Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2([CH3:14])[CH3:13])=[CH:5][C:4]=1[CH3:15].C(O)(=[O:18])C>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][C:4]=1[CH3:15])[C:7](=[O:18])[CH2:8][CH2:9][C:10]2([CH3:13])[CH3:14]
Reactant: COc1cc2c(cc1C)CCCC2(C)C
Reactant: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1C)C(=O)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 7-methoxy-1,1,6-trimethyl-1,2,3,4-tetrahydronaphthalene (Compound 29, 14.7 g, 72.1 mmol) and 30 mL of glacial acetic acid at 0° C. was added a cold solution of CrO3 (14.5 g, 144.2 mmol) in 30 mL of glacial acetic acid and 15 mL of water. The resulting dark solution was stirred at 0° C. for 1 h, then quenched with NaOH 2N, extracted with diethyl ether, washed with brine, dried over MgSO4, and filtered. The solvent was removed to give 11.3 g (72%) of the title compound as a dark brown solid. PNMR (300 MHz, CDCl3) δ 1.38 (s, 6H), 1.98 (t, 2H, J=7.5 Hz), 2.10 (s, 3H), 2.68 (t, 2H, J=7.5 Hz), 3.90 (s, 3H), 6.76 (s, 1H), 7.83 (d, 1H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Sn](CCCC)(CCCC)CCCC)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].Br[C:31]1[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:47]([N:44]1[CH2:43][CH2:42][N:41]([C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[C:31]([C:14]3[CH:13]=[CH:12][C:11]([C@H:8]4[CH2:7][CH2:6][C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)[N:32]=2)[CH2:46][CH2:45]1)[CH3:48]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1[C@H]1CC[C@@H](OC(C)=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc([C@H]4CC[C@@H](OC(C)=O)CC4)cc3)cc3ccccc23)CC1

Procedure:
cis-4-(Tributylstannylphenyl)cyclohexyl acetate (1.37 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.11 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.16 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.24 g) of 1-(4-ethylpiperazin-1-yl)-3-[4-(cis-4-acetoxycyclohexyl)phenyl]isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])[N:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[H-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:10][C:9]1([CH3:12])[O:11][CH2:2][C:3]2=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[N:6][N:7]2[CH2:8]1
Reactant: CC(C)(O)Cn1nc([N+](=O)[O-])cc1CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC1(C)Cn2nc([N+](=O)[O-])cc2CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
To a solution of 330e (1.1 g, 5.1 mmol) in DMF (10 mL), was added NaH (60 percent dispersion in mineral oil, 246 mg, 6.14 mmol) at 0° C. The resulting suspension was stirred for 30 min, followed by the addition of p-toluenesulfonyl chloride (1169 mg, 6.14 mmol). The mixture was stirred at 60° C. overnight. After cooling to room temperature, saturated ammonium chloride solution was added and the mixture was extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate gradient (9:1 to 2:1) to afford 330f (228 mg, 22%). MS-ESI: [M+H]+ 198.3
Reaction SMILES: [N:1]1([C:5](=[O:7])[CH3:6])[CH:4]=[CH:3][CH2:2]1.[CH:8](=[N:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC1C=CC=CC=1N>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[N:15]=[C:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([CH2:2][NH:1][C:5](=[O:7])[CH3:6])=[CH:4]2
Reactant: Fc1ccccc1/N=C/c1ccccc1
Reactant: CC(=O)N1C=CC1
Agent: Nc1ccccc1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: CC#N
Product: CC(=O)NCc1cc2cccc(F)c2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 1-(azet-1(2H)-yl)ethanone (22 mg, 227 μmol, eq), (E)-N-benzylidene-2-fluorobenzenamine (45 mg, 227 μmol, 1 eq), 2-fluorobenzenamine (22 μl, 227 μmol, 1 eq), and yttrium trifluoromethanesulfonate (6 mg, 11 μmol, 0.05 eq) in 9 mL of acetonitrile. The reaction was stirred at rt overnight. The reaction was heated to 90° C. for 5 h. The reaction was cooled to rt and the solvent was removed under vacuum. The residue was dissolved in 20 mL of DCM and washed with 1×5 mL of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Purification by column chromatography (7:3 hexanes:ethyl acetate) afforded N-((8-fluoro-2-phenylquinolin-3-yl)methyl)acetamide. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (s, 1H), 7.60 (d, J=7.83, 1H), 7.50 (m, 2H), 7.45 (m, 4H), 7.37 (ddd, J=10.6, 7.8, 1.6 Hz, 1H), 5.92 (br t, J=5.9 Hz, 1H), 4.55 (d, J=6.3 Hz, 2H), 1.96 (s, 3H). Mass Spectrum (ESI) m/e=295.