Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=3)[C:12](=[O:31])[C:11]=2[N:10]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[N:9]=1)=[O:7])[CH3:4].[CH3:39]I>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]3[CH:18]=[CH:19][C:20]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH3:39])=[CH:21][CH:22]=3)[C:12](=[O:31])[C:11]=2[N:10]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[N:9]=1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(NC(=O)OC(C)(C)C)cc1)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(N(C)C(=O)OC(C)(C)C)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
Part D. In a 200 mL of flask was placed 60% sodium hydride (0.23 g, 5.69 mmol) and DMF (10 mL). After being cooled to 0° C., a solution of 6-(4-tert-butoxycarbonylamino-phenyl)-1-(3-chloro-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (1.45 g, 2.84 mmol) in DMF (5 mL) was then added. The reaction was stirred for 30 min and then treated with methyl iodide (0.86 g, 5.69 mmol). The reaction was allowed to stir at rt overnight. After quenching with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with sodium sulfate, and concentrated to give 6-[4-(tert-butoxycarbonyl-methyl-amino)-phenyl]-1-(3-chloro-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (1.12 g). APCI MS m/z 525 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[O:29]>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:29]
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Reactant: O=C=Nc1ccccc1Cl
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccccc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:17])=O>C1C=CC=CC=1>[CH2:1]([O:8][CH:9]1[CH2:10][O:11][C:15]([CH3:17])([CH3:14])[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: CC(C)=O
Solvent: c1ccccc1
Product: CC1(C)OCC(OCc2ccccc2)CO1

Procedure:
Using the procedure of Example 51, 2-benzyloxy-1,3-propanediol and acetone were reacted, using benzene as solvent, to give, after distillation using a short path column, 5-benzyloxy-2,2-dimethyl-1,3-dioxane. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+].C(O)=O>CO.[OH-].[OH-].[Pd+2]>[O:14]1[CH2:15][CH2:16][CH:11]([O:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1cccnc1OC1CCOCC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O=CO
Product: Nc1cccnc1OC1CCOCC1
Temperature: 50 °C

Procedure:
To a solution of 3-nitro-2-(tetrahydro-2H-pyran-4-yloxy)pyridine (2.31 g, 10.3 mmol) in anhydrous MeOH (20 mL) was added ammonium formate (1.2 g, 19.1 mmol) and palladium hydroxide on carbon (20%, 0.40 g). The mixture was stirred at ambient temperature for 8 hours when an additional aliquot of ammonium formate (1.0 g) was added. The mixture was heated at 50° C. for 4 hours, the solution adjusted to pH 8 with formic acid before further heating at 50° C. for one hour. The reaction was filtered through Celite and the catalyst residue washed with MeOH. The solvent was concentrated in vacuo to give a deep purple solid. The crude product was purified by ion-exchange chromatography (SCX-2 eluting with hydrochloric acid/MeOH ammonia/MeOH). The product crystallised as a white solid (1.8 g, 90%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]([O:16][CH3:17])=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:7]=1)[C:8]([C:9](=[CH:22][N:23]([CH3:25])[CH3:24])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(Br)c(OC)cc1OC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)c(OC)cc1OC
Temperature: 95 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, ethyl 3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropionate (52.8 g) obtained in Step 3 of Example 1 and N,N-dimethylformamide dimethyl acetal (44.6 g) were dissolved in toluene. The solution was stirred at 95° C. for 16 hr, and the completion of the reaction was confirmed by HPLC. The reaction mixture was cooled to room temperature to give a solution of ethyl 2-(5-bromo-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylate in toluene. The reaction mixture was directly used in the next step.
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][N:5]1[C:9]([CH2:10][N:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH3:18])[CH2:13][C:12]2=[O:19])=[CH:8][N:7]=[CH:6]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:4][N:5]1[C:9]([CH2:10][N:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH3:18])[CH2:13][C:12]2=[O:19])=[CH:8][N:7]=[C:6]1[C:2]#[N:1]
Reactant: CCCC1CC(=O)N(Cc2cncn2C)C1
Reactant: N#CBr
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCC1CC(=O)N(Cc2cnc(C#N)n2C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
In a 2 l, three-necked flask fitted with a magnetic stirrer and reflux condenser under inert atmosphere, DMAP (60.4 g, 0.495 mol) is dissolved in DMF (900 ml) and the solution is cooled to 0° C. Cyanogen bromide (54.4 g, 0.495 mol) is added by portions while the temperature is maintained between 0 and 10° C. The mixture is stirred for 0.5 h at this temperature and a solution of 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 121 (36.5 g, 0.165 mol) in DMF (500 ml) is added. The mixture is heated at 40° C. overnight. The DMAP-BrCN complex (0.165 mol) in 350 ml of DMF is added at 5° C. (after being stirred for 1 h) and the mixture is heated at 45° C. overnight. One equivalent of the DMAP-BrCN complex in DMF (150 ml) is prepared again and added to the mixture at a temperature comprised between 0° C. and 10° C. The mixture is stirred at 45° C. overnight. The solvent is evaporated, the residue is dissolved in AcOEt, then the organic phase is washed with a saturated solution of NaHCO3 and brine, dried over MgSO4 and concentrated to dryness. Purification by preparative chromatography on silicagel affords 13.5 g 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carbonitrile 125.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][OH:15]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:15][CH2:14][CH2:13][O:12][CH3:11])[CH:3]=1
Reactant: COCCO
Reactant: N#Cc1ccc(Cl)cc1F
Product: COCCOc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 2-methoxy-ethanol analogously to the preparation of Intermediate 98.1 as a colorless solid; ES-MS: M+=216.1; HPLC: AtRet=2.51 min.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+].C1C(=O)N([O:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=O)C(=O)C1>O.CC(C)=O>[CH2:27]([O:26][C:24]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])=[O:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)CNCC(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To the solution of iminodiacetic acid XLV (10 g, 75.13 mmol) and K2CO3 (41.53 g, 300.52 mmol) in water (225 mL) was added a solution of CBzOsu (20.6 g, 82.64 mmol) in acetone (150 mL). The mixture was stirred at r.t. overnight. The acetone was evaporated under reduced pressure and the remaining water was washed with ethyl ether (2×). The aqueous layer was acidified to pH=2 with 2 M aq. HCl and then saturated with NaCl, washed with EtOAc (3×). The combined EtOAc was dried over MgSO4 and evaporated under reduced pressure to give 2-{[(benzyloxy)carbonyl](carboxymethyl) amino}acetic acid XLVI (15 g, 56.17 mmol, 75% yield). ESIMS found for C12H13NO6 m/z 290 (M+Na).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]([NH:17][C@@H:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[C:28]([F:37])[CH:27]=2)[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[N+:38]([O-])=O)C1C=CC=CC=1.[H][H].CCOC(C)=O>C1COCC1.[Pd]>[NH2:38][C:10]1[CH:11]=[CH:12][C:13]([C:15]([NH:17][C@@H:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[C:28]([F:37])[CH:27]=2)[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:16])=[N:14][C:9]=1[OH:8]
Reactant: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1O

Procedure:
To a stirred mixture of (S)-6-(benzyloxy)-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-nitropicolinamide (800 mg, 0.0014 mol) in THF (8 mL), was added 10% Pd/C (800 mg, Aldrich). The reaction mixture was stirred under hydrogen atmosphere in the form of hydrogen bladder (˜20-22 PSI) for 12 h at room temperature. After completion of the reaction (monitored by TLC, 100% EtOAc), the reaction mixture was filtered through Celite® brand filter agent, the filtrate dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.00 (s, 1H), 9.13 (d, J=6 Hz, 1H), 8.46 (d, J=4 Hz, 1H), 7.79 (t, J=9.2 Hz, 1H), 7.57-7.46 (m, 3H), 7.33 (d, J=8.4 Hz, 1H), 7.08 (br. s., 1H), 6.62 (d, J=7.6 Hz, 1H), 6.40 (br. s., 1H), 5.83 (br. s., 2H). MS (ESI, positive ion) m/z: 440.9 (M+H).
Reaction SMILES: CS(O[CH:6]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([N+:32]([O-:34])=[O:33])[CH:26]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=O)=O.[C:35]([C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].O>CN(C=O)C>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([N:43]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=3)[CH2:8][CH2:7][CH:6]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([N+:32]([O-:34])=[O:33])[CH:26]=2)=[CH:44][CH:45]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N2C(c3ccc(Cl)c([N+](=O)[O-])c3)CCC2c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: 55 °C
Yield: 72.4 %

Procedure:
The product from Example 28C (6.6 g, 11.84 mmol) was slurried in DMF (30 mL) and 4-t-butyl aniline (18.7 mL, 118 mmol) was added and the solution was heated at 55° C. for 2 h then cooled and poured into water and extracted into dichloromethane. The organics were concentrated and the residue was purified by chromatography on silica gel 120 g column, eluting with 0-5% ethyl acetate/hexanes to give 4.41 g (72%) of a thick oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)[N:3]=1>C1CCCCC=1.C1COCC1.[Pd]>[NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1ccc(C(=O)n2nc(Nc3ccc(OCc4ccccc4)cc3)nc2N)cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)n2nc(Nc3ccc(O)cc3)nc2N)cc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 35.3 %

Procedure:
A mixture of 5-amino-3-[4-(benzyloxy)phenylamino]-1-(4-methylphenyl)carbonyl-1H-1,2,4-triazole (Ia-3) (3.95 g, 9.89 mmol) and 10% Pd/C (0.80 g) in cyclohexene (64 mL) and THF (128 mL) was stirred and heated at 70° C. After 2 d, additional 10% Pd/C (0.80 9) was added and heating and stirring at 70° C. was continued for an additional 3 d. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth and concentrated to give a yellow-brown residue. Purification by flash chromatography (95:5 methylene chloride/methanol) followed by trituration with methylene chloride afforded 5-amino-3-[4-(hydroxy)phenylamino]-1-(4-methylphenyl)carbonyl-1H-1,2,4-triazole (Ia-4) (1.08 g, 35%) as a pale yellow solid: Rf 0.36 (95:5 methylene chloride/methanol); mp 221-223° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.88 (s, 1H), 8.13 (d, J=8.2 Hz, 2H), 7.74 (br s, 2H), 7.38-7.32 (m, 4H), 6.64 (d, J=8.8 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.1, 158.4, 157.3, 151.0, 142.9, 132.9, 130.6, 129.8, 128.4, 118.1, 115.1, 21.1; IR (ATR) 1697 cm−1; ESI MS m/z 310 [C16H15N5O2+H]+; HPLC (Method A) >99% (AUC), tR=11.22 min. Anal. Calcd for C16H15N5O2 0.5H2O: C, 60.47; H, 4.92; N, 22.04. Found: C, 60.27; H, 4.70; N, 21.51.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:22])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:43]1[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=1.[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:22])/[C:13](/[C:43]1[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:50])=[O:51])=[C:45]([C:53]([F:55])([F:56])[F:54])[CH:44]=1)=[CH:14]/[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCCC1
Reactant: CS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
A mixture of zinc dust (1.3 g, 20 mmol, Aldrich, -325 mesh) and dry tetrahydrofiran (2 mL) under argon was treated with 1,2-dibromoethane (187 mg, 1 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (110 mg, 1 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (prepared as in Example 108, 2.5 g, 8.5 mmol) in dry tetrahydrofuran (3 mL) over 5 min. After the addition, the reaction mixture was stirred for 1 h at 40-45° C. and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (4 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (108 mg, 0.2 mmol) and triphenylphosphine (209 mg, 0.8 mmol) in dry tetrahydrofuran (10 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromo-1-methanesulfonyl-2-trifluoromethyl-benzene (2.12 g, 7 mmol) and the freshly prepared zinc compound in tetrahydroftiran. The resulting brick red solution was heated at 40-45° C. for 2 d. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (100 mL), and the organic compound was extracted into ethyl acetate (3×75 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 9/1 to 3/1 hexanes/ethyl acetate) afforded (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylic acid methyl ester (2.7 g, 99%) as a viscous oil: EI-HRMS m/e calcd for C18H21F3O4S (M+) 391.1191, found 391.1200.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[C:24]([CH3:29])=[N:23][CH:22]=4)[C:18]([F:30])=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>C1COCC1>[NH2:1][CH:4]1[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:27])[CH3:28])[C:24]([CH3:29])=[N:23][CH:22]=4)[C:18]([F:30])=[CH:17][N:16]=3)=[CH:12][CH:13]=2)[CH2:7]1
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(N=[N+]=[N-])C4)cc3)ncc2F)n1C(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC(N)C4)cc3)ncc2F)n1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
To a solution N-[4-(3-azidoazetidin-1-yl)phenyl]-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 139; 382 mg, 938 mM) in THF (10 ml), triphenylphosphine (260 mg, 0.984 mM) was added. The reaction was stirred at room temperature under nitrogen for 24 hours. Water (2.0 ml) was then added and the mixture stirred and heated at 65° C. for 3 hours. Hydrochloric acid (1M, 1.5 ml) was added and the THF removed in vacuo. More water was then added and the solution extracted with EtOAc. Sodium hydroxide (1M, 1.5 ml) was added to the water layer and the solution was extracted with EtOAc. The organic layers were combined, dried with anhydrous sodium sulphate, filtered and evaporated to give the title compound as a yellow foam (324 mg, 91%). NMR (DMSO-d6+d4-acetic acid) 1.38 (d, 6H), 2.5 (s, 3H), 3.73 (m, 2H), 4.05 (m, 3H), 5.43 (m, 1H), 6.45 (d, 2H), 7.33 (s, 1H), 7.4 (d, 2H), 8.4 (d, 1H); m/z 382.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[CH:27]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2ccc3c(c2)C(C)(C)CC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-methylphenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 251.2; HRMS: calcd for C18H18O+H+, 251.14304; found (ESI, [M+H]+), 251.1428.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][N:18]([C@@H:21]2[CH2:25][CH2:24][N:23]([C:26](=[O:56])[CH:27]([N:34]3[C:38]4[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=4[N:36]([S:44]([C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)(=[O:46])=[O:45])[C:35]3=[O:55])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22]2)[CH2:17][CH2:16]1)C1C=CC=CC=1>ClCCl>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]2[N:36]([S:44]([C:47]3[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=3)(=[O:46])=[O:45])[C:35](=[O:55])[N:34]([CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:26](=[O:56])[N:23]3[CH2:24][CH2:25][C@@H:21]([N:18]4[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]4)[CH2:22]3)[C:38]=2[CH:39]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CC[C@@H](N4CCN(Cc5ccccc5)CC4)C3)c3ccccc3)c3cc(Cl)ccc32)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CC[C@@H](N4CCNCC4)C3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 0 °C

Procedure:
