Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]Br.[C:4]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>ClCCl.O1CCCC1.CCCCC.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[CH2:2]=[C:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: BrCBr
Reactant: O=C1CCCCCCCCCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=C1CCCCCCCCCCCC1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a stirred mixture of 3 g of zinc dust, 50 ml of anhydrous tetrahydrofuran and 2.66 g of dibromomethane, was added dropwise a solution of 2.13 g of anhydrous titanium tetrachloride in 5 ml of dichloromethane. After 15 minutes, to the resulting solution was added dropwise a solution of 2 g of cyclotridecanone in 8 ml of anhydrous tetrahydrofuran. The mixture was allowed to react at room temperature for 12 hours. The reaction mixture was diluted with 50 ml of pentane, admixed with 100 ml of 1-M hydrochloric acid, and intermixed by shaking. The organic layer was washed successively with water, dilute aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, then dried, and concentrated to yield methylenecyclotridecane. To a solution of this substance in 40 ml of anhydrous dichloromethane, after having been cooled to -15° C., was added dropwise with stirring a solution of 2.64 g of m-chloroperbenzoic acid in 40 ml of anhydrous dichloromethane. After 3 hours of reaction, the organic layer was washed successively with 10-% sodium sulfite solution, 7-% sodium hydrogencarbonate solution, and saturated sodium chloride solution, then dried and concentrated under reduced pressure. The residue was purified by the silica gel chromatography [developed with a petroleum ether-ethyl acetate (20:1) mixture] to yield 2.04 g (95% yield based on the ketone compound) of an epoxide. To a solution of the epoxide in anhydrous dichloromethane, after having been cooled to -18° C., was added dropwise a borontrifluoride-ether complex. After completion of the addition, water was added to the reaction mixture. The organic layer was separated, then concentrated, and purified by the silica gel chromatography to yield oily cyclotridecanecarbaldehyde in a yield of 60-70%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:12](OCC)[O:13]CC)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Na+]>Cl>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCOC(COC1CCN(C(C)=O)CC1)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CC(=O)N1CCC(OCCO)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
N-Acetyl-4-(2,2-diethoxyethoxy)piperidine (12 g.) in 0.5 N hydrochloric acid (50 ml.) was stirred at room temperature overnight. The solution was saturated with sodium chloride and extracted several times with chloroform (total 500 mls.). The chloroform extract was dried (Na2SO4) and the solvent evaporated in vacuo and with a bath temperature below 30° C. The resultant intermediate aldehyde (9.8 g.) was reduced immediately with sodium borohydride (0.75 g.) in ethanol (75 ml.), at pH 6. After stirring for 3 hours at room temperature reduction was complete. Water was then added to the stirred solution and the organic solvent evaporated in vacuo. The residue was taken up in water (30 ml.), extracted with chloroform (10×30 ml.), the combined chloroform extracts dried (Na2SO4) and the solvent evaporated in vacuo. The residue was taken up in water (70 ml.) and washed with petroleum ether (2×10 ml.). The aqueous phase was concentrated to give N-acetyl-4-(2-hydroxyethoxy)piperidine (6.9 g.) characterized spectroscopically. A sample was distilled and had a b.p. of 139°-140° C./0.3 mm.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N>[N+:18]([C:17]1[C:12]2[N:11]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:2][O:21][C:13]=2[CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c1N=C(c1ccccc1)CO2
Reaction time: 3 h
Yield: 100.8 %

Procedure:
The 2-bromoacetophenone (3.9 g, 19 mmol) [Aldrich, cat. #115835] was added portion wise to a stirred suspension of 2-amino-3-nitrophenol (2.5 g, 16 mmol) [Aldrich, cat. #297003] and K2CO3 (3.4 g, 24 mmol) in MeCN (100 mL) at room temperature. The reaction was monitored by LC/MS. After stirring for 3 h the reaction was complete and then EtOAc added and solution filtered to remove the solids and the organic layer was washed with water, 1 N HCl, brine, dried over MgSO4, filtered and concentrated to give 5-nitro-3-phenyl-2H-1,4-benzoxazine as a dark oil (4.1 g, 100%). LCMS calc. for C14H11N2O3 (M+H)+: m/z=255.3. found: 255.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[C:7]([N+:11]([O-])=O)[CH:8]=[CH:9][CH:10]=1)[OH:6].[H][H]>[Ni].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[OH:6]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1O
Temperature: 80 °C