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[C:20]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([O:10][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)[C@H](CC(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (2.08 g, 11.9 mmol) in dry dichloromethane (20 ml) was treated with triethylamine (1.83 ml, 13.1 mmol) followed by a solution of t-butylchlorodiphenylsilane (3.44 g, 12.5 mmol) in dichloromethane (5 ml) added dropwise over 5 minutes. After 3 hours at 22° C., the reaction mixture was diluted with toluene (250 ml) washed with water, saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (4×12 cm) using a mixture of toluene and ethyl acetate (0-2%) as eluent gave 4.90 g (99% yield) of the title material as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.13 (s, 9), 1.58 (s, 3), 3.05 (m, 2), 4.79 (dd, 1, J=4, 7), 7.4-7.8 (m, 10).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([CH3:24])([CH3:23])[C:21]#[N:22]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[NH:22])[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])([CH3:24])[CH3:23])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C#N)c1ccccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C(=N)Nc1ccc(Br)cc1)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To an oven dried, N2 purged 250 mL round bottom flask attached with addition funnel was added 4-bromoaniline (7.31 g, 42.5 mmol) and anhydrous toluene (40 mL). To the reaction solution at 0° C. was added a 2.0 M Me3Al (32 mL, 1.5 molar equiv) solution. The reaction solution was stirred at 0° C. for 30 min, then a solution of 2-(2-fluorophenyl)-2-methylpropanenitrile (7.62 g, 46.7 mmol) in toluene (25 mL) was added to the reaction flask. The reaction solution was allowed to stir at 90° C. for 5 hr. The cooled reaction solution was quenched with an aq sodium potassium tartrate solution. After standing 20 min, the organic phase was partitioned and washed with sodium potassium tartrate solution. The organic solution was extracted with 1N aq HCl (100 mL×3). The combined aq HCl solution was neutralized by addition of 1N aq NaOH and extracted with dichloromethane (200 mL×2). The dichloromethane product solution was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (5.5 g, 39% yield). GCMS m/z=334, 336 [M]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[N:12]=[CH:11][C:10]([C:14]3[CH:15]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:17]=[N:18][CH:19]=3)=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:37][C:38]1([F:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[F:37][C:38]1([F:44])[CH2:43][CH2:42][N:41]([C:21](=[O:22])[CH2:20][C:16]2[CH:15]=[C:14]([C:10]3[CH:9]=[C:8]4[C:13](=[N:12][CH:11]=3)[N:4]([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6][CH2:7]4)[CH:19]=[N:18][CH:17]=2)[CH2:40][CH2:39]1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(CC(=O)O)c3)cnc21
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cncc(CC(=O)N4CCC(F)(F)CC4)c3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
To a suspension of [5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-acetic acid (25 mg, 0.080 mmol) in DMF (1.5 mL) is added 1,1′-carbonyldiimidazole (14 mg, 0.088 mmol) and the mixture is stirred at room temperature for 16 h. 4,4-Difluoro-piperidine hydrochloride salt (15 mg, 0.096 mmol) and N,N-diisopropylethylamine (0.042 mL, 0.24 mmol) are added and stifling continues for an additional 16 h. H2O is added and the resulting precipitate is collected by filtration to afford 21 mg of the titled product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C>S(Cl)(Cl)=O>[CH3:15][O:14][N:13]([CH3:12])[C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:7]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A suspension of 6-chloronicotinic acid (80 g, 0.5 mol) in thionyl chloride (400 ml) was heated under reflux for 3 hours to give a yellow solution. The mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane (600 ml) and treated with N,O-dimethylhydroxylamine hydrochloride (56.5 g, 0.58 mol). The suspension was cooled in ice then treated dropwise with triethylamine (220ml, 1.5 mol) and stirred for 1 hour at room temperature. The mixture was filtered, the filtrate was washed with aqueous sodium hydroxide (2N, 200 ml), dried over magnesium sulphate then concentrated under reduced pressure. The resulting liquid was distilled under reduced pressure to yield the title compound (90 g), b.p. 106-110° C. (0.5 mm Hg), which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]#[C:22][CH3:23])[N:16]=[CH:15][N:14]=1.[Cl-].[NH4+]>O1CCCC1>[F:3][C:4]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]#[C:22][CH3:23])[N:16]=[CH:15][N:14]=1
