Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[N:10]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[N:10]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]3[C:42](=[O:43])[C:41]4[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:39]3=[O:48])[CH:24]=2)[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cn1cc(-c2cn(C(=O)OC(C)(C)C)c(=O)n2-c2c[nH]c3ccccc23)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cn(C(=O)OC(C)(C)C)c(=O)n2-c2cn(CCCCN3C(=O)c4ccccc4C3=O)c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
The product of step e) (0.034 g, 0.080 mmol), N-(4-bromobutyl)phthalimide (0.028 g, 0.10 mmol) and sodium hydride (95%, 0.0024 g, 0.10 mmol) was dissolved in dry DMF (0.5 ml). After stirring at room temperature for 1.5 hour HPLC shows complete reaction. The reaction was quenched by addition of aqueous acetic acid (1 M, 2 ml) and ethyl acetate (2 ml), the phases were separated and the organic phase washed with water (1×2 ml). Solvent removal followed by chromatographic purification on silica, eluting with heptane—ethyl acetate (20:80), furnishes the sub-title product (0.019 g, 38%) as a slightly brown solid.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CC(C)([O-])C.[K+].[Cl:12][C:13]1[C:14]([O:30][C:31]2[CH:32]=[N:33][C:34]([O:38][C@@H:39]([CH3:44])[C:40]([F:43])([F:42])[F:41])=[C:35]([Cl:37])[CH:36]=2)=[CH:15][C:16]([F:29])=[C:17]([CH:28]=1)[C:18](OC1C=CC(C)=CC=1)=[O:19]>C1COCC1>[Cl:12][C:13]1[C:14]([O:30][C:31]2[CH:32]=[N:33][C:34]([O:38][C@@H:39]([CH3:44])[C:40]([F:42])([F:43])[F:41])=[C:35]([Cl:37])[CH:36]=2)=[CH:15][C:16]([F:29])=[C:17]([CH:28]=1)[C:18]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:19]
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3cnc(O[C@@H](C)C(F)(F)F)c(Cl)c3)cc2F)cc1
Reactant: CS(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.1 %

Procedure:
To a solution of methanesulfonamide (26 mg, 0.28 mmol) in THF (2 mL) was added potassium tert-butoxide (32 mg, 0.28 mmol) and the mixture was stirred for 10 minutes at room temperature. A solution of 4-methylphenyl 5-chloro-4-({5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-yl}oxy)-2-fluorobenzoate (Preparation 230, 108 mg, 0.21 mmol) in THF (2 mL) was added and the mixture was stirred at 50° C. for 10 hours. The reaction mixture was allowed to cool to room temperature. The reaction was quenched with water and acidified with 1N aqueous citric acid solution. The mixture was extracted with DCM (3×5 mL) and filtered using a phase separation cartridge. The filtrate was concentrated in vacuo to give a crude product that was purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to give a product mixture as a white solid. The solid was purified by reverse phase column chromatography eluting with 5-95% CH3CN in water to give a white solid that was further purified using trituration with heptanes/acetone 9/1 to give the title compound (28 mg, 27%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([O:9]C(=O)C)=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17](O)=O.N>P(Cl)(Cl)(Cl)=O>[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[C:5]([OH:9])[CH:6]=2
Reactant: CC(=O)Oc1cnc(N)c(N)c1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ncc(O)cc2[nH]1
Temperature: 0 °C

