propanol was prepared by the following modification of a procedure described in U.S. Pat. No. 3,470,258 (Teroso et al.). (R)-glycidol (5.0 g, 67.5 mmol) was added dropwise to a 120° C. solution of 2,2,3,3,4,4,5,5,6,6,6-undecafluorohexanol (30 g, 101 mmol) and N,N'-diisopropylethylamine (0.47 ml, 2.7 mmol). The resulting mixture was then stirred for one hour. The resulting product was distilled (79°-81° C. at 0.4 mm Hg) from the mixture to give 14.7 g of (S)-2-hydroxy-3-(2,2,3,3,4,4,5,5,6,6,6-undecafluorohexyloxy)-1-propanol as a clear liquid. (R)-2-fluoro-3-(2,2,3,3,4,4,5,5,6,6,6-undecafluorohexane-1-p-toluenesulfonate was then prepared using essentially the procedure described in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][C:29]1([CH3:42])[CH3:41])=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([N:31]4[CH2:32][CH2:33][NH:28][C:29]([CH3:42])([CH3:41])[CH2:30]4)=[CH:35][N:36]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1(C)C
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNC(C)(C)C4)cn3)nc2n1C1CCCC1
Yield: 28.8 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 0.17 mmol) and 4-(6-amino-pyridin-3-yl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.15 mmol) gave 7-cyclopentyl-2-[5-(3,3-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (20 mg, 25%). MS(ESI) m/z 463.3 (M+H)+
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:26][CH2:25][C@:12]34[C:13]5[C:14]6[O:24][C@H:11]3[CH:10]([N:27]3[C:31](=[O:32])[C:30]7=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=[C:29]7[C:28]3=[O:38])[CH2:9][CH2:8][C@@:7]4([OH:39])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH2:21][O:22][CH3:23])[CH2:3][CH2:2]1.[C:40](=O)([O-])[O-].[K+].[K+].CI.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[CH2:26][CH2:25][C@:12]34[C:13]5[C:14]6[O:24][C@H:11]3[C@H:10]([N:27]3[C:31](=[O:32])[C:30]7=[C:33]([O:37][CH3:40])[CH:34]=[CH:35][CH:36]=[C:29]7[C:28]3=[O:38])[CH2:9][CH2:8][C@@:7]4([OH:39])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH2:21][O:22][CH3:23])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: COCOc1ccc2c3c1O[C@H]1C(N4C(=O)c5cccc(O)c5C4=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCOc1ccc2c3c1O[C@H]1[C@H](N4C(=O)c5cccc(OC)c5C4=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.1 %

Procedure:
In 5 mL of DMF, 119 mg (0.22 mmol) of N-(17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6-yl)-3-hydroxy-phthalimide obtained in Example 102-1 was dissolved, and 93 mg of potassium carbonate and 0.02 mL of methyl iodide were added thereto, followed by stirring the mixture at room temperature for 3.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added to this reaction solution, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain 112 mg of N-(17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl)-3-methoxy-phthalimide as a crude product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]Br.[OH:13][CH:14]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[OH:13][CH:14]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: BrCc1ccc2ccccc2n1
Reactant: CCCCCC(O)c1cccc(N)c1
Product: CCCCCC(O)c1cccc(NCc2ccc3ccccc3n2)c1

Procedure:
For compounds in which X is --NR2 --(CHR1)n --, the corresponding amino starting compounds are employed to form the desired amino coppound. Thus, 2-aminopyridine is condensed with 3-(1-hydroxyhexyl)benzyloromide to form 2-[3-(1-hydroxyhexyl)benzylamino]pyridine. Alternatively, 2-quinolylmethylbromide is condensed with 3-(1-hydroxyhexyl)aniline to form 2-[3-(1-hydoxyhexyl) anilinomethyl]quinoline.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22]C(=O)C)=[N:19][CH:20]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][OH:22])=[N:19][CH:20]=1
Reactant: CC(=O)OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A mixture of [5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]acetate (18.0 g), 1N aqueous sodium hydroxide solution (75 mL) and methanol (100 mL) was stirred at room temperature for 3 hrs. and concentrated. The residue was dissolved in ethyl acetate, washed with water and then with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give 5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethanol (14.29 g, yield 91%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 125-126° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1ccc(Nc2nc3ccccc3[nH]2)cc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-fluoro-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 255-257° C.). MS(ES+) m/z 296 ([M+1]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1O>CO.ClCCl>[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1
Reactant: Cc1ccc(O)c(C)c1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(OC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c(C)c1
Yield: 71 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2,4-dimethylphenol (16 mg, 0.13 mmol) as the source alcohol. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 48 mg (71%) of the titled compound as a white solid. ESI-MS m/z 396 (MH+), 394 (M−H−).