Procedure:
One-tenth mol of methyl-m-nitrosalicylate is dissolved in 250 ml. of ethyl acetate and 10 gms. of Raney nickel added. The mixture is placed in a suitable container to permit pressure hydrogenation and hydrogen gas is passed into the solution. When the gas pressure reaches 10 pounds psi. at 80° C., the mixture is agitated and when the absorption of hydrogen has reached equilibrium, it is shaken for four hours and cooled. The mixture is filtered and the formed methyl-m-aminosalicylat is isolated by distillation and is obtained as an oily compound which distills at 126° C. at 2 mm. Hg. pressure.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][CH2:27][CH3:28])[C:21]([OH:23])=O)[N:19]=1.[NH2:29][CH:30]1[C:50](=[O:51])[N:32]2[C:33]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=[O:38])=[CH:34][CH2:35][S:36][C@H:31]12.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>O1CCCC1.CC(C)=O.O.CN(C)C=O>[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][CH2:27][CH3:28])[C:21]([NH:29][CH:30]2[C:50](=[O:51])[N:32]3[C:33]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=4)=[O:38])=[CH:34][CH2:35][S:36][C@H:31]23)=[O:23])[N:19]=1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CCCON=C(C(=O)O)c1csc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
Phosphoryl chloride (4.6 g.), trimethylsilylacetamide (0.95 g.) and N,N-dimethylformamide (1.2 g.) were added to a stirred suspension of 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetic acid (syn isomer, 2.8 g.) in tetrahydrofuran (25 ml.) below 5° C., and stirred for 20 minutes. The solution was dropwise added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (3.9 g.) in a mixture of tetrahydrofuran (20 ml.), water (20 ml.) and acetone (20 ml.) at -5° to 5° C. while keeping the pH value at 6.9 to 7.1 with 20% aqueous solution of sodium carbonate. The solution was stirred at -5° to 5° C. for 30 minutes and further at 10° C. for an hour, and adjusted to pH 7.5. After tetrahydrofuran (100 ml.) and a saturated aqueous solution of sodium chloride (200 ml.) were added to the resultant solution, the insoluble substance was filtered out. The organic layer was separated from the filtrate, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was triturated with diisopropyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-propoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 5.8 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](O)=[O:22])[CH:14]=1.P(Cl)(Cl)(Cl)=O.CO>N1C=CC=CC=1.O>[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](=[O:22])[NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:14]=1
Reactant: COC(=O)c1cccc(OCC(=O)O)c1
Reactant: N#Cc1cccc(N)c1
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cccc(OCC(=O)Nc2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.3 %

Procedure:
Cool a solution of 3-aminobenzonitrile (0.35 g, 2.96 mmol) in pyridine (6 mL), to 0° C., and add 3-carboxymethoxy-benzoic acid methyl ester (0.75 g, 3.57 mmol) followed by phosphorous oxychloride (0.34 mL, 3.6 mmol). Warm the mixture to room temperature and stir for 15 hours. Dilute the mixture with water causing a material to oil out of solution. Add MeOH and stir the mixture vigorously causing a solid to slowly form. Collect the solid by filtration, wash with water and dry on the filter pad to provide 0.940 g of 3-[(3-cyano-phenylcarbamoyl)-methoxy]-benzoic acid methyl ester.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH:18]=O)[N:13]=2)[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[C:1]([NH:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[N:10][CH:11]=[C:12]([N:13]=2)[CH2:18][NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[N:8]=1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)Nc1nc2ncc(C=O)nc2c(=O)[nH]1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)C(=O)Nc1nc2ncc(CNc3ccc(C(=O)O)cc3)nc2c(=O)[nH]1
Reaction time: 0.17 h

Procedure:
N2-iBu-6-formylpterin (25) 4.0 gm, 15 mmole) was suspended in MeOH. To this suspension was added 4-aminobenzoic acid (2.1 g, 15 mmole) followed by stirring for 10 minutes. The reaction mixture was then cooled in an ice bath with continuous stirring. A solution of pyridinium para-toluene sulfonate (PPTS, 1 M in MeOH, 15 ml, 15 mmol) was added in one portion, followed by the addition of pyridine-borane complex (1.9 ml of 8M solution, 15 mmol) dropwise over a period of 10 minutes. The ice bath was removed, and stirring was continued at room temperature for 3 hours. The fine precipitated product was collected by centrifugation and washed with a 1:1 mixture of hexanes—MeOH several times, and finally with MeOH. The product was dried in vacuum over P2O5 for 24 hours to give light cream-colored powder, yield=5.3 gm, 91%. 1H NMR (DMSO): δ8.87 (s, 1H), 4.62 (s, 2H), 2.75-2.82 (m, 1H), 1.13, 1.16 (2 s, 6H); MS, m/z, M−H+=383 for C18H18N6O4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14]O)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:14][CH:13]([N:12]1[C:11]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 9 %

Procedure:
The solution of 0.2 g (0.51 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 3 mL dichloromethane was cooled to 0° C. and 134 mg (0.51 mmol) triphenylphosphine and 170 mg (0.51 mmol) carbon tetrabromide were added. The reaction was stirred for 48 h at rt. and then evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) to give the desired compound as white solid (9%). MS (Turbo Spray): m/z=453.0 [M+H].
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=CN(C)C)=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH2:14]([N:19]=[C:20]=[O:21])[CH2:15][CH2:16][CH2:17][CH3:18]>C(Cl)Cl>[NH2:9][C:3]1[C:2]([F:1])=[CH:7][N:6]([C:20]([NH:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:21])[C:5](=[O:8])[N:4]=1
Reactant: CCCCCN=C=O
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: ClCCl
Product: CCCCCNC(=O)n1cc(F)c(N)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.7 %

Procedure:
To a suspension of N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (0.25 g, 1.35 mmol) in CH2Cl2 (5 mL) was added pentyl isocyanate (0.194 mL, 1.49 mmol) forming a solution that was stirred at room temperature for 3 h. The solvent was removed to give a solid residue that was purified by reverse phase chromatography (gradient, CH3CN/H2O) to yield 4-amino-5-fluoro-2-oxo-N-pentylpyrimidine-1(2H)-carboxamide (0.022 g, 6%) as a white solid: mp 289-292° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.27 (t, J=5.49 Hz, 1H), 8.43 (s, 1H), 8.32 (d, J=7.58 Hz, 1H), 8.19 (s, 1H), 3.24 (q, J=6.99 Hz, 2H), 1.51-1.46 (m, 2H), 1.3-1.21 (m, 4H), 0.85 (t, J=6.59 Hz, 3H); ESIMS m/z 241.2 ([M−H]−).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C:9](=[O:11])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:26]([O:29][CH2:30][CH3:31])(=[O:28])C.C(Cl)(Cl)Cl>O1CCOC1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C:9](=[O:11])[CH2:8][C@@H:7]1[CH:26]1[O:29][CH2:30][CH2:31][O:28]1)(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)OC[C@@H]1C=CC(=O)O1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: C1COCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1OC(=O)C[C@@H]1C1OCCO1
Yield: 92 %