Procedure:
0.5 g of 2,3-diamino-5-acetoxy-pyridine and 0.83 g of 2-methoxy-4-methanesulfonylamino-benzoic acid were refluxed for one hour in 20 ml of phosphorus oxychloride. The reaction mixture was combined with ice water and then ad]usted to pH 7 with concentrated aqueous ammonia. The product was then extracted with ethyl acetate and purified by column chromatography (silica gel, eluant: methylene chloride/ethanol 1:0.02 to 1:0.1). Yield: 0.06 g (6% of theory). Melting point: 225° C. (decomp.).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[NH:9][C:10](=[O:17])[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5]1.Br[CH2:25][C:26]([O:28]CC)=[O:27].O>CN(C=O)C>[CH3:3][N:4]1[C:8]2=[N:9][C:10]([O:17][CH2:25][C:26]([OH:28])=[O:27])=[CH:11][C:12]([C:13]([F:14])([F:16])[F:15])=[C:7]2[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5]1
Reactant: Cn1cc(-c2ccccc2)c2c(C(F)(F)F)cc(=O)[nH]c21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccccc2)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
NaH (23 mg, 0.56 mmol) was added to a stirred solution of 1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6(7H)-one (41 mg, 0.14 mmol) in DMF (4 ml) and the resulting mixture was stirred for 30 min. Then ethyl bromoacetate (47 mg, 6.50 mmol) was added and the mixture was stirred for additional 1 h. To the mixture water (0.5 ml) was added and stirred for 2 h. The reaction mixture was concentrated. 1N aqueous HCL was added to the mixture and the solution was extracted with diethyl ether. The organic layer was washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The crude product was purified by flash column chromatography (80% EtOAc in hexane) to yield the title compound (29 mg, 59%) [1H-NMR (CDCl3, 300 MHz) δ 7.45-7.30 (m, 5H), 7.05 (s, 1H), 7.00 (s, 1H), 5.03 (s, 2H), 3.81 (s, 3H); LCMS RtE=1.94 min; [M+H]+=351.0]
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.BrCC.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)=[O:20])[CH3:19]
Reactant: Brc1cccc2nccn12
Reactant: CCOC(=O)C(=O)OCC
Solvent: C1CCOC1
Solvent: CCBr
Product: CCOC(=O)C(=O)c1cccc2nccn12
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
Add Mg turnings (0.25 g, 9.95 mmol) to a solution of 5-Bromoimidazo[1,2-a]pyridine (1.5 g, 7.65 mmol) in tetrahydrofuran (20 ml). Heat the reaction to 60° C. and add bromoethane (1.2 ml, 11.1 mmol). Reflux for another 0.5 hours, cool and cannula dropwise into a solution of diethyl oxalate (5 ml) in tetrahydrofuran (5 ml) at −15° C. Stir at −15° C. for 0.5 hours and at room temperature for 0.5 hours. Quench the reaction by adding pH 7 buffer, extract into ethyl acetate, wash with saturated sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexane: methanol gradient gives the title compound as a light brown oil.
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18](Br)[CH:19]=[N:20][CH:21]=1.[Li]CCCC.Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([B:1]([OH:6])[OH:2])[CH:19]=[N:20][CH:21]=1
Reactant: COc1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cncc(B(O)O)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Triisopropyl borate (29.3 mL, 128 mmol) was added over 2 min to a solution of 5-methoxy-3-bromopyridine (20.00 g, 106.4 mmol) in toluene (140 mL) and tetrahydrofuran (35 mL) at −40° C. To this solution was added 2.5 M n-BuLi (51.1 mL, 128 mmol) drop-wise over 35 min while maintaining the temperature at −40° C. After the addition was complete, the reaction was stirred an additional 30 min at −40° C. and then was warmed to −15° C. over one hour. Into the reaction was poured 1 N HCl (175 mL), and the mixture was stirred vigorously for 30 minutes. The layers were separated, and the organic washed once with water (15 mL). The aqueous phases were combined and neutralized (to pH 7) with 5 N NaOH, at which point the boronic acid precipitated out. The biphasic mixture was extracted with THF (3×150 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to yield 15.36 g of 5-methoxy-3-pyridinylboronic acid as a light brown solid (94%).
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[K+]>O1CCCC1.CO>[CH3:1][N:2]([S:17]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3nccn3C)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1nccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
Ethyl 7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxylate (2.87 g) was dissolved in a mixed solvent of tetrahydrofuran (30 mL)-methanol (20 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (2.0 g) in water (20 mL)) was added to this solution, and the mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure to evaporate methanol. The obtained residue was acidified with aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.65 g, yield: 100%) as colorless crystals. MS: 335(MH+). melting point: 241-242° C.
Reaction SMILES: [C:1]1([C:11]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)(O)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O>[C:1]1([C:11]([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: C=C(c1c[nH]cn1)c1cccc2ccccc12

Procedure:
1-Naphthalen-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate H1) in acetic acid:water (˜2:1) was heated to 100° C. for 1 h. The mixture was basified with 1 M NaOH and extracted (6×) with CHCl3: iPrOH (3:1). The organic solution was dried over MgSO4, filtered, and concentrated onto silica gel. The material was eluted from a column of silica with 5% NH3-MeOH: CH2Cl2 to give 4-(1-naphthalen-1-yl-vinyl)-1H-imidazole.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[N:23][CH:22]=[C:21](Cl)[N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>CN1CCN(C)C1=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[N:23][CH:22]=[C:21]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nc(Cl)cnc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Solvent: CN1CCN(C)C1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nc(N3CCOCC3)cnc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 72 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(6-chloropyrazin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (300 mg) is dissolved in 1,3-dimethylimidazolidinone (2 ml), then thereto are added diisopropylethylamine (0.13 ml) and morpholine (0.6 ml), and the mixture is heated to 100° C. and stirred for 3 days. After adding distilled water, the mixture is extracted with ether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane: ethyl acetate=9:1→7:3) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[6-(morpholin-4-yl)pyrazin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (223.2 mg). MS (m/z): 669 [M+H]+
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[F:31][C:2]([F:1])([F:32])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH:29]=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1
Reactant: OCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=CCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a reaction vial charged with 2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanol 150 (0.250 g, 0.540 mmol) was added 4 mL DCM to give a slurry. Next, Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 0.2522 g, 0.594 mmol) was added portion-wise and the reaction mixture was stirred at room temperature with LCMS monitor. Full conversion was seen after 30 minutes reaction time. The reaction mixture was diluted with water to give a white precipitate. This solid was collected by vacuum filtration, washed with EtOAc and dried on high vacuum to give the intermediate aