Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[S:45])[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)NCC4)cc2)CCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=S)NCC4)cc2)CCC1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
To a solution of tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (223 mg, 0.47 mmol) in toluene (15 mL) was added lawesson's reagent (192 mg, 0.47 mmol) under nitrogen. The resulting mixture was heated under reflux for 2 h. After cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 1% MeOH in dichloromethane) to give the title compound as a yellow solid (231 mg, quantitative). 1H NMR (500 MHz, MeOD): 8.76 (1H, s), 7.37-7.33 (4H, m), 7.31-7.28 (3H, m), 7.22-7.20 (2H, m), 3.69 (2H, t), 3.25 (2H, t), 2.49-2.39 (4H, m), 2.15-2.05 (1H, m), 1.91-1.80 (1H, m), 1.45-1.15 (9H, br).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:15]([Br:16])=[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:15]([Br:16])=[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: Nc1ccnn1-c1nn2c(c1Br)CCCC2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1c([N+](=O)[O-])cnn1-c1nn2c(c1Br)CCCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.6 g (12.7 mmol) 5-Amino-1-(3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)pyrazole was suspended in 15 ml acetic acid and treated with 1.23 ml (13.0 mmol) acetic anhydride. The mixture was stirred for 5 hours at room temperature. 1.5 ml (15.9 mmol) acetic anhydride was added and then, with ice-bath cooling, 0.66 ml (15.5 mmol) fuming nitric acid was added, dropwise. After stirring for 12 hours at room temperature, the mixture was concentrated. The residue was dissolved in 30 ml ethanol and treated with 11.2 ml concentrated hydrochloric acid. After heating for 3 hours under reflux, the mixture was concentrated and the residue taken up in water and ethyl acetate. It was made basic with 2N aqueous sodium hydroxide and the organic phase separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with water and once with saturated aqueous sodium chloride. The organic phase was dried and concentrated. The residue was recrystallised from ethyl acetate.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[CH2:5]([O:12][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([Cl:3])=[O:31])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)CCCCCCCCCCCCCCC(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCCCCCCCCCC(=O)OCc1ccccc1

Procedure:
One drop of dimethyl formamide and 2.32 ml of thionyl chloride were added to 3.01 g (8 millimoles) of the 1,14-tetradecane dicarboxylic acid monobenzyl ester obtained in Production Example 4. The reaction mixture was heated and allowed to reflux for one hour. Unreacted thionyl chloride was subsequently removed using distillation under reduced pressure to obtain 3.2 g of 1,14-tetradecane dicarboxylic acid monochloride monobenzyl ester in the form of a pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+].C>O.C(O)CO>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: COc1ccc(Nc2ccccc2C(=O)O)cc1
Temperature: 125 °C
Yield: 49.3 %

