Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:9](C([Sn])=C(CCCC)CCCC)[CH2:10]CC>CN(C=O)C.C1COCC1.O.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>[CH3:8][C:5]1[CH:4]=[N:3][C:2]([CH:9]=[CH2:10])=[CH:7][N:6]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cnc(C)cn1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-methyl pyrazine (2.0 g, 11 mmol) was dissolved in DMF:THF (3:1, 24 mL). Tributylvinyltin (3.0 g, 12.6 mmol) and Pd(PPh3)4 (0.172 g, 0.143 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 3 h. The reaction mixture was cooled to RT and diluted with water (240 mL) and extracted with ethyl acetate (3×150 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure below 40° C. The crude was purified through column chromatography (2% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-methyl-5-vinylpyrazine as a light yellow oil (1.0 g, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1c(Cl)cc(C=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1c(Cl)cc(CO)cc1OC
Yield: 86.2 %

Procedure:
The compound was prepared according to general procedure F with Ethyl 2-(2-chloro-4-formyl-6-methoxyphenoxy)acetate (1.5 mmol) in THF (20 ml) and water (20 ml) and NaBH4 (1.5 mmol). 355 mg of compound were obtained. This compound was used without further purification. 1H NMR (250 MHz, CDCl3): δ 1.31 (t, J=7.1 Hz, 3H), 3.86 (s, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.55 (s, 2H), 4.60 (s, 2H) 6.95 (s, 1H), 6.98 (s, 1H). MS (ESI): m/z 274.9 and 276.9 [M+H]+, 570.7 and 572.7 [2M+Na]+
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20]1[N:29]=[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([Cl:40])[CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:41]#[N:42])[CH:26]=2)[N:21]=1>CC(O)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:20]2[N:29]=[C:28]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([Cl:40])[CH:33]=3)[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:41]#[N:42])[CH:26]=3)[N:21]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: COc1ccc(CNc2nc(Cl)nc3ccc(C#N)cc23)cc1Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2nc(NCc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc3n2)CC1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
3.5 g of ethyl isonipecotate, 2.25 g of triethylamine and 30 ml of 2-propanol were added to 1 g of 2-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was refluxed for 30 minutes and cooled to room temperature. The crystals thus precipitated were recovered by filtration and washed with water and ethanol successively to give 1.13 g of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.Br[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]#[N:25])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCC#N)cc3=O)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (3.0 g), bromoacetonitrile (0.82 ml), potassium carbonate (4.42 g) and DMF (10 ml) was stirred at 80° C. for 2 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc). The resulting solid was washed with IPE to give the title compound (2.39 g) as a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:11])=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:11])[CH:5]=2)=[N:14][CH:15]=1
Reactant: Cc1cc(B(O)O)sc1C=O
Reactant: Clc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(Cl)cn2)sc1C=O
Temperature: 80 °C

Procedure:
To a degassed solution of 5-formyl-4-methylthiophen-2-ylboronic acid (2.21 g, 13.0 mmol, commercially available), 2-bromo-5-chloropyridine (2.00 g, 10.4 mmol, commercially available) and 2 N Na2CO3 (10.4 mL, 20.8 mmol) in DMF (70.2 mL) was added PdCl2dppf (0.380 g, 0.520 mmol); the flask degassed and heated to 80° C. for 2.0 h. Upon cooling, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×75 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography (silica gel, CH2Cl2:EtOAc, 100:0 to 0:100) to afford 2.01 g of the title compound as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.96 (1H, s), 8.57 (1H, s), 7.98 (2H, s), 7.75 (1H, s), 2.49 (3H, s).HPLC retention time: 3.158 min; LCMS (ES): m/z 238 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([OH:12])=O)[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[N:24][N:23]([CH3:26])[C:22]=1[C:27]([N:29]1[CH2:32][CH2:31][CH2:30]1)=[O:28]>>[N:29]1([C:27]([C:22]2[N:23]([CH3:26])[N:24]=[CH:25][C:21]=2[NH:20][C:10]([C:8]2[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)=[O:12])=[O:28])[CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)c1nc(C2CC2)cnc1Nc1cccnc1
Reactant: Cn1ncc(N)c1C(=O)N1CCC1
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cccnc2)c1C(=O)N1CCC1

