Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[C:9]([CH3:12])[N:10]=2)[N:5]([C@@H:14]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[CH2:15]2)[C:4](=[O:22])[N:3]=1.[Cl-].C[N+]1C=CN([C:30]([O:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:31])C=1.O>CN(C=O)C>[CH3:12][C:9]1[N:10]=[C:11]2[C:6](=[N:7][C:8]=1[CH3:13])[N:5]([C@@H:14]1[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[CH2:15]1)[C:4](=[O:22])[N:3]=[C:2]2[NH:1][C:30]([O:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:31]
Reactant: C[n+]1ccn(C(=O)OCCc2ccc([N+](=O)[O-])cc2)c1
Reactant: Cc1nc2c(N)nc(=O)n([C@H]3C[C@H](O)[C@@H](CO)O3)c2nc1C
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(NC(=O)OCCc3ccc([N+](=O)[O-])cc3)nc(=O)n([C@H]3C[C@H](O)[C@@H](CO)O3)c2nc1C
Temperature: 25 °C

Procedure:
A mixture of 1.54 g (5 mmol) of 4-amino-6,7-dimethyl-1-(2-deoxy-β-D-ribofuranosyl)-pteridine-2-one (56) and 1.87 g (6 mmol) of 1-methyl-3-[2(4-nitrophenyl)ethoxycarbonyl]imidazolium chloride (see Himmelsbach, et al. Tetrahedron 40: 59 (1984) which is herein incorporated by reference) in 80 mL of anhydrous DMF was stirred at room temperature over night. To this solution was slowly added 100 mL of H2O with stirring. The solution was then cooled and the precipitate collected by suction and, after washing with methanol and ether and drying in a desiccator, gave 57 as 2.0 g (80% yield) of crude material. Recrystallization from methanol yielded 1.5 g (60% yield) of colorless crystals (m.p. 154°-155° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([Si](C)(C)C)=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F-].[Cs+]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C[Si](C)(C)c1c(Br)cc(C=O)c(F)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cc(F)c1F
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 18.0 g of 5-bromo-2,3-difluoro-4-trimethylsilanyl benzaldehyde in 20 mL of N,N-dimethylformamide and 2 mL of water was added 1.63 g of cesium fluoride at room temperature, and stirred at this temperature for 1 hour. After diluting with ethyl acetate, the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to afford 10.26 g of the title compound as a colorless oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)C)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 46.8 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 486 mg (4.0 mmol) of pivaloyl chloride, to provide 594 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[C:11]4[O:19][CH2:18][CH2:17][O:16][C:12]4=[CH:13][CH:14]=3)[C:9](=O)[O:8]2)[CH2:4][CH2:3]1.O1CCCC1.B.Cl>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[C:11]4[O:19][CH2:18][CH2:17][O:16][C:12]4=[CH:13][CH:14]=3)[CH2:9][O:8]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)OC(=O)c1c2ccc2c1OCCO2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC2(CC1)OCc1c2ccc2c1OCCO2
Yield: 70.3 %

Procedure:
Into a 100 ml round bottom flask fitted with a nitrogen inlet, condenser, and magnetic stirring bar containing 10.9 ml of anhydrous tetrahydrofuran at 0° was placed 1′-methyl-(4,5-ethylendioxy)spiro(isobenzofuran-1(3H),4′-piperidin)-3-one (1.124 g, 4.08 mmol). Borane tetrahydrofuran complex (1.0 M in tetrahydrofuran, 10.2 mmol) was added slowly via syringe. The mixture was heated to reflux for 72 hours and then cooled to 0°. 5N hydrochloric acid (4 ml) was then added via syringe before heating the mixture to reflux again for 5 hours. The solution was then concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was made basic with concentrated ammonium hydroxide and sodium chloride was added past point of saturation. The aqueous layer was extracted again with ethyl acetate (three times) and the combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was taken up in 2% methanol:ammonium hydroxide and chromatographed (100:10:1 methylene chloride:methanol:ammonium hydroxide) to give 750 mg of subtitled product (70%) which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of 3 g (21.56 mmol) of 3-nitrophenol, 4.3 g (22 mmol) of tert-butyl bromoacetate, 3.2 g of anhydrous potassium carbonate and 50 ml of acetone is stirred overnight at room temperature. The mixture is filtered and washed with acetone and both the filtrate and the washing product are evaporated to give a yellow oil. The oil is purified on a silica gel chromatography column using an EtOAc/cyclohexane mixture (50/50) as the eluent to give 5 g (92%) of tert-butyl 3-nitrophenoxyacetate (colourless oil). 2 g of Pd/C (10%) are added to a solution of 4.8 g (18.95 mmol) of tert-butyl 3-nitrophenoxyacetate in 20 ml of ethanol and the mixture is hydrogenated overnight at one atmosphere. The catalyst is filtered off. The solvent is evaporated off to give 3.38 g (80%) of tert-butyl 3-amidophenoxyacetate, which is chromatographed on a silica gel column using an EtOAc/cyclohexane mixture (50/50) as the eluent. A mixture of the resulting amine (0.5 g, 2.24 mmol) and 1,2-epoxy-3-phenoxypropane is heated at 70° C. overnight. After cooling, the product is washed with ethanol and the precipitate is filtered off to give 0.6 g of the tert-butyl ester. 0.6 g of this ester and 15 ml of 6 N HCl are mixed overnight at 80° C. The solvent is evaporated off and the residue is washed with an EtOH/CH3CN mixture and then recrystallized from CH3CN to give 0.36 g of a salt with the following characteristics: melting point 138-139° C.; 1H NMR (DMSO-d6) δ 3.82 (m, 2H), 3.96 (m, 4H), 4.06 (m, 1H), 4.72 (s, 2H), 6.88-7.00 (n, 5H Ar), 7.24-7.45 (m, 4H Ar).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH2:14][CH:13]2[C:19]([OH:21])=[O:20].N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH:17]1[CH:12]2[CH2:18][CH:15]([CH2:14][CH:13]2[C:19]([OH:21])=[O:20])[CH2:16]1
Reactant: O=C(O)C1CC2C=CC1C2
Reactant: Sc1ccc2ccccc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Product: O=C(O)C1CC2CC(Sc3ccc4ccccc4c3)C1C2
Temperature: 65 °C
Reaction time: 24 h

Procedure:
In a 50-mL one neck round bottom flask, 2-naphthalenethiol, Catalog No. 270849 from Aldrich Co. (1.50 g) was dissolved in tetrahydrofuran (3.36 g). In the same flask, 5-norbornene-2-carboxylic acid, Catalog No. 147230 from Aldrich Co. (1.32 g), and 2,2′-azobis(2-methylpropionitrile), Catalog No. 441090 from Aldrich Co. (0.014 g), were added. The flask was heated while stirring in a 65° C. oil bath for 24 hours. The product, 6-(2-naphthylthio)bicyclo[2.2.1]heptane-2-carboxylic acid (2.82 g) was isolated by removing tetrahydrofuran by rotary evaporation.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[CH2:33]([N:40]1[CH2:45][CH2:44][N:43]([C:46](=[O:68])[C@@H:47]([NH:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:59][CH:58]=2)[CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:48]([C@H:47]([N:55]([CH2:56][C:57]1[CH:58]=[CH:59][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:61][CH:62]=1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1)[C:46]([N:43]1[CH2:42][CH2:41][N:40]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:45][CH2:44]1)=[O:68])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCCCOc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
In an inert atmosphere, trans-4-(trifluoromethyl)cinnamic acid (28 mg, 0.13 mmol) was dissolved in DCM (0.5 mL) followed by the addition of 1-chloro-N,N,2-trimethylpropenylamine (19.4 mg, 0.145 mmol). The mixture was stirred at rt for 30 min followed by the addition of DIPEA (34 mg, 0.26 mmol) and 1-(4-benzyl-piperazin-1-yl)-2-(4-butoxy-benzylamino)-(S)-3-phenyl-propan-1-one (63 mg, 0.13 mmol). Stirring was continued for 30 min. The mixture was concentrated in vacuo and the residue was directly purified by prep. HPLC to give 51 mg (57%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-butoxy-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.02 min; [M+H]+=684.49.
Reaction SMILES: [CH2:1]([C:3]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:8][CH2:7][N:6]([C:9]([C@:11]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:34])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([OH:33])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:10])[CH2:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[CH3:52][C:53]1([CH3:60])[CH2:57][C:56](=[O:58])[O:55][C:54]1=[O:59]>C(OCC)(=O)C>[CH2:44]([O:43][C:41]([C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([C:9]([C@:11]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:34])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([O:33][C:56](=[O:58])[CH2:57][C:53]([CH3:60])([CH3:52])[C:54]([OH:59])=[O:55])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:10])[CH2:7][CH2:8]1)=[O:42])[CH3:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(CC)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of ethyl 4-ethyl-1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)piperidine-4-carboxylate (Example 73, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) was added then 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) was added and the contents were refluxed for about 16 hours. Completion of the reaction was monitored by TLC, the reaction mixture was diluted with ethyl acetate (30 ml) and the organic layer was washed with 5% aqueous HCl, washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 753; (100%), [M+1].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[OH:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1.[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:40][C:41]1[CH:46]=[C:45]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(O)c2)c1
Temperature: 100 °C
Reaction time: 26 h
Yield: 57.4 %

Procedure:
To 400.0 mg (0.66 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 16 ml toluene were added 15.17 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 108.6 mg (0.79 mmol) (3-hydroxyphenyl)boronic acid in 4.0 ml ethanol and 118.3 mg (2.04 mmol) potassium fluoride in 4.0 ml water. The mixture was stirred at 100° C. for 26 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 236 mg (58%) tert-butyl 4-{3-[(3R)-3-({1-[5-(3-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH:9]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=O)(C)(C)C.[F:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[C:43]([F:45])[CH:44]=1>>[F:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH:48][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][C@@H:9]([CH2:28][C:29]5[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[NH:31][CH:30]=5)[CH2:10]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:42]=[C:43]([F:45])[CH:44]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1Cc1c[nH]c2ccccc12
Product: Fc1cc(F)cc(CCNc2nccc(-c3cccc(CN4CCN[C@@H](Cc5c[nH]c6ccccc56)C4)c3)n2)c1

Procedure:
Intermediate 109 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 540. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.59 (s, 1H), 8.34 (d, 1H), 8.29 (d, 1H), 7.84 (d, 1H), 7.60 (m, 3H), 7.33 (d, 1H), 7.26 (s, 1H), 6.98 (m, 4H), 6.72 (s, 1H), 4.63 (s, 2H), 4.16 (m, 1H), 4.04 (s, 2H), 3.49 (m, 4H), 3.26 (m, 4H), 3.05 (t, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][C@H:31]4[CH2:35][OH:36])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Reactant: OC[C@@H]1CCCN1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC[C@H]5CO)c34)cc2C)cn1
Yield: 7 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (S)-2-pyrrolidinemethanol to give the title compound in 7% yield; NMR Spectrum: 1.50-1.54 (m, 1H), 1.61-1.67 (m, 2H), 1.77-1.82 (m, 1H), 2.19 (s, 3H), 2.32-2.36 (m, 1H), 2.43 (s, 3H), 2.55-2.60 (m, 1H), 2.77-2.80 (m, 1H), 3.15 (br t, 1H), 3.25-3.29 (m, 2H), 3.37-3.42 (m, 1H), 4.40 (t, 2H), 6.95 (d, 1H), 7.18-7.24 (m, 2H), 7.63-7.66 (m, 2H), 8.16 (s, 1H), 8.28 (s, 1H), 8.31 (s, 1H); Mass Spectrum: 476 (MH+).
Reaction SMILES: C([NH:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(=O)(CNCc1ccccc1)OCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CN)OCC
Yield: 37113.4 %