Reactant: Nc1cccc(F)c1F
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Nc2cccc(F)c2F)ncn1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.33 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.42 g of 2,3-difluoroaniline were slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 1 ml of a tetrahydrofuran solution containing 0.5 g of 4-chloro-6-(2-butynyloxy)pyrimidine was slowly added dropwise, followed by stirring at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.25 g of 4-(N-(2,3-difluorophenyl)amino)-6-(2-butynyloxy)pyrimidine (the present compound (73)), m.p.: 147.6° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C:41]([CH3:46])([CH3:45])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[Na+]>O1CCCC1>[CH3:46][C:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:45])[C:42]([NH:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:43]
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the tetrahydrofuran solution of (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide were sequentially added 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (20.4 g), 1-hydroxybenzotriazole (15.3 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.2 g) under cooling on ice, and the mixture was stirred at room temperature for two hours. Saturated aqueous sodium chloride solution was added to the resultant mixture, and the organic layer was separated, whereby a solution of the title compound in tetrahydrofuran was yielded.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=1.[CH:32](OCC)=[O:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][CH:32]=[O:33])[N:20]=[C:15]2[CH:14]=1
Reactant: CCOC=O
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CN)cnc3n1COCC[Si](C)(C)C)cn2C
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC=O)cnc3n1COCC[Si](C)(C)C)cn2C
Yield: 97.6 %

Procedure:
(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (0.095 g, 0.22 mmol, Example #20, Step G) in ethyl formate (4.4 mL, 54.0 mmol) was heated at about 60° C. in an oil bath for about 45 min. The mixture was cooled and evaporated to give N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide (0.10 g, 100%): LC/MS (Table 2, Method a) Rt=2.65 min; MS m/z: 466 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]1.[F:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@H:13]([O:14][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2F)C1
Reactant: Oc1ccc(F)cc1
Product: CN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2F)C1

Procedure:
The procedure of Example 53 is repeated with cis-3-(2-fluorophenyl)-1-methyl-4-piperidinol and 4-fluorophenol to yield trans-3-(2-fluorophenyl)-4-(4-fluorophenoxy)-1-methylpiperidine. This compound is treated with a solution of fumaric acid in ether containing ethanol to yield trans-4-(4-fluorophenoxy)-3-(2-fluorophenyl)-1-methylpiperidine fumarate, m.p. 205.5°-206.5° C. The crude salt is recrystallized from isopropanol to afford colorless crystals, m.p. 205.5-106.5.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18](/[N:20]=[CH:21]\[N:22](C)C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1>CCO.CO>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][N:22]=[CH:21][N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)/C=N\C(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Solvent: CO
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1N2C[C@@H](CC[C@H]2c2ncno2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
(2S,5R,Z)-6-(benzyloxy)-N-((dimethylamino)methylene)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide (1.33 g, 4.03 mmol) in EtOH (22 mL) was treated with pyridine (0.64 ml, 8.06 mmol), followed by the addition of a solution of HOSA (547 mg, 4.84 mmol) in MeOH (4.5 mL). The resulting mixture was stirred at rt for 30 minutes and then concentrated under vacuum. The residue was dissolved in DCM/THF (1:2, 30 mL) and washed with water (10 mL). The organic layer was dried overNa2SO4, and concentrated. The residue was re-dissolved in EtOH (22 mL) and 2N HCl (8.0 mL). The mixture was heated at reflux for 20 minutes, concentrated and extracted with DCM (2×). The crude material was purified by prep-HPLC to give (2S,5R)-6-(benzyloxy)-2-(1,2,4-oxadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (50 mg, 4.1%) as a light yellow oil. ESI-MS (EI+, 301, m/z): [M+H]+. 