Procedure:
4-Methoxyaniline (1.86 gm; 20 mmol), 2-chlorobenzoic acid (1.56 gm; 10 mmol), ethylene glycol (5 ml) and anhydrous sodium carbonate (1.1 gm; 10 mmol) were placed in a reaction vessel and stirred until effervescence ceased. Cupric chloride (100 mg; 0.75 mmol) dissolved in 2 ml of water was added to the reaction mixture which was then heated to 125° C. for 6 hours. The reaction was allowed to cool then water (30 ml) and charcoal were added. The mixture was filtered and acidified to pH 2 with conc. hydrochloric acid. The precipitate was collected by filtration, washed with water and then re-dissolved in 1M sodium hydroxide solution. Material was re-precipitated by the addition of acetic acid, filtered off, washed with aqueous acetic acid, then water and finally dried under vacuum over phosphorous pentoxide to give 1200 mg (49%) of N-(4-methoxyphenyl)anthranilic acid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:31].CCOCC>O1CCOCC1>[ClH:31].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2nc3ccccc3s2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1ccc2sc(Cc3ccc(OC[C@H]4CCCN4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 2 (170 mg, 0.4 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. The resulting solid was filtered out and dried in vacuo to yield the title product, (120 mg, 80%); LCMS; 98% ESI+, Calcd: 324.5; Found m/z: 326.1 (M+2); 1H NMR (400 MHz, DMSO-d6); δ 1.66-1.79 (m, 1H), 1.84-2.05 (m, 2H), 2.05-2.16 (m, 1H), 3.15-3.27 (m, 2H), 3.82-3.97 (m, 1H), 4.13-4.16 (m, 1H), 4.24 (dd, J1=10.4 Hz, J2=3.2 Hz, 1H), 4.62 (s, 2H), 6.98 (d, J=8.4, 2H), 7.35 (d, J=8.4, 2H), 7.39 (d, J=7.6, 1H), 7.48 (t, J=7.2, 1H), 7.94 (d, J=8.4, 1H), 8.01 (d, J=8.0, 1H),
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9](O)=[O:10])=[C:6]([N:12]([CH3:14])[CH3:13])[N:5]=[C:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[O:24])=[CH:18][CH:17]=2)[N:3]=1.C(N1C=CN=C1)([N:37]1C=CN=C1)=O.N>C1COCC1>[NH2:37][C:9](=[O:10])[CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[O:24])=[CH:18][CH:17]=2)=[N:5][C:6]=1[N:12]([CH3:14])[CH3:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(Cl)c1CC(=O)O
Agent: N
Solvent: C1CCOC1
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(Cl)c1CC(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetic acid (0.940 g, 1.98 mmol) in THF (18 mL) was added 1,1′-carbonyldiimidazole (0.353 mg, 2.18 mmol). The reaction mixture was stirred at room temperature for 2 hours followed by the addition of aqueous ammonia solution (28% NH3, 0.94 mL). After stirring for 16 hours at room temperature, the reaction mixture was partitioned between EtOAc and water and the separated organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo and the remaining residue was passed through a short pad of silica gel. Removal of acidic impurities via PS-carbonate resin then gave N-(4-{[5-(2-amino-2-oxoethyl)-4-chloro-6-(dimethylamino)pyrimidin-2-yl]methyl}phenyl)-2-naphthamide as a white solid (0.670 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.Br[CH2:36][C:37]1[CH:50]=[CH:49][C:40]([O:41][CH2:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])=[CH:39][CH:38]=1>CN(C=O)C>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][O:41][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][O:12][C:9]2[CH:8]=[CH:7][C:6]([C:4](=[O:5])[C:3]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=3[NH2:1])=[CH:11][CH:10]=2)=[CH:50][CH:49]=1)[CH:47]=[CH2:48]
Reactant: C=CCOC(=O)COc1ccc(CBr)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)COc1ccc(COc2ccc(C(=O)c3cc(Cl)ccc3N)cc2)cc1

Procedure:
A solution was formed by dissolving 2-amino-5-chloro-4'-hydroxybenzophenone (1.72 g, 8.07 mmol) in 40 mL of DMF. Potassium bis(trimethylsilyl)amide that was 0.5M in toluene (16.1 mL, 8.07 mmol, 1.0 equivalents) was added dropwise with stirring. Allyl 2-(4-bromomethylphenoxy)acetate (2.30 g, 8.07 mmol, 1.0 equivalents) was then added and the resulting orange slurry was stirred at ambient temperature for 45 minutes. The slurry was concentrated in vacuo, then diluted with CH2Cl2 (150 mL) and was extracted with 1N aqueous sodium bicarbonate (100 mL) and with 1N aqueous sodium chloride (100 mL), then dried over sodium sulfate and concentrated in vacuo to give the product as a yellow solid which was approximately 95% pure and was taken to the next step without purification. The product had Rf of 0.55 in 50:50:2 ethyl acetate/hexane/triethylamine. The structure was confirmed by proton NMR, carbon-13 NMR, and electron impact mass spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>C(#N)C>[CH3:42][O:43][C:44]1[CH:45]=[CH:46][C:47]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1
Yield: 45 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0315 g, 0.0682 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.409 mmol) and 4-methoxybenzenesulfonyl chloride (0.0420 g, 0.205 mmol) to obtain 4-(4-methoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0194 g, yield 45%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Br[CH2:10][CH2:11]Cl.[H-].[Na+]>CS(C)=O.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:7]#[N:8])[CH2:11][CH2:10]1
Reactant: N#CCc1ccco1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccco2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of furan-2-acetonitrile (28.4 g) and 1-bromo-2-chloroethane (33.1 ml) in dimethyl sulphoxide (50 ml) was added slowly to a stirred suspension of sodium hydride (60% dispersion in mineral oil ; 31.85 g) in dry dimethyl sulphoxide (300 ml) keeping the internal temperature just below 35° C. by occasional cooling. After stirring for 18 hours at ambient temperature the mixture was diluted with water (500 ml) and extracted with ether (1×200 then 2×100 ml). The combined extracts were dried over potassium carbonate and evaporated to an oil which was distilled at reduced pressure to give 1-(2-furyl)cyclopropanecarbonitrile (28.0 g) as a colourless oil, bp 54° C./0.55 mbar.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.I[CH:12]([CH3:14])[CH3:13].C(N(CC)CC)C>CO>[CH:12]([NH:6][C:5]1[CH:7]=[CH:8][C:9]2[O:10][CH2:1][O:2][C:3]=2[CH:4]=1)([CH3:14])[CH3:13]
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CC(C)I
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Nc1ccc2c(c1)OCO2
Yield: 85 %