Procedure:
A solution of diethyl (N-benzyl)aminomethylphosphonate (2.5 g, 9.7 mmol) in 30 ml of EtOH and 0.5 g of Pd(OH)2 was stirred under an atmosphere of hydrogen (1 atm) overnight. The reaction was filtered through celite and concentrated to give diethyl aminomethylphosphonate (600 mg, 3.6 mol). The crude phosphonate was dissolved in 30 ml of dichloromethane, cooled to 0° C., and treated with 4-phenoxybenzenesulfonyl chloride (800 mg, 3 mol) and triethylamine (1 ml, 7.2 mol). The ice bath was removed, the reaction was stirred for 4 h, and 20 mL of 5% HCl was added. The aqueous layer was extracted with 30 mL of dichloromethane, and the combined dichloromethane fractions were washed with brine, dried over magnesium sulfate, and concentrated to give diethyl[(4-phenoxy)benzenesulfonyl]aminomethylphosphonate (1.26 g, 88%) as a clear oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:6][CH2:5][C:4]=2[N:3]=1.[CH:22]([B-](F)(F)F)=[CH2:23].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CCO.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>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:7]2[CH2:6][CH2:5][C:4]3[N:3]=[C:2]([CH:22]=[CH2:23])[CH:11]=[CH:10][C:9]=3[C:8]2=[O:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CN2CCc3nc(Cl)ccc3C2=O)cc1
Reactant: C=C[B-](F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: C=Cc1ccc2c(n1)CCN(Cc1ccc(OC)cc1)C2=O
Temperature: 150 °C

Procedure:
2-chloro-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one, (1.5 g, 4.97 mmol) was dissolved in EtOH with potassium vinyltrifluoroborate (865 mg, 6.46 mmol), Cs2CO3 (2.42 g, 7.46 mmol) and Pd(PPh3)4 (115 mg, 0.01 mmol). The reaction was heated in a microwave synthesizer at 150° C. for 1 h. It was then concentrated and purified over silica gel (EtOAc/hexanes) to give after solvent removal and drying in vacuo the compound as an off-white solid (1.1 g, 76%). LC-MS (M+H)=295.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])CC2C=CC(OC)=CC=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[C:27]([Cl:49])=[C:28]([N:34]2[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C@H:36]([OH:48])[CH2:35]2)[CH:29]=[C:30]([C:32]#[N:33])[CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:49][C:27]1[C:26]([NH:25][C:2]2[N:7]=[C:6]([NH:8][CH2:18][CH3:19])[C:5]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]3[N:3]=2)=[CH:31][C:30]([C:32]#[N:33])=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])[C@H:36]([OH:48])[CH2:35]1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 10) (350.0 mg, 1.021 mmol), tert-butyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)carbamate (412.0 mg, 1.123 mmol), DPPF (39.6 mg, 0.071 mmol), Cs2CO3 (566 mg, 1.736 mmol), Xantphos (59.1 mg, 0.102 mmol), Palladium(II)Acetate (68.8 mg, 0.306 mmol) and 1,4-dioxane (11 ml) were combined in a microwave vial. The vial was evacuated and backfilled with Nitrogen 3×. The reaction stirred at 100° C. for 3 hr. The reaction mixture cooled to 25° C., diluted with EtOAc, washed with brine and dried (Na2SO4). The solvents were removed and the material purified on silica gel 25% EtOAc in DCM to afford tert-butyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (335 mg).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>>[CH2:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])([CH3:3])[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH3:8]
Reactant: ClCc1cccs1
Reactant: CCOC(=O)C(C)C
Product: CCOC(=O)C(C)(C)Cc1cccs1
Yield: 95 %

Procedure:
Ethyl isobutyrate (10.9 mL, 81.7 mmol) is alkylated with 2-(chloromethyl)thiophene according to general procedure F to give the product 44 as a yellow liquid (16.4 g, 95%). 1H NMR (CDCl3) 7.15-7.10 (m, 1), 6.95-6.90 (m, 1), 6.77 (d, 1, J=3.6), 4.15 (t, 2, J=7.0), 3.07 (s, 2), 1.26 (t, 3, J=7.0), 1.21 (s, 6); 13C NMR (CDCl3) 176.96, 139.80, 126.74, 126.42, 123.94, 60.59, 43.65, 40.30, 25.07, 14.22; MS (MW=212.3, CI/CH4, eE=70 eV) m/z 213 [(M+H)30 , base peak], 193, 179, 167, 140, 139, 125, 98, 97.