Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([O:29][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(Oc2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1
Temperature: 155 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmoles) was dissolved in 2 mL DMF. 3-Methoxyphenol 8e (0.033 g, 0.282 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol). Nitrogen was bubbled through the resultant reaction mixture and heated in a microwave at 155° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered and the organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, solvent removed, and purified to obtain the desired product which was to obtain 107 as a white solid (15.0 mg, 30%)
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.CN([C:13]([O:17][N:18]1N=NC2C=CC=[N:24][C:19]1=2)=[N+:14](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOCC.CC(OC)(C)C.CCOC(C)=O>[CH2:9]1[CH:6]2[CH:1]([C:13]3[O:17][N:18]=[C:19]([NH2:24])[N:14]=3)[CH2:2][N:3]([CH2:4]2)[CH2:7]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Nc1noc(C2CN3CCC2C3)n1
Temperature: 0 °C
Reaction time: 0.29 h

Procedure:
DIEA (2.0 to 2.2 eq) and HATU (1.0 to 1.1 eq) were added into a solution of the carboxylic acid derivative (1 eq) in anhydrous DMF (4 mL/mmol of carboxylic acid derivative) cooled at 0° C. The resulting mixture was stirred at 0° C. for a period of 5 to 30 minutes. Then the amidoxime derivative (1.0 to 1.2 eq) was added neat or as a DMF solution. The resulting mixture was stirred at 0° C. or RT for a period of 30 minutes to 18 hours. The reaction mixture was diluted with an adequate solvent, such as Et2O, MTBE or EtOAc, and then washed with water and brine. The aqueous layers were extracted once. The organic layers were combined, dried (MgSO4 or Na2SO4) and the solvents were removed under reduced pressure. The residue was taken up with ACN (8.5 mL/mmol of carboxylic acid derivative). The resulting mixture was heated at 150° C. for 30 min under MW irradiation. The reaction mixture was diluted with an adequate solvent, such as Et2O, MTBE or EtOAc, and then washed with water and brine. The aqueous layers were extracted once. The organic layers were combined, dried (MgSO4 or Na2SO4) and the solvents were evaporated under reduced pressure. Purification by flash chromatography or precipitation gave the expected oxadiazole derivative.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1([O:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:25]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:31][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 4-phenyloxyaniline as the starting materials.
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[N-:19]=[N+:20]=[N-:21].[Al+3].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[Cl-].[Al+3].[Cl-].[Cl-].[N-]=[N+]=[N-].[Na+].Cl>O1CCCC1.O>[CH2:17]([C:16]1[C:11]2=[N:10][CH:9]=[C:3]([C:1]3[NH:2][N:21]=[N:20][N:19]=3)[C:4](=[O:5])[N:12]2[CH:13]=[CH:14][CH:15]=1)[CH3:18]
Reactant: CCOC(=O)C(C#N)=CNc1ncccc1CC
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccn2c(=O)c(-c3nnn[nH]3)cnc12
Reaction time: 0.25 h
Yield: 27 %

Procedure:
Ethyl 2-cyano-3-(3-ethyl-2-pyridylamino)acrylate (10.0 g., 0.0408 mole) was added to a stirred mixture of aluminum azide in tetrahydrofuran at 0°. The aluminum azide had been prepared in situ in the usual manner from aluminum chloride (6.5 g., 0.0488 mole) and sodium azide (9.5 g., 0.1464 mole) in tetrahydrofuran (100 ml.). The mixture was stirred at 0° for 15 minutes and then heated under reflux for 19 hours. The mixture was cooled, diluted with water, and acidified with concentrated hydrochloric acid (20 ml.). The mixture was filtered to give the title compound (2.7 g., 27%), m.p. 285°-288°. The product was recrystallized from N,N-dimethylformamide with charcoal treatment to give analytical material, m.p. 288°-290° (decomp).
Reaction SMILES: [Cl-].[Yb+3].[Cl-].[Cl-].C([C@H:8]1COC(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)=[N:9]1)(C)C.[O:27]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[N:28]1.[Si](C#N)(C)(C)C.[Cl-].[NH4+]>C(#N)C>[OH:33][C@@H:32]([C:29]1[CH:30]=[CH:31][O:27][N:28]=1)[CH2:8][NH2:9]
Reactant: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Reactant: O=Cc1ccon1
Agent: C[Si](C)(C)C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Product: NC[C@@H](O)c1ccon1
Temperature: 0 °C
Reaction time: 1 h
Yield: 326.7 %