1H-NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.45-7.35 (m, 5H), 5.09 (d, J=11.5 Hz, 1H), 4.94 (d, J=11.5 Hz, 1H), 4.85 (d, J=8.0 Hz, 1H), 3.36 (m, 1H), 3.01 (d, J=12.0 Hz, 1H), 2.81 (d, J=12.0 Hz, 1H), 2.37-2.35 (m, 1H), 2.25-2.21 (m, 1H), 2.01-2.00 (m, 1H), 1.85-1.84 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10]C1CCCCO1.[I-].C([NH3+])CCC.[Cl:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:32]1[NH:37][C:36](=[O:38])[C:35]2=[C:39]([CH:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH:40]=[C:41]([CH3:42])[N:34]2[N:33]=1>C(OCC)(=O)C.CN(C)C=O>[Cl:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:32]1[N:37]([CH2:8][CH2:9][OH:10])[C:36](=[O:38])[C:35]2=[C:39]([CH:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH:40]=[C:41]([CH3:42])[N:34]2[N:33]=1
Reactant: CCC(CC)c1cc(C)n2nc(-c3ccc(OC)cc3Cl)[nH]c(=O)c12
Reactant: BrCCOC1CCCCO1
Agent: CCCC[NH3+]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)n2nc(-c3ccc(OC)cc3Cl)n(CCO)c(=O)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (60 mg), 2-(2-bromoethoxy)tetrahydro-2H-pyran (175 μL) and n-butylammonium iodide (20 mg) were added to the N,N-dimethylformamide solution (2 mL) of the compound prepared in Example 36 (104 mg). The reaction mixture was stirred at room temperature for 4 hours 10 minutes. Ethyl acetate (50 mL) was added to the reaction mixture. The reaction mixture was washed twice with water and washed once with a saturated aqueous solution of sodium chloride. The reaction mixture was dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. A rough product of the title compound was obtained. The obtained rough product was purified by column chromatography on silica gel (Yamazen corporation, high flash L, n-hexane→ethyl acetate/n-hexane=1/1) to obtain the compound of the present invention (82 mg) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[F:22].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([F:22])=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:20]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Fc1ccc(Cl)cc1Br
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cc(Cl)ccc2F)C1=O
Yield: 69.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84650 mmol) was reacted with 2-bromo-4-chloro-1-fluoro-benzene (177 mg, 0.84650 mmol), 1,4-dioxane (10 mL), copper iodide (16 mg, 0.084650 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium phosphate (538 mg, 2.539 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 180 mg of the product (69.7% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[C:6]2[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=12.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C(OCC)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:6]3[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cn(C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Reactant: Nc1cccc(Cl)c1
Solvent: CCOCC
Product: Cc1cn(C)c2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCOCC3)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 1-(7-chloro-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-morpholin-4-yl-methanone (100 mg) and using 3-chloroaniline (72 ul) instead of 3-bromoaniline. Isolated by MDAP rather than trituration with diethyl ether to give 1-[7-(3-chloro-phenylamino)-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-morpholin-4-yl-methanone (69 mg).
Reaction SMILES: [Br:1]Br.[CH:3]([S:6][C:7]1[CH:11]=[C:10]([Si](C)(C)C)[O:9][C:8]=1[C:16]([NH:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1)=[O:17])([CH3:5])[CH3:4].O>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:1][C:10]1[O:9][C:8]([C:16]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:17])=[C:7]([S:6][CH:3]([CH3:5])[CH3:4])[CH:11]=1
Reactant: CC(C)Sc1cc([Si](C)(C)C)oc1C(=O)Nc1nnn[nH]1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Sc1cc(Br)oc1C(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of 3.1 g (19.5 mmol, 1.6 equiv) of bromine in 7 mL of chloroform is added dropwise to a room temperature solution of 3.98 g (12.22 mmol) of 3-isopropylthio-5-trimethylsilyl-N-1H-tetrazol-5-yl-2-furancarboxamide in 13 mL of chloroform and 20 mL of glacial acetic acid under nitrogen atmosphere. The resulting mixture is stirred at room temperature for 23 hours then poured onto 200 mL of water. The aqueous mixture is extracted with ethyl acetate (3x). The combined extracts are washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo to give a yellow solid. Recrystallization from isopropanol/water gave 1.58 g (4.06 g theo., 38%) of the desired product as a yellow solid; mp 200°-210° C. (dec).