Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][CH2:17][C:18]([N:20]2[C@@H:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:22][C:21]2=[O:28])=[O:19])=[CH:14][C:13]=1[CH3:31].I[CH2:33][CH:34]=[CH:35][CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[NH4+].[Cl-]>C1COCC1>[CH2:38]([O:37][CH2:36]/[CH:35]=[CH:34]\[CH2:33][C@@H:17]([O:16][C:15]1[CH:29]=[CH:30][C:12]([F:11])=[C:13]([CH3:31])[CH:14]=1)[C:18]([N:20]1[C@@H:24]([CH:25]([CH3:26])[CH3:27])[CH2:23][O:22][C:21]1=[O:28])=[O:19])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: ICC=CCOCc1ccccc1
Reactant: Cc1cc(OCC(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(O[C@H](C/C=C\COCc2ccccc2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To the solution of lithium bis(trimethylsilyl)amide (1.2 mL, 1.2 mmol, 1M in THF) in anhydrous 20 mL THF at −70° C. was slowly added over 15 minutes (S)-3-(2-(4-fluoro-3-methylphenoxy)acetyl)-4-isopropyloxazolidin-2-one (295 mg, 1.0 mmol) as a solution in 3.0 mL THF. The reaction mixture was stirred for 30 min at −70° C. and then was slowly added a pre-cooled solution of (4-Iodo-but-2-enyloxymethyl)-benzene (576 mg, 2.0 mmol) in 3 mL of THF. The resulting mixture was stirred at −70° C. for 1 h and the temperature was slowly raised over a period of 2 h. The mixture was poured into 20 mL saturated NH4Cl and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×20 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to give 294 mg of the title compound as a light yellow oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C[Si](C)(C)[O:15][CH:16]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:17]#N.BrC[C:30]1[S:34][C:33]([C:35]([F:38])([F:37])[F:36])=[N:32][CH:31]=1.Cl.F.C[SiH](C)C>O1CCCC1.CC(C)=O.CCCCCC.CO>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:16](=[O:15])[CH2:17][C:30]2[S:34][C:33]([C:35]([F:38])([F:37])[F:36])=[N:32][CH:31]=2)=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)OC(C#N)c1ccc(F)cc1
Reactant: FC(F)(F)c1ncc(CBr)s1
Agent: C[SiH](C)C
Agent: Cl
Agent: F
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: CC(C)=O
Product: O=C(Cc1cnc(C(F)(F)F)s1)c1ccc(F)cc1
Temperature: -70 °C

Procedure:
A solution of 2.4M n-butyl lithium in hexane (6.4 mL, 15.4 mmol) was added to a solution of 2.15 mL (15.4 mmol) of diisopropylamine in 50 mL of dry tetrahydrofuran at -10° C. under nitrogen with stirring over a 2-min period. The resulting solution was cooled to -70° C. and a solution containing 3.18 g (14 mmol) of 2-(trimethylsilyloxy)-2-(4'-fluorophenyl)acetonitrile in 3 mL of dry tetrahydrofuran was added dropwise by means of a syringe pump over a 20-min period under nitrogen with stirring. The resulting bright yellow solution was stirred for an additional 30 min at -70° C. or below and then a solution of 2.92 g (11.9 mmol) of 5-bromomethyl-2-trifluoromethylthiazole in 5 mL of dry tetrahydrofuran was added over 30 min under nitrogen with stirring to obtain a dark, thick slurry. After a 45-min reaction period this mixture was allowed to warm and was poured into a rapidly stirred mixture consisting of 25 mL of 10 percent aqueous hydrochloric acid and 10 mL of methanol. Aqueous hydrofluoric acid (0.5 mL of 48 percent) was then added and the mixture was stirred until all of the trimethylsilane protecting group was removed. Sufficient 10 percent aqueous sodium hydroxide was added with stirring to adjust the pH to about 10 and after 15 min the phases were separated. The aqueous phase was extracted with 2×30 mL of ether and the combined organic phases were washed with 50 mL of 10 percent aqueous hydrochloric acid and 50 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was kugelrohr distilled, first at 70° C. and 0.05 torr (6.7 Pa (Pascals)) to remove 4-fluorobenzaldehyde and then at 100°-110° C. and 0.05 torr (6.7 Pa) to distill 2.93 g (85 percent of theory) of the title compound, which was obtained as a waxy yellow solid of 95 percent purity (by gas liquid chromatography). An analytical sample obtained by crystallization from a mixture of hexane and acetone melted at 66.5°-68.5° C.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:11]/1)=[O:5].[CH:31](B(OCCCC)OCCCC)=[CH2:32].[F-].[Cs+]>CO.COCCOC.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>[C:12]([C:10]1[N:9]([CH3:16])[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)/[C:7](=[N:6]/[C:4](=[O:5])[C:3]2[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:2]=2[CH:31]=[CH2:32])/[CH:11]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C=CB(OCCCC)OCCCC