Procedure:
To a solution of 3,4-(methylenedioxy)aniline (9.0 g), and 2-iodopropane (5.9 ml) in methanol (100 mL) was added triethylamine (8.2 mL). The mixture was refluxed for 50 h, and then concentrated in vacuo. The residue was taken with 1:1 hexane/EtOA (180 mL), washed with water and brine, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by chromatography (3:1 hexane/EtOAc) to yield the title compound as an oil (10.1 g, 85%). 1H NMR (CDCl3): 6.64 (d, J=8.3, 1H), 6.23 (d, J=2.2, 1H), 6.03 (dd, J=2.2, 8.3, 1H), 5.85 (s, 2H), 3.51 (m, 1H), 3.19 (br s, 1H), 1.18 (d, J=6.1, 6H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH2:18][CH2:19][CH3:20])[CH:3]=1.[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[N:10]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]([CH2:18][CH2:19][CH3:20])[CH:3]=1
Reactant: BrC1CCCC1
Reactant: CCCc1cc(I)ccc1N=C1NC2(CCCC2)CS1
Product: CCCc1cc(I)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
4-Iodo-2-n-propylaniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-iodo-2-n-propylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2-n-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2-n-propylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2-n-propylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [NH2:1][C@@:2]([C:8]1[CH:13]=[C:12]([Br:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])([CH3:7])[CH2:3][CH:4](O)[CH3:5].C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1.Cl>C1COCC1>[Br:14][C:12]1[C:11]([F:15])=[CH:10][C:9]([F:16])=[C:8]([C@:2]2([CH3:7])[CH2:3][CH:4]([CH3:5])[S:27][C:26]([NH2:25])=[N:1]2)[CH:13]=1
Reactant: CC(O)C[C@](C)(N)c1cc(Br)c(F)cc1F
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC1C[C@@](C)(c2cc(Br)c(F)cc2F)N=C(N)S1
Temperature: 100 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a 0° C. solution of (4S)-4-amino-4-(5-bromo-2,4-difluorophenyl)pentan-2-ol (1.3 g, 4.4 mmoles) as a mixture of diastereomers in THF (50 mL) is added benzoyl isothiocyanate (1.4 g, 1.2 mmoles) dropwise and the reaction is stirred for 1 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in dioxane (5 mL) and transferred to a thick-walled glass reaction vessel. To the mixture is added 5 N hydrogen chloride (75 mL, 375 mmoles) and the reaction is heated to 100° C. After 36 h, the solvent is removed under reduced pressure and the residue is dissolved in water. The water mixture is extracted with ethyl acetate. The aqueous phase is made basic with 5N NaOH and extracted with 3:1 chloroform:IPA. The chloroform: IPA phase is dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH3:15])=[O:8])[N:6]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH3:15])=[O:8])[N:6]=1
Reactant: CC1CCCCN1C(=O)c1csc(I)n1
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccccc1-c1nc(C(=O)N2CCCCC2C)cs1
Temperature: 78 °C

Procedure:
A mixture of (2-iodo-thiazol-4-yl)-(2-methyl-piperidin-1-yl)-methanone (Step 3; 200 mg, 0.59 mmol), 2-methoxyphenylboronic acid (Combi-Blocks, Inc., San Diego, Calif.; 135 mg, 0.89 mmol), potassium carbonate (201 mg, 1.45 mmol), and PdCl2dppf (Strem Chemicals, Inc., Newburyport, Mass.; 22 mg, 0.03 mmol) in dimethoxyethane (3 mL) in a scintillation vial was heated at ˜78° C. for 72 h with shaking. The reaction mixture was cooled to room temperature, concentrated in vacuo using a Genevac evaporator, and purified using automated mass-directed LC-MS purification.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>C1COCC1>[Br:1][C:2]1[O:6][C:5]([C:7](=[O:9])[CH2:8][C:22](=[O:23])[C:21]([F:28])([F:27])[F:20])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)o1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccc(Br)o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a stirred solution of compound 43 (4.8 g, 25.4 mmol) in THF (60 mL) at −78° C., LiHMDS (38 mL, 38.1 mmol) was added dropwise and the reaction stirred −78° C. for 1 h. Ethyl 2,2,2-trifluoroacetate (4.5 g, 38.1 mmol) was then added dropwise. The reaction mixture was allowed to gradually warm to room temperature in cooling bath and stirred overnight. Solvent was removed, cold water (50 mL) was added, and the reaction mixture extracted with diethyl ether (100 mL×3). Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure. Crude compound was washed with diethyl ether and hexane to afford compound 44 (5 g, 69%) as a white solid.
Reaction SMILES: Cl.[CH3:2][CH:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)N)[CH3:4].CC[O:16][C:17]([CH2:19][CH:20]1[C:25](=O)[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18]>>[F:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[N:5]([CH:3]([CH3:4])[CH3:2])[C:25]1[CH:20]([CH2:19][C:17]([OH:16])=[O:18])[CH2:21][CH2:22][CH2:23][C:24]2=1
Reactant: CC(C)N(N)c1ccc(F)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CC(C)n1c2c(c3cc(F)ccc31)CCCC2CC(=O)O

Procedure:
Following the procedure of Example 1, but using 1-(2-propyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH2:1]([N:5]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:7][CH2:6]1)[CH2:2][CH:3]=C.O.I([O-])(=O)(=O)=[O:25].[Na+]>CC(O)(C)C>[O:12]=[C:11]1[N:5]([CH2:1][CH2:2][CH:3]=[O:25])[CH2:6][CH2:7][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:9][CH2:10]1
Reactant: C=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 1 h
Yield: 636.3 %

Procedure:
To a solution of 4-but-3-enyl-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one 0.09 g (0.03 mmol) in tBuOH:water (2 ml 1:1) was added potassium osmate dihydrate 0.001 g (0.001 mmol) and sodium periodate 0.13 g (0.1 mmol). The mixture was stirred for 1 h, then extracted with CH2Cl2, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 1:1→1:0) afforded the title compound 0.06 g (64%) as a brown gum. MS: 315.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].N12CCN(CC1)CC2.CCCCCCC>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC1(C)CCN(c2ccc(O)nc2)CC1
Agent: C1CN2CCN1CC2
Solvent: CCCCCCC
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(N2CCC(C)(C)CC2)cn1)c1ccccc1
Yield: 41 %

Procedure:
A solution of 4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ol (0.86 g, 4.17 mmol), N-methyl-N-phenylcarbamoyl chloride (0.71 g, 4.17 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.47 g, 4.17 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. Extra dichloromethane was added and the solution was washed with water, dried over sodium sulphate, filtered and evaporated in vacuo. Crystallisation from ethyl acetate:heptane yielded the title compound (0.58 g, 41% yield)
Reaction SMILES: [N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])[NH:14][C@H:15]([CH3:30])[C:16]([NH:18][CH:19]2[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])[NH:14][C@@H:15]([CH3:30])[C:16]([NH:18][CH:19]2[CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CNC1

Procedure:
To a solution of the compound (846 mg), which had been obtained in (1), in anhydrous dichloromethane (10 ml), trifluoroacetic acid (3 ml) was added dropwise under ice cooling. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(2), whereby the title compound was obtained. The product was provided for use in the subsequent reaction without isolation. Infrared absorption spectrum (Liquid film) νmax cm-1 : 3213, 1758, 1677, 1610, 1600, 1560, 1526.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH:16](O[Si](C(C)(C)C)(C)C)[O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:53]CC1>>[C:1]([N:11]1[CH2:15][C@H:14]([OH:53])[CH2:13][C@H:12]1[CH2:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)(C)[Si](C)(C)OC(Oc1cccnc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1COc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 700 mg (1.6 mmol) sample of 3-(1-CBZ-(t-butyldimethylsilyloxy)-2-(S)-pyrrolidinylmethoxy)pyridine, prepared as in Example 72d above, was dissolved in 10 mL of THF and 5.0 mL (4.8 mmol) of 1 M tetra-n-butylammonium fluoride was added. The reaction mixture was stirred at room temperature for 2 hours, and the solvent was removed. The residue was purified on a column of silica gel, eluting with 3:1 ethyl acetate:hexane to give 466 mg of the title compound. MS (DCI/NH3) m/e: 328 (M+H)+. 1H NMR (CDCl3,300 MHz) δ: 8.28 (s, 1H), 8.21 (m, 1H), 7.33 (s, 5H), 7.27 (m, 1H), 7.20 (m, 1H), 5.13 (s, 2H), 4.59 (m, 1H), 4.37 (m, 1H), 3.62 (m, 2H), 3.59 (m, 1H), 3.20 (m, 1H), 2.18 (m, 1H).