Procedure:
The product was obtained starting from 6-cyclopropyl-3-(pyridin-3-ylamino)pyrazine-2-carboxylic acid (30 mg, 0.12 mmol; example 217, step 2) and (4-amino-2-methyl-2H-pyrazol-3-yl)-azetidin-1-yl-methanone (27 mg, 0.15 mmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as light yellow solid (37 mg, 75%).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:2].C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.C(=O)(O)[O-]>C(O)C>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]([C@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([CH2:9][C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:16]
Reactant: CCN(CC)C(=O)C1CN2CCC1C(=O)C2
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Agent: O=C([O-])O
Solvent: CCO
Product: CCN(CC)C(=O)[C@@H]1CN2CC[C@@H]1C(=O)C2
Reaction time: 8 h
Yield: 40.5 %

Procedure:
(3R*, 4R*)-N,N-Diethyl-5oxo-1-azabicyclo[2.2.2]octane-3-carboxamide (180 g, 0.804 mol) and (-)-dibenzoyl-L-tartaric acid (L-DBT) monohydrate (211 g, 0.561 mol) were added to ethanol (3.65L), and the resultant mixture was heated at reflux until a clear solution was obtained. The solution was rapidly cooled down to c.a. 40° C. in a water-bath, and allowed to stand overnight to form crystals, which were collected by filtration. The obtained crystals (100.5 g, 21.5%) were found to be (+)-(3R,4R)-N,N-diethyl-5-oxo-1-azabicyclo[2.2.2]-octane-3-carboxamide L-DBT salt with 97% optical purity. An additional amount of (-)-L-DBT monohydrate (90.6 g, 0.241 mol) was added to the mother liquor, which was concentrated to c.a. 3.5L by evaporation. The resulting mixture was heated at reflux to give a clear solution, which was allowed to stand at room temperature. After 2 days, formed crystals were collected by filtration. The crystals (117 g, 25%) were found to be (-)-(3S,4S)-N,N-diethyl-5-oxo-1-azabicyclo[2.2.2]-octane-3-carboxamide L-DBT salt with 92% optical purity. The same resolution process was repeated starting from 220 g of (3R*, 4R*)-N,N-diethyl-6-oxo-1-azabicyclo[2.2.2]-octane-3-carboxamide. From this run, the L-DBT salt of the (+) enantiomer (180 g, 31%) with 95% optical purity and the L-DBT salt of the (-) enantiomer (91 g, 16%) with 97% optical purity were obtained. The L-DBT salt of the (-) enantiomer from the above two runs were combined, and suspended in 1.5L of ethanol. The resulting suspension was heated at reflux for 3 hours, and allowed to stand overnight at room temperature. The obtained crystals were converted to the free amine by base treatment (aqueous bicarbonate) followed by extraction with methylene chloride to afford (-)-(3S,4S)-N,N-diethyl-5-oxo-1-azabicyclo[2.2.2]-octane-3-carboxamide (73 g, 18%) having greater than 99% optical purity. Similarly, 83 g of of the (+) enantiomer (21%) was obtained with greater than 99% optical purity. The above mentioned optical purities were determined using a chiral HPLC. The absolute configuration was determined by X-ray crystallography of the dibenzoyl-L-tartaric acid salt of the (-) enantiomer.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[N:3]=1>CO.[OH-].[NH4+].[Ni]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH2:9])[N:3]=1
Reactant: Cc1ccnc(C#N)n1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccnc(CN)n1
Reaction time: 2 h