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2Br)n1C[C@H]1CCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: C=Cc1ccc(C(F)(F)F)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Temperature: 130 °C
Yield: 86 %

Procedure:
To the mixture of Example 88, tetrakis(triphenylphosphine)palladium (0.231 g, 0.200 mmol), dibutyl vinylboronate (0.863 ml, 4.00 mmol) and cesium fluoride (1.82 g, 12.0 mmol) in MeOH (1 mL) and DME (2 mL) was added tetrakis(triphenylphosphine)palladium (0.231 g, 0.200 mmol). The mixture was heated in a sealed tube at 130° C. for 20 min. After cooling to ambient temperature, the solvent was removed under reduced pressure and the residue was diluted with EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3 and brine and then concentrated. Purification by column chromatography (silica gel, 5-30% gradient of 9:1 MeOH/Et3N in EtOAC) provided the title compound 1.5 g (86% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H) 1.62-1.95 (m, 4H) 3.59-3.68 (m, 1H) 3.70-3.81 (m, J=7.14, 7.14 Hz, 1H) 3.90 (s, 3H) 4.11-4.22 (m, J=6.15, 4.16 Hz, 1H) 4.26-4.46 (m, 2H) 5.31 (d, J=12.29 Hz, 1H) 5.76 (d, J=17.85 Hz, 1H) 6.85 (s, 1H) 7.54-7.68 (m, 2H) 7.76 (d, J=8.33 Hz, 1H) 8.04 (d, J=1.59 Hz, 1H); MS (ESI) m/z 436 (M+H)+, 434 (M−H)−.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1>O1CCCC1>[CH:1]1([C:4]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: O=C(C1CC1)n1ccnc1
Temperature: 0 °C
Yield: 102.1 %

Procedure:
A solution of cyclopropanecarbonyl chloride (10.0 g) in dry tetrahydrofuran was added dropwise to a solution of imidazole (13.0 g, 2 equivalents) stirred at 0° C. After 1 hour the solid was filtered and the filtrate evaporated to give the title compound (13.3 g), NMR 1.2 (m, 2H), 1.38 (m, 2H), 2.21 (m, 1H), 7.12 (d, 1H), 7.55 (d, 1H), 8.34 (s, 1H).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:22]([CH2:24][NH:25][C:26](=[O:33])[C@@H:27]([OH:32])[CH2:28][CH:29]([CH3:31])[CH3:30])#[N:23].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>ClCCCl>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:32][C@@H:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:26]([NH:25][CH2:24][C:22]#[N:23])=[O:33])=[N:13][CH:14]=1
Reactant: N=C(OC(c1ccccc1)c1ccc(Br)cn1)C(Cl)(Cl)Cl
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCCl
Product: CC(C)C[C@H](OC(c1ccccc1)c1ccc(Br)cn1)C(=O)NCC#N

Procedure:
To a solution of (5-bromopyridin-2-yl)(phenyl)methyl 2,2,2-trichloroethanimidoate from example 53 step 2 (2 g, 4.9 mmol) in 1,2-dichloroethane (50 mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide (830 mg, 4.9 mmol, 1 eg) and camphor sulfonic acid (114 mg, 0.49 mmol, 0.10 eg). The suspension was heated to reflux for 18 hours, then concentrated to dryness. Residue was chromatographed with 25% EtOAc/hexane to yield the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:9])=[C:6]([NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:5]=1)(O)=[O:2].ClC(OCC)=O.CN1CCOCC1.[BH4-].[Na+]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:18]=[CH:19][C:4]([CH2:1][OH:2])=[CH:5][C:6]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]2)=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(C(=O)O)ccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(CO)ccc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 74.5 %

Procedure:
Using a similar procedure to that described in Example 47-A, 4-carboxy-N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-ylmethyl)amino]benzamide (2.0 g, 4.1 mmol), ethyl chloroformate (0.40 mL, 4.1 mmol), N-methylmorpholine (0.46 mL, 4.1 mmol), and sodium borohydride (466 mg, 12.3 mmol) afforded 1.45 g (75%) of the title compound, which was used without further purification.
Reaction SMILES: [N+:1]([O:4][C@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:29]=[CH:28][C:23]([NH:24]C(=O)C)=[N:22][C:20]1=[O:21])([O-:3])=[O:2].C[O-].[Ba+2].C[O-].O>CO>[N+:1]([O:4][C@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:29]=[CH:28][C:23]([NH2:24])=[N:22][C:20]1=[O:21])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2O[N+](=O)[O-])c(=O)n1
Agent: C[O-]
Agent: [Ba+2]
Solvent: O
Solvent: CO
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O[N+](=O)[O-])c(=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 1-(2-O-nitro-3,5-di-O-acetyl-β-D-arabinofuranosyl)-N4 -acetylcytosine (10 g., 24 mmol) in anhydrous methanol (425 ml) under an atmosphere of dry nitrogen was added 1.9N barium methoxide (5 ml., 9.5 meq) in methanol. The reaction mixture was stirred at room temperature under an inert atmosphere for one hour and was then neutralized with a cation exchange resin (90 g., Bio-Rex 70/H+, 100-200 mesh )in the presence of water (5 ml). The resin was separated by filtration and washed with methanol. The combined filtrate and washings were evaporated under reduced pressure to yield crude 1-(2-O-nitro-β-D-arabinofuranosyl)cytosine (6.60 g., 95%), which was crystallized from H2O to yield pure 1-(2-O-nitro-β-D-arabinofuranosyl)cytosine (5.97 g., 86%): m.p. 151.3°-152.7° C.;
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:10]([NH:15][C:16](=[O:27])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:11][CH2:12][C:13]#[CH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[Si:1]([O:8][C@H:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@H:10]([NH:15][C:16](=[O:27])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:11][CH2:12][C:13]#[C:14][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#CCC[C@@H](NC(=O)OCc1ccc(OC)cc1)[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)N[C@H](CCC#Cc2ccc([N+](=O)[O-])cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of acetylene (from Step E, 40 g, 80 mmol) and 4-iodonitrobenzene (21.8 g, 88 mmol) in anhydrous DMF (500 ml) was added triethylamine (111 mL, 797 mmol). Pd(dppf)Cl2 (1.95 g, 2.39 mmol) and copper(I) iodide (910 mg, 4.78 mmol) was added and the mixture degassed with nitrogen (bubble 15 min) and the resulting solution stirred at room temperature for 5 h. The mixture was poured into water (1200 m) and extracted with EtOAc (3×300 mL). The combined organics were then washed with water (2×500 mL), sat. NaCl (200 mL), dried over magnesium sulfate, filtered and evaporated under vacuum. Residue was purified by MPLC (Horizon Biotage 2× Flash 65i) eluting with a gradient of 0-30% ethyl acetate in hexane to give 41 g (84%) as a dark red oil. %). 1H NMR (500 MHz, CDCl3): 8.11-8.04 (m, 2H), 7.94-8.01 (m, 1H), 7.38-7.21 (m, 8H), 6.87 (d, J=8.4 Hz, 2H), 4.98 (s, 2H), 4.77-4.59 (m, 2H), 4.00-3.95 (m, 3H), 3.81 (s, 3H), 2.56 (t, J=7.1 Hz, H=2H), 2.00-1.95 (m, 1H), 1.66-1.61 (m, 1H), 0.93 (s, 9H), 0.10 (s, 3H), −0.10 (s, 3H). LC-MS: m/z (ES) 589.3 (MH)+, 611.2 (MNa)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Br:21].[Cl:22]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O>O1CCCC1>[Cl:22][C:19]1[C:14]([F:13])=[C:15]([Br:21])[CH:16]=[CH:17][C:18]=1[F:20]
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1ccc(Br)c(F)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 19 ml (0.135 mole) of diisopropylamine in 125 ml of tetrahydrofuran (THF) cooled at −20° C. is added 80 ml of n-butyllithium (1.6 M in hexane). The temperature is raised to 0° C. for 5 minutes and lowered to −78° C. Then 25 g (0.129 mole) of 2,4-difluoro-bromobenzene is then added and the reaction is stirred at −65° C. for 2 hours. Then, 25 ml (0.164 mole) of hexachloroacetone is added and the solution is warmed at room temperature. After evaporation of the solvent, the residue is distilled under vacuum to give the desired product.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11](OC)=[O:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)([CH3:4])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)([CH3:1])[CH3:3]
Reactant: CCOc1cccc(-c2ccc(C(=O)OC)cc2C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cccc(-c2ccc(CO)cc2C(C)(C)C)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a cooled solution of 41.1 (0.87 g, 2.79 mmol) in dry THF (10.0 mL) at 0° C., was added LAH (1.0 M solution in THF (5.5 mL, 5.5 mmol)). Upon complete addition, the reaction was allowed to warm to room temperature and monitored by TLC and LCMS. Upon completion, 1N NaOH (5 mL) was carefully added to quench the reaction. The resulting solution was extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-40% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 41.2 as a colorless oil (0.72, 91%). 1H NMR (500 MHz, CDCl3) δ ppm 7.53 (1H, d, J=1.5 Hz), 7.26 (1H, m), 7.19 (1H, dd, J=7.7, 1.8 Hz), 7.04 (1H, d, J=7.6 Hz), 6.89 (3H, m), 4.74 (2H, d, J=3.2 Hz), 4.08 (2H, m), 1.71 (1H, s), 1.42 (3H, t, J=7.0 Hz), 1.23 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:27])[CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1)[CH:6]=[CH:5]2.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:27])[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14]([O:17][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@@H](O)C3)ccc12
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)O[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 33(a), using N-[6-chloro-2-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 28) (0.46 g) and methanesulphonyl chloride (0.183 mL) to afford the sub-title compound (0.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH2:16])([O-:13])=[O:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=2[N+:11]([O-:13])=[O:12])=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2,4-dinitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.69 (bs, 1H), 9.28-9.23 (m, 2H), 9.06-9.05 (m, 1H), 8.61-8.57 (m, 1H), 8.28-8.24 (m, 1H), 7.59-7.56 (m, 1H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH3:15]>O>[CH2:11]([S:10][C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCBr
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCSc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 34.9 %

Procedure:
To a solution of 8.0 g (0.2 mole) of sodium hydroxide in 100 ml of water is added 29 g (0.2 mole) of p-chlorothiophenol in small portions. Stirring is continued until the mixture becomes clear. To this solution is added 30.2 g (0.2 mole) of pentyl bromide dropwise. The reaction mixture is heated at 60° C. for one hour. It is then poured into water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO4. Solvent is evaporated to give a pale yellow oil which is purified further by vacuum distillation (85°-8°/0.03 mm) to give 15 g of pure product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[O:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])[C:9](=[O:19])[NH:8][C:7]1=[O:20].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([C@:29]23[CH2:34][C@H:33]2[CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CCO>[ClH:1].[CH3:17][C:15]1[O:16][C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][C@H:33]4[C@:29]([C:26]5[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:36])[F:35])=[CH:28][CH:27]=5)([CH2:34]4)[CH2:30]3)[CH:11]=2)=[C:13]([CH3:18])[N:14]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: Cc1nc(C)c(-c2cn(CCCCCl)c(=O)[nH]c2=O)o1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1nc(C)c(-c2cn(CCCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)o1
Reaction time: 3 h
Yield: 24 %