Procedure:
To ytterbium(III) chloride in acetonitrile (10 ml) was added 2,6-bis[(4S)-(−)-isopropyl-2-oxazolin-2-yl]pyridine (180 mg) and the solution stirred for 1 h. After cooling to 0° C., 3-isoxazolecarboxaldehyde (580 mg) in acetonitrile (5 ml) followed by TMSCN (0.96 ml) were added. After warming to room temperature overnight, aqueous ammonium chloride solution was added and the product extracted into diethyl ether. The extracts were dried (Na2SO4), the solvent was evaporated off, and the residue taken up in diethyl ether (50 ml). After cooling to 0° C., the solution was added to lithium aluimnium hydride (570 mg) in diethyl ether (10 ml) at 0° C. After 3 h at room temperature, water (0.54 ml), 15% aqueous sodium hydroxide (1.62 ml) and water (0.54 ml) were added sequentially. The mixture was filtered through celite and the solvent was evaporated off to give the sub-title compound as a yellow oil (250 mg, 40% ee).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:17](Cl)[O:18][CH3:19]>CC(C)=O>[OH:7][C:8]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11]
Reactant: O=Cc1ccc(O)cc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(C=O)c(O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Oven-dried potassium carbonate (1.38 g, 10 mmol) was added to an ice cooled solution of 2,4-dihydroxy-benzaldehyde (1.38 g, 10 mmol) in 10 mL of acetone. MOMCl (1.54 mL, 20 mmol) was added drop-wise and the mixture was stirred at 0° C. for one hour, after which it was gradually allowed to come to RT. The reaction was further stirred for 24 hours at RT and then poured into ice water with vigorous stirring. A Buff colored solid precipitated. The solid was filtered, dried and recrystallized from MeOH:DCM (ca. 30:5 mL) to obtain 1.31 g (72%) of white solid: mp 52-53° C. [Lit.(65) 50-51° C.]; TLC Rf0.43 in hexanes:EtOAc (2:1), 1H NMR (400 MHz, CDCl3) δ 11.38 (s, 1H, OH), 9.74 (s, 1H, CHO), 7.46-7.44 (d, 1H, J=8.4 Hz, Ar—H6), 6.66-6.64 (dd, 1H, 2J=8.4 Hz, 3J=2 Hz, Ar—H5), 6.60 (d, 1H, 3J=2 Hz), 5.24 (s, 2H, O—CH2—O), 3.48 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3) δ 194.8, 164.5, 164.4, 135.6, 116.2, 109.3, 103.6, 94.3, 56.7.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[C:6]([O:12][CH3:13])[C:5]=1[Br:14]>[OH-].[Na+]>[Br:14][C:5]1[C:6]([O:12][CH3:13])=[CH:7][C:8]([OH:11])=[C:9]([CH3:10])[C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1c(C)c(O)cc(OC)c1Br
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(O)c(C)c(C(=O)O)c1Br
Temperature: 70 °C
Reaction time: 85 h
Yield: 96.2 %