Procedure:
4-methylpyrimidine-2-carbonitrile (450 mg) in MeOH (5 mL), aqueous ammonium hydroxide (1 mL) and Raney Nickel (catalytic) were added and the reaction mixture was hydrogenated at 55 psi for 2 h. Then the reaction mixture was filtered and solvent evaporated to afford (4-methylpyrimidin-2-yl)methanamine, which was carried to next step without purification.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][C:14]=2[CH:23]2[CH2:25][CH2:24]2)[C:8]2[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:7]=2[N:6]([C:32]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[C@H:5]1[CH3:40].[C:41]([N:48]([CH3:54])[C@H:49]([C:51](O)=[O:52])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:30]([C:28]1[CH:27]=[CH:26][C:8]2[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][C:14]=3[CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:11])[C@@H:4]([NH:3][C:51](=[O:52])[C@@H:49]([N:48]([CH3:54])[C:41](=[O:42])[O:43][C:44]([CH3:45])([CH3:47])[CH3:46])[CH3:50])[C@H:5]([CH3:40])[N:6]([C:32]([CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[O:33])[C:7]=2[CH:29]=1)#[N:31]
Reactant: C[C@H]1[C@H](N)C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N1C(=O)C1CCOCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a 0° C. solution of (3S,4S)-3-amino-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile dihydrochloride (60 mg, 103 μmol) in DMF (343 μl) was added Boc-N-methyl-L-alanine (23.0 mg, 113 μmol), N,N-diisopropylethylamine (89.1 μl, 515 μmol), and HBTU (43.0 mg, 113 μmol). The reaction was stirred at rt for 30 min, then diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (55.3 mg, 77%) as a white solid. MS m/z 695 (MH)+.
Reaction SMILES: [O:1]=[C:2]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccc([N+](=O)[O-])cc4)CC3)ccc2N1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCN(CCCC(O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1

Procedure:
1.5 Gram of 6-{1-oxo-4-[4-(4-nitrophenyl)piperazinyl]-butyl}-3,4-dihydrocarbostyril and 0.3 g of 5% palladium-carbon were dispersed in 150 ml of ethanol and catalytically reduced under 2 kg/cm2 of hydrogen gas for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was recrystallized from methanol to obtain 0.7 g of 6-{1-hydroxy-4-[4-(4-aminophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in brown powdery crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17](=[CH2:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[O:8][CH2:18][C:17]([CH3:19])=[CH2:16]
Reactant: C=C(C)CCl
Reactant: Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C)cc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of 2-bromo-p-cresol (10 ml, 82.7 mmol) in N,N-dimethylformamide (200 ml) were added potassium carbonate (17.2 g, 124 mmol) and methallyl chloride (9.8 ml, 99.2 mmol), and the mixture was stirred at 100° C. overnight. The mixture was diluted with ethyl acetate, and washed with water and saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give 2-bromo-4-methyl-1-[(2-methyl-2-propenyl)oxy]benzene (19.67 g, 99%) as a colorless transparent oil.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[C@@H:9]([CH3:11])[OH:10])=[O:6])[CH3:3].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>CN(C)C=O>[CH3:15][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[C@@H:9]([CH3:11])[O:10][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])=[O:6])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccccc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
A solution of N-[(1,1-dimethylethoxy)-carbonyl]-L-threonine (5.02 g., 22.9 mmol.) in dry dimethylformamide (10 ml.) was added dropwise over a period of 30 minutes to a cooled (0° C.) suspension of 60% sodium hydride (1.93 g., 48.25 mmol., 2.11 eq.) in dry dimethylformamide (40 ml.). The reaction was stirred at 0° C. until the frothing subsided (about 3.5 hours). The reaction mixture was treated dropwise with 1-fluoro-2-nitrobenzene (2.67 ml., 25.2 mmol., 1.1 eq.) over a period of 20 minutes and stirred at 0° C. under argon for 2 hours. The reaction mixture was then placed in the cold room (5° C.) and stirred overnight. The reaction mixture was poured into ice-water (500 ml.) and extracted with ethyl ether (2×200 ml.). The aqueous phase was brought to pH 1.0 with 6N hydrochloric acid (200 ml.) and extracted with ethyl acetate (3×300 ml.). The combined ethyl acetate extracts were washed with water (2×300 ml.), and brine (300 ml.), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude residue was loaded onto celite and purified by chromatography on a 10×20 cm. silica gel column. Elution with methylene chloride (31.), 99:1 methylene chloride:methanol (21.), 95:5 methylene chloride:methanol, and 100:5;0.5 methylene chloride:methanol:acetic acid (5 l.) gave 6.07 g. of title compound. TLC (methylene chloride:methanol:acetic acid, 100:5;0.5) Rf =0.16.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:9]2[N:5]([C:6](=[O:23])[N:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[C:8]2=[O:10])[CH2:4][CH2:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:24]([O:1][CH:2]1[CH:9]2[N:5]([C:6](=[O:23])[N:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[C:8]2=[O:10])[CH2:4][CH2:3]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC1CCN2C(=O)N(c3ccc(C#N)c4ccccc34)C(=O)C12
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a solution of 6C (123 mg, 0.4 mmol) in pyridine (3 mL) was added acetic anhydride (0.26 mL, 2.8 mmol), followed by 4-dimethylaminopyridine (15 mg). The reaction mixture was stirred at RT for 3 h, then quenched with water and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with 2% MeOH in EtOAc/hexane (1:1) to give 70 mg of the title compound (racemate) as a white solid. m.p. 105° C.; HPLC: 99% at 4.8 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 350 [M+1]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[OH:8][CH2:9][CH2:10][C@@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:25][CH2:26][CH:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:28][CH2:29]4)[C:13]=3[C:12]1=2
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO)CC4)CC1
Yield: 96.6 %