Procedure:
A solution of 1-(4-chloro-butyl)-5-(2,4-dimethyl-oxazol-5-yl)-1H-pyrimidine-2,4-dione (Prep65, 100 mg, 0.34 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 68 mg, 0.3 mmol), and DIPEA (130 mg, 1 mmol) in absolute EtOH (3 ml) was placed in a microwave oven and irradiated at 130° C. for 3 hours. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was evaporated, the crude dissolved in dichloromethane and treated with PS-isocyanate resin (400 mg) under stirring for 3 h. After filtration, the solvent was evaporated and the crude purified by preparative LC-MS. The residue was loaded over a SCX cartridge eluting with MeOH and the product obtained was treated with 4N HCl in dioxane (1 eq), to give the title compound as a white powder. (43 mg, 24% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[N:14]=[N:13][N:12]([C@H:15]3[C@@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@@H:18]4[C@@H:17]([O:25][CH2:26][CH2:27][OH:28])[CH2:16]3)[C:4]=2[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=1.[F:29][C:30]1[CH:31]=[C:32]([C@@H:37]2[CH2:39][C@H:38]2[NH2:40])[CH:33]=[CH:34][C:35]=1[F:36].C(N(CC)C(C)C)(C)C.O>ClCCl>[F:29][C:30]1[CH:31]=[C:32]([C@@H:37]2[CH2:39][C@H:38]2[NH:40][C:2]2[C:3]3[N:14]=[N:13][N:12]([C@H:15]4[C@@H:19]5[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@@H:18]5[C@@H:17]([O:25][CH2:26][CH2:27][OH:28])[CH2:16]4)[C:4]=3[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: N[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Reactant: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Yield: 93 %

Procedure:
A solution of 2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (370 mg, 0.86 mmol, 1.00 equiv) (15 mL), (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (145.6 mg, 0.86 mmol, 1.00 equiv.) and N,N-diisopropylethylamine (155.7 mg, 1.21 mmol, 1.20 equiv.) in dichloromethane was stirred at ambient temperature for about 16 hours, and then water (10 mL) was added. Standard extractive workup with dichloromethane (3×10 mL) gave the title product as a yellow oil (450 mg; yield=93%). m/z=563 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:38][C:24]4[N:25]=[CH:26][N:27]=[C:28]([NH:29][C@@H:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH3:31])[C:23]=4[CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[C:32]1([C@H:30]([NH:29][C:28]2[C:23]3[CH:22]=[C:21]([C:18]4[CH:19]=[CH:20][C:15]([CH2:14][N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:16][CH:17]=4)[NH:38][C:24]=3[N:25]=[CH:26][N:27]=2)[CH3:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN4CCNCC4)cc3)cc12)c1ccccc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
4-{4-[4-((R)-1-Phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-piperazine-1-carboxylic acid tert-butyl ester (1.8 g, 3.5 mmol) is dissolved in 150 mL of dioxane by gentle warming. To this solution is added a solution of 4 N hydrochloric acid in dioxane (Aldrich, Buchs, Switzerland) (5 mL, 20 mmol) and the mixture stirred at 50 to 60° C. for 1 hour. The resulting suspension is diluted with 75 mL of methanol and stirred for 1 additional hour under reflux after which the mixture is cooled and the solvent evaporated. The residue is dissolved in diluted hydrochloric acid and washed with ethyl acetate. The aqueous phase is treated with solid potassium carbonate until basic and evaporated. The residue which contains inorganic salts is purified by flash chromatography using dichloromethane/methanol 7:3 containing 1% conc. ammonia. Pure fractions were taken up in ethyl acetate, washed with water and brine, dried with sodium sulfate and evaporated to give the title compound as a solid; m.p. 240-242° C.; MS-ES+: (M+H)+=413; TLC Rf(dichloromethane/methanol 7:3 containing 1% conc. ammonia) 0.35; HPLC tR=6.86 min.