Procedure:
A suspension of 23 g 2-bromo-5-hydroxy-3-methoxy-6-methyl-benzoic acid methyl ester in 200 ml of 3N sodium hydroxide was stirred at 70° C. for 85 h. The cooled solution was washed with diethyl ether and then acidified to pH 1 by the addition of 3N hydrochloric acid. The aqueous layer was extracted with diethyl ether and the organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from diethyl ether/pentane to yield 21 g of 2-bromo-5-hydroxy-3-methoxy-6-methyl-benzoic acid as white crystals, m.p. 79°-80° C.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.I[C:19]1[NH:23][C:22]([CH:24]([CH3:26])[CH3:25])=[N:21][C:20]=1[CH3:27].IC1NC(C)=NC=1C.[CH3:36][C:37]1[CH:46]=[C:45]([CH3:47])[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:38]=1[C:39]([O:41]C)=[O:40].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1>>[CH:24]([C:22]1[NH:23][C:19]([C:44]2[C:45]([CH3:47])=[CH:46][C:37]([CH3:36])=[C:38]([CH:43]=2)[C:39]([OH:41])=[O:40])=[C:20]([CH3:27])[N:21]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Reactant: Cc1nc(C(C)C)[nH]c1I
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1cc(C)c(-c2[nH]c(C(C)C)nc2C)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except 5-iodo-2-isopropyl-4-methyl-1H-imidazole (compound 159.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5) and methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:13](=O)[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH2:18][C:19]([CH3:21])=[CH2:20].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([N:27]=[C:13]2[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]([CH2:18][C:19]([CH3:21])=[CH2:20])=[C:8]2[CH3:7])=[CH:25][CH:24]=1
Reactant: C=C(C)CC1=C(C)C(=O)C(C)=C(C)C1=O
Reactant: Nc1ccc(Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: C=C(C)CC1=C(C)C(=Nc2ccc(Cl)cc2)C(C)=C(C)C1=O
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
Titanium tetrachloride (2.42 ml, 22.1 mmol) was added dropwise to a solution of pyridine (7.13 ml, 88.2 mmol) in 1,2-dichloroethane (40 ml) and, after completion of addition, the reaction mixture was heated under reflux minutes in an argon atmosphere. After cooling of the reaction mixture, to the mixture was added a solution of 3,5,6-trimethyl-2-(2-methyl-2-propenyl)-1,4-benzoquinone (3.00 g, 14.7 mmol) and p-chloroaniline (5.62 g, 44.1 mmol) in 1,2-dichloroenhane (20 ml) and the mixture was stirred 90° C. for 45 minutes in an argon atmosphere. The reaction mixture was cooled and filtered through Cerite and the filtrate was washed with a saturated saline solution, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 93:7) to obtain the desired compound as oil (4.43 g, yield: 96.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[OH:10]O>C(O)(=O)C>[NH2:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([Cl:1])=[CH:7][N+:6]=1[O-:10]
Reactant: Nc1ncc(Cl)cc1F
Reactant: OO
Solvent: CC(=O)O
Product: Nc1c(F)cc(Cl)c[n+]1[O-]

Procedure:
The title compound was prepared following the procedure described for Intermediate-40 using 5-chloro-3-fluoropyridin-2-amine (0.500 g, 3.42 mmol), acetic acid (5.0 mL) and 50% hydrogen peroxide (2.0 mL) to afford 0.450 g of the desired product. 1HNMR (DMSO-d6): δ 7.14 (s, 2H), 7.55 (d, J=10.8 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:34][C@@:32]3([CH3:33])[C@@H:28]([CH2:29][CH2:30][C@@H:31]3[OH:35])[C@H:27]3[C@H:18]2[C:19]2[CH:20]=[CH:21][C:22]([OH:36])=[CH:23][C:24]=2[CH2:25][CH2:26]3)=[CH:13][CH:12]=1>CC(CC)=O.C(OCC)(=O)C>[I:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:34][C@@:32]3([CH3:33])[C@@H:28]([CH2:29][CH2:30][C@@H:31]3[OH:35])[C@H:27]3[C@H:18]2[C:19]2[CH:20]=[CH:21][C:22]([OH:36])=[CH:23][C:24]=2[CH2:25][CH2:26]3)=[CH:13][CH:12]=1
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCCCl)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: C[C@]12C[C@H](c3ccc(OCCCCCCI)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 24 h

Procedure:
150 mg of sodium iodide is added to a solution of 310 mg of the product obtained in Stage C in 6 cm3 of methylethylketone and agitation is carried out for 24 hours under reflux. 100 mg of sodium iodide is added, followed by agitation for 2 hours under reflux and for 16 hours while leaving the temperature to return to ambient, taking up in ethyl acetate, washing, drying and evaporating to dryness under reduced pressure. 470 mg of expected product is collected which is used as it is for the following stage.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:9]=1[CH3:20])[CH3:6])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]([N:7]([C:30](=[O:31])[CH2:29][O:28][CH3:27])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:9]=1[CH3:20])[CH3:6])=[O:4]
Reactant: COC(=O)C(C)Nc1c(C)ccc(COC(C)=O)c1C
Reactant: COCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCC(=O)N(c1c(C)ccc(COC(C)=O)c1C)C(C)C(=O)OC
Reaction time: 7 h