Procedure:
A solution containing 1.20 g (7.69 mmol) of compound (2c) and 107 mg (0.587 mmol) benzophenone in 230 mL [1,3]-dioxolane was irradiated at 0° C. for 8.5 hours according to the general procedure. Column chromatography (silica gel 120 g, ethyl acetate in hexanes 50%) gave compound (3c) (1.63 mg. 92%) as a colorless solid, Rf=0.32, [α]25D 36.2°, c 1.3, CHCl3, IR (neat) 1780, 1745, 1216, 759 cm−1; 1H-NMR (500 MHz, CDCl3) δ: 2.08 (s, 3H), 2.52 (dd, 1H, J=10.4 Hz, J=21.7 Hz), 2.61-2.66 (m, 2H), 3.84-3.88 (m, 2H), 3.94-3.98 (m, 2H), 4.09 (dd, 1H, J=5.0 Hz, J=12.3 Hz), 4.32 (dd, 1H, J=2.9 Hz, J=12.3 Hz), 4.62 (mc, 1H), 4.87 (d, 1H, J=3.6 Hz). 13C-NMR (125.8 MHz, CDCl3, Dept) δ: 21.11 (+), 30.16 (−), 40.45 (+), 65.65 (−), 65.78 (−), 65.91 (−), 77.82 (+), 103.54 (+), 170.91 (quat), 175.88 (quat). C10H14O6; Exact Mass: 230.08; Mol. Wt.: 230.21; C, 52.17; H, 6.13; O, 41.70.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[CH3:9][CH:10]([CH3:14])[CH2:11][CH2:12][Zn]>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:12][CH2:11][CH:10]([CH3:14])[CH3:9]
Reactant: Brc1ccccc1I
Reactant: CC(C)CC[Zn]
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: CC(C)CCc1ccccc1Br
Reaction time: 0.03 h
Yield: 78.1 %

Procedure:
Charge a Schlenck flask with palladium dibenzylidene acetone (88 mg, 0.16 mmol) and tri-o-furyl phosphine (72 mg, 0.31 mmol), purge with nitrogen and add 2 ml of dry THF. Stir for 2 minutes, until the deep purple solution turns to greenish yellow and add 1-iodo-2-bromo benzene (0.8 ml. 6.2 mmol) followed by 3-methyl-butyl zinc (0.5 M solution in THF, 30 ml, 15 mmol). React at rt for 4 hours. Add silica gel, concentrate, load onto a flash chromatography column and elute with hexane to obtain the title compound as a colorless liquid (1.1 g, 75%).
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[N:57]=[C:56]([CH2:58][CH2:59][C:60]4[C:65]([CH2:66][C:67]([O-])=[O:68])=[CH:64][CH:63]=[CH:62][N:61]=4)[C:55]([C:70]([F:73])([F:72])[F:71])=[CH:54][N:53]=3)=[CH:47][CH:46]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[Li+].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:2][C:67](=[O:68])[CH2:66][C:65]1[C:60]([CH2:59][CH2:58][C:56]2[C:55]([C:70]([F:72])([F:73])[F:71])=[CH:54][N:53]=[C:52]([NH:51][C:48]3[CH:47]=[CH:46][C:45]([CH:42]4[CH2:41][CH2:40][N:39]([C:37]([O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:38])[CH2:44][CH2:43]4)=[CH:50][CH:49]=3)[N:57]=2)=[N:61][CH:62]=[CH:63][CH:64]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(=O)[O-])n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Hydroxybenzotriazole (20.4 mg, 0.151 mmol), EDCl (29.0 mg, 0.151 mmol) and N,N-diisopropylethylamine (0.192 mL, 1.10 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetate (I123) (81.3 mg, 0.137 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. Ammonium carbonate (106 mg, 1.10 mmol) was added in one portion to the stirred reaction mixture after 10 minutes. The reaction was left to stir at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed in vacuo to afford a pale yellow oil. The crude material was purified by column chromatography on silica gel (0-100% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I124) (66.3 mg, 83%) as a white semi-solid; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=0.4 Hz, 1H), 8.49 (dd, J=4.8, 1.7 Hz, 1H), 7.62 (s, 1H), 7.54 (dd, J=7.7, 1.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.19-7.13 (m, 3H), 5.40-5.35 (m, 2H), 4.23 (s, 2H), 3.68 (s, 2H), 3.41-3.35 (m, 2H), 3.32-3.24 (m, 2H), 2.80 (t, J=12.6 Hz, 2H), 2.63 (tt, J=12.0, 3.4 Hz, 1H), 1.81 (d, J=12.5 Hz, 2H), 1.65-1.57 (m, peaks obscured by solvent), 1.48 (s, 9H). LCMS Method C: rt 5.25 min; m/z 607 [M+Na]+, 585 [M+H]+, 529 [M-tButyl+2H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([OH:15])[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5]1.I[CH2:23][CH2:24][CH3:25]>CCOCC>[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:23][CH2:24][CH3:25])[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5]1
Reactant: Cn1nc(-c2ccccc2)c(O)c1-c1ccccc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (57%, 0.92 g, 0.022 mole) is added slowly to a suspension of 1-methyl-3,5-diphenyl-4-pyrazolol (5 g, 0.02 mole) in anhydrous ether (100 ml). An off-white precipitate forms. After stirring for 45 minutes, the solid is removed by filtration, added to dry DMF (30 ml) and treated with 1-iodopropane (5 ml, 0.05 mole). The reaction mixture is stirred, heated at 60° C. for 14 hours and then poured into ice water (600 ml). After standing for 24 hours in the refrigerator, a tacky yellow solid is formed. Recrystallization from hexane at -20° C. affords an off-white solid, melting point 56°-57° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)=O)=[CH:4][CH:3]=1.[NH2:38][NH2:39].O>CCO.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:39][N:38]=[C:11]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=3)[CH:10]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Cc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Fc1ccc(Cc2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a mixture of 4-(4-fluorophenyl)-1-(1-trityl-1H-imidazol-4-yl)butane-1,3-dione (80 g, 0.165 mol) and anhydrous EtOH/AcOH (400 mL/100 mL) was added NH2NH2.H2O (80 mL, 0.96 mol) dropwise at 0° C. After the addition, the mixture was stirred at RT overnight. The solvent mixture was evaporated, the residue washed with anhydrous Et2O (4×250 mL) and the resulting precipitate was dried in oven to yield the title compound (58.8 g, 73.0%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[Na+:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[Na+:17]
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C([O-])c1ccc(Cl)cc1
Yield: 94.7 %