118 mg (0.82 mmol) of 1-chloroethyl chloroformate were added to a solution of 550 mg (0.79 mmol) of 3-{2-[(R)-3-(4-benzylpiperazin-1-yl)-pyrrolidin-1-yl]-2-oxo-1-phenylethyl}-5-chloro-1-(4-methoxybenzenesulfonyl)-1,3-dihydrobenzimidazol-2-one (Example 142) in 5 ml dry dichloromethane while stirring at 0° C. The reaction mixture was subsequently stirred at 0° C. for 1 h and then at room temperature overnight. The solvent was removed in vacuo, and the residue was dissolved in 20 ml of methanol. The methanolic solution was stirred at 60° C. for 1 h and then concentrated under reduced pressure. The residue was dissolved in dichloromethane, mixed with 3 eq. of MP-carbonate (Argonaut, 1.69 mmol/g) and stirred at room temperature for 2 h. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure and dried in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 4-7% 1N ammoniacal methanol in dichloromethane) or by HPLC as described above. Yield: 231 mg (48%) of colorless solid
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:17]=O)[C:12]([CH:15]=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[NH2:24][CH2:25][C:26]#[N:27].C(N(CC)CC)C>CN(C=O)C>[O:16]=[C:15]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:6]3[CH:19]=[CH:20][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=2)[CH2:17][N:27]1[CH2:26][C:25]#[N:24]
Reactant: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1C=O
Reactant: N#CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCN1Cc2cc(OCc3ccc(C(F)(F)F)cc3)ccc2C1=O
Temperature: 25 °C
Yield: 7 %

Procedure:
To a cooled (0° C.) solution of 4-(4-trifluoromethyl-benzyloxy)-benzene-1,2-dicarbaldehyde (250.0 mg, 0.81 mmol) in DMF (7 mL) was added aminoacetonitrile HCl (150.1 mg, 1.62 mmol) and triethylamine (164.1 mg, 1.62 mmol) and the resulting mixture was warmed up to RT over 1 h and then heated at 50° C. for 1 h. After cooling to RT, the mixture was evaporated and the residue partioned between ethyl acetate and hydrochloric acid (1 N). The organic layer was then dried over sodium sulfate, filtered and evaporated to leave a clear oil which was purified by chromatography (SiO2, DCM:MeOH 9:1) to afford the title product (19.6 mg, 7%) as a light brown solid. MS m/e 345.2 (M−H−).
Reaction SMILES: C1(NN)C=CC=CC=1.C(OC)(OC)(OC)C.[C:17]1([NH:23][N:24]=[C:25](OC)[CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-:29][C:30]#[N:31].[Na+]>CO.O.C(O)(=O)C>[CH3:26][C:25]1[NH:31][C:30](=[O:29])[N:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:24]=1
Reactant: N#C[O-]
Reactant: COC(C)=NNc1ccccc1
Agent: COC(C)(OC)OC
Agent: [Na+]
Solvent: O
Solvent: NNc1ccccc1
Solvent: CO
Product: Cc1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
A stirred solution of 2.0 grams (0.019 mole) of phenylhydrazine and 11.1 grams (0.092 mole-5 eq.) of trimethyl orthoacetate (TMOA) in 20 mL of methanol was heated at reflux for about six hours. The reaction mixture was then allowed to cool to ambient temperature where it stirred for about 18 hours. The reaction mixture was again warmed to reflux where it stirred for another six hours, until the reaction to the intermediate N--phenyl--N'--(1-methoxyethylidene) hydrazine was complete. The progress of the reaction was monitored by gas chromatograph (GC). After this time, the reaction mixture was cooled in an ice-water bath (0° C.), and 1.5 grams (0.023 mole-1.2 eq.) of sodium cyanate was added. Upon completion of addition, 1.6 grams (0.026 mole-1.4 eq.) of acetic acid was added dropwise. The reaction mixture was then stirred at the ice-water bath temperature for about 10 minutes and then was allowed to warm to ambient temperature. After this time, two mL of water was added to the reaction mixture. Analysis of the reaction mixture by GC showed formation of the targeted compound. One mL of acetic acid was then added to the reaction mixture, followed by the addition of two mL of water. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was concentrated under reduced pressure, yielding 2.5 grams (75.9% yield) of 4,5-dihydro-3-methyl-l-phenyl-1,2,4-triazol-5(1H)-one.