Procedure:
35.0 g of N-(1'-methoxycarbonyl-ethyl)-2,6-dimethyl-3-acetoxymethylaniline and 13.3 g of sodium carbonate were placed into 250 ml of toluene, and 20.0 g of methoxyacetic acid chloride, dissolved in 50 ml of toluene, were slowly added. After the exothermic reaction had subsided, the temperature was held at 45° C. for 7 hours by means of a water-bath. The cooled reaction mixture was filtered, and the filtrate was concentrated in a rotary evaporator. The oily residue was distilled: b.p. 167°-171° C. at 0.07 bar.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:54]=[CH:53][C:13]([CH2:14][N:15]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[CH:24]=[C:25]([CH2:30][N:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[CH:26]=[N:27][C:28]=3[F:29])[CH:17]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>ClCCl>[F:29][C:28]1[C:23]([C:18]2[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([N:15]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)[CH2:14][C:13]3[CH:53]=[CH:54][C:10]([O:9][CH3:8])=[CH:11][CH:12]=3)[CH:17]=2)=[CH:24][C:25]([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([S:63]([CH3:62])(=[O:65])=[O:64])[CH2:33][CH2:32]2)=[CH:26][N:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
2,2,2-Trifluoroacetic acid (0.7 mL, 9.09 mmol) was added dropwise to tert-butyl 4-((5-(6-(bis(4-methoxybenzyl)amino)-2-methylpyrimidin-4-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (64.3 mg, 0.100 mmol) in dichloromethane (1.0 mL) at 25° C., and the resulting solution was stirred at 25° C. for 30 min. The reaction mixture was then concentrated in vacuo, and the residue was taken up in DCM (3.0 mL) and cooled to 0° C. Triethylamine (0.105 mL, 0.750 mmol) was added to the resulting solution, immediately followed by methanesulfonyl chloride (0.015 mL, 0.200 mmol). The resulting mixture was stirred at 0° C. for 20 min and then was concentrated onto silica gel and chromatographically purified (ISCO, 4 g, 0 to100% (10% MeOH-EtOAc)/hexanes) to provide 6-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (54.5 mg, 0.088 mmol, 88% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=9.39 Hz, 1H); 8.14 (s, 1H); 7.17 (d, J=6.85 Hz, 4H); 6.86 (d, J=8.80 Hz, 5H); 4.74 (br. s., 4H); 3.79 (s, 6H); 3.60 (s, 2H); 3.25 (br. s., 4H); 2.78 (s, 3H); 2.62 (s, 3H); 2.58 (br. s., 4H). 19F NMR (377 MHz, CDCl3) 6-70.62 (d, J=8.01 Hz, 1 F). m/z (ESI, +ve ion) 621.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3=[N:17][NH:18][CH:19]=[C:13]3[CH:12]2[CH2:20][OH:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3=[N:17][NH:18][CH:19]=[C:13]3[CH:12]2[CH:20]=[O:21])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1CCc2n[nH]cc2C1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CC1c2c[nH]nc2CCN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Compound 78 (0.50 g, 1.5 mmol) was dissolved in CH2Cl2 (5 mL). NaHCO3 (0.3 g, 3.6 mmol) was added, followed by Dess-Martin periodinane (0.78 g, 1.8 mmol). The reaction stirred at room temperature for two hours and was quenched with sat. NaHCO3 (10 mL) and 10% w/v sodium bisulfite (10 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with CH2Cl2 and the combined organic layers were washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to yield 0.4 g of 79 as a white solid that was used without further purification.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:23][CH:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:23][CH:24]=4)[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CC(N2CCC(CC3CCNCC3)CC2)C1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.3 %

Procedure:
1-Cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) (0.50 g), 1,1-dimethylethyl 5-bromo-2-pyridinecarboxylate (may be prepared as described in Description 12) (0.66 g), BINAP (0.15 g) and Cs2CO3 (1.6 g) were added to toluene (20 ml) under argon and the reaction mixture degassed by sequential freezing in dry ice followed by warming to room temp under vacuum (3×). After stirring for 5 min Pd(OAc)2 (0.05 g) was added and the reaction mixture heated at 80° C. for 20 h. The reaction mixture was filtered and evaporated, after which chromatography (silica gel, eluting with methanol/dichloromethane, 0-20%) afforded the title compound (E3) as a solid (0.23 g). MS electrospray (+ion) 414 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]1.Cl.[CH3:15]O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([O:13][CH3:15])=[O:12])[CH2:10][CH2:9]1
Reactant: O=C(O)C1(c2ccccc2Br)CC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(2-bromophenyl)cyclopropanecarboxylic acid (500 mg, 2.07 mmol) in MeOH (10 mL) was treated with a solution of concentrated aqueous HCl (0.5 mL). The resulting mixture was stirred for 16 hours at room temperature and then heated to reflux and stirred for a further 24 hours. The volatiles were evaporated and the residue was dissolved in EtOAc. The organic layer was washed with saturated solution of NaHCO3, brine and then dried over MgSO4. The solvent was removed in vacuo to give the title compound I4 (400 mg, 76%) as an orange oil; 1H NMR (400 MHz, CDCl3) δ 7.60-7.54 (m, 1H), 7.32-7.24 (m, 2H), 7.15 (m, 1H), 3.63 (s, 3H), 1.75 (d, J=3.1 Hz, 2H), 1.21 (q, J=4.0 Hz, 2H).
Reaction SMILES: Cl[Si:2](Cl)([CH3:4])[CH3:3].[C:6]([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:20]2[C:21]([OH:34])=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)[C:11]=1[OH:35])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>>[C:16]([C:14]1[CH:15]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:11]2[O:35][Si:2]([CH3:4])([CH3:3])[O:34][C:21]3[C:22]([C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:23][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:25][C:20]=3[C:12]=2[CH:13]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: C[Si](C)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[Si](C)(C)Oc1c-2cc(C(C)(C)C)cc1C(C)(C)C
Yield: 46.8 %

Procedure:
Utilizing procedure of Example 1, this compound is prepared from 25.8 grams (0.20 mole) dichlorodimethylsilane, 82.1 grams (0.20 mole) 3,3',5,5'-tetra-tert-butyl-biphenyl-2,2'-diol and 40.5 grams (0.40 mole) of triethylamine. Recrystallization from 2-butanone gives 43.7 grams (47%) of a white powder, mp 170°-176° C.
Reaction SMILES: II.[CH2:3]1[O:14][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)[O:5][CH2:4]1.CO[CH:17]=[C:18]=[CH2:19].[Cl-]>C1COCC1.[Cu]Cl>[CH2:3]1[O:14][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:19][C:18]#[CH:17])[CH:8]=2)[O:5][CH2:4]1
Reactant: C=C=COC
Reactant: Brc1cccc(C2OCCO2)c1
Agent: Cl[Cu]
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: C#CCc1cccc(C2OCCO2)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Dry Mg (0.74 g) under dry N2 in a flask is covered with THF (10 ml) and a crystal of I2 added. 5 ml of a solution of 3-bromobenzaldehyde ethylene acetal (7.0 g) in THF (30 ml) is added and kept until it becomes warm, when it is cooled to 15°, and the remainder of the acetal solution added over 15 minutes, then stirred for an additional 1 hour. A mixture of methoxyallene (2.45 g), copper (1)chloride (0.30 g) and THF (30 ml) is cooled to -20°. The above Grignard solution (under moisture excluding conditions) is then added to this solution during 5 minutes, and allowed to warm to 20° C. with stirring over 30 minutes. Saturated aqueous ammnium chloride is added and the product is extracted with ether. The ether layer is washed with water, dried (MgSO4) and the residue distilled in vacuo. Yield 4.3 g (75%) 89°-96° (0.03 m Hg), nD20 1.5422.
Reaction SMILES: [C:1]1(S(OCC#C)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([OH:20])C=C[CH:17]=[CH:16][CH:15]=1.C1C(O)=CC=CC=1C>>[CH2:14]([O:20][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:15][C:16]#[CH:17]
Reactant: Oc1ccccc1
Reactant: C#CCOS(=O)(=O)c1ccccc1
Solvent: Cc1cccc(O)c1
Product: C#CCCOc1ccccc1

Procedure:
The procedure for Example 614 was used, substituting 3-butynyl p-toluenesulfonate for propargyl benzenesulfonate and phenol for m-cresol to provide Example 633. 1H NMR (500 MHz, CDCl3) δ 2.02 (t, J=2 Hz, 1H), 2.68 (dt, J=8, 2 Hz, 2H), 4.08 (t, J=8 Hz, 2H), 6.96 (m, 3H), 7.30 (m, 2H).