Procedure:
The procedure of Example 1 was followed using methyl 4-chlorobenzoate (4.55 g, 26.6 mmol), sodium trimethylsilanolate (2.99 g, 26.6 mmol), dry toluene (150 mL), and 4 h of heating at 80°. Sodium 4-chlorobenzoate (4.50 g, 86% yield) was isolated as a white solid: 1H NMR (D2O, DSS, 80 MHz) δ 7.65 ppm (ABq, Δν1-3 =29 Hz, J=8 Hz, Ar--H's, 4H).
Reaction SMILES: [F:1][CH2:2][C@@H:3]([NH:9]C(OCC1C=CC=CC=1)=O)[CH2:4][CH2:5][C:6]([NH2:8])=[O:7].[ClH:20].[H][H]>CO.[Pd]>[ClH:20].[F:1][CH2:2][C@@H:3]([NH2:9])[CH2:4][CH2:5][C:6]([NH2:8])=[O:7]
Reactant: [H][H]
Reactant: NC(=O)CC[C@@H](CF)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)CC[C@H](N)CF

Procedure:
0.46 g of 21 was hydrogenated in a Parr bottle, in methanol containing a small amount of concentrated hydrochloric acid and 10% palladium-on-carbon catalyst, at 32 p.s.i.g. hydrogen pressure for 6 hours at room temperature. The resulting mixture was filtered and the filtrate was stripped of solvent. The residue was triturated with ethyl acetate and the mixture was filtered to give 22, as a brownish solid, m.p.; 165°-175° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][O:30][CH:31]([C:33]1[NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]=1)[CH3:32]>>[CH3:29][O:30][C@H:31]([C:33]1[N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: COC(C)c1nc2ccccc2[nH]1
Product: CO[C@@H](C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Yield: 15.9 %

Procedure:
2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.15 g) was reacted with 2-(1-methoxyethyl)-1H-benzo[d]imidazole (97 mg) via General Procedure I for Buchwald coupling to give 32.1 mg of 516 [MS (Q1) 549.4 (M)+] and 32.4 mg of 519 [MS (Q1) 549.3 (M)+] following reverse phase purification and subsequent chiral separation.