Procedure:
A solution of 22.2 (6.5 g, 11.57 mmol, 1.00 equiv) and Bu4NF (4.5 g, 17.24 mmol, 1.49 equiv) in tetrahydrofuran (100 mL) was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:1) and purified to give tert-butyl N-(4-[[(3S)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (22.3, 5 g, 97%) as a yellow oil. MS: m/z 448 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10](=[CH:16][NH:17][CH:18]2[CH2:20][CH2:19]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:21])[C:3]=1[Cl:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:21][C:4]1[C:3]([Cl:22])=[C:2]2[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]2[CH:18]2[CH2:20][CH2:19]2)=[CH:6][N:5]=1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cnc(Cl)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
17.5 g (0.048 mol) of ethyl 2-(4,5,6-trichloronicotinoyl)-3-cyclopropylamino-acrylate are heated with 7.7 g (0.056 mol) of potassium carbonate in 100 ml of DMF at 60° C. for two hours. Ice-water is added to the cooled mixture, and the product is isolated.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[NH2:20][C:19]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NNc1ccccc1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccc2)c1N
Temperature: 0 °C
Reaction time: 48 h
Yield: 55.7 %

Procedure:
A solution of 31.9 g of phenylhydrazine and 50.0 g of ethyl (ethoxymethylene)cyanoacetate (both reactants were obtained from Aldrich Chemical Company, Milwaukee, Wis.) disssolved in 500 ml of ethanol was refluxed for 6 hours. The mixture was allowed to stand for approximately 48 hours and was refluxed for an additional 8 hours. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration. The solid was recrystallized from ethanol to afford 38.0 g of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 44%. mp=101°-103° C.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C@@H:15]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36]C)[CH:31]=2)[C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:23]3)=[CH:18][CH:17]=2)[C@@H:10]([CH3:38])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C@@H:15]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)[C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:23]3)=[CH:18][CH:17]=2)[C@@H:10]([CH3:38])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc([C@@H](c2ccc3c(c2)CN(CC(=O)O)CC3)N2C[C@H](C)N(Cc3ccccc3)C[C@@H]2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H]1CN([C@@H](c2cccc(O)c2)c2ccc3c(c2)CN(CC(=O)O)CC3)[C@@H](C)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a solution of the compound of Example 105 (0.34 g) in dichloromethane (20 ml ) at —78° C. was added boron tribromide (2.6 ml ). the reaction was allowed to warm to room temperature. After 2 hours, the reaction was quenched with ammoniacal methanol solution and the solvent removed under reduced pressure. The crude material was purified on silica eluting with 80:20:3 dichloromethane:methanol:ammonium hydroxide. The product containing fractions were pooled and the solvent removed under reduced pressure. The solid was purified further using MCI gel chromatography eluting with a solvent gradient of 100:0 to 0:100 water:methanol. The product-containing fractions were concentrated, a small volume of concentrated ammonium hydroxide added and the solution freeze-dried to give the title compound (0.11 g).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13]I.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCNCC1
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)C1CCN(CCC(F)(F)F)CC1
Yield: 23.4 %

Procedure:
Prepared from isonipecotamide (2.85 g, 22.3 mmol), 3,3,3-trifluoropropyl iodide (5 g, 22.3 mmol) and potassium carbonate (3.08 g, 22.3 mmol) of according to the procedure used for Example 8 (Step A) to give 1.17 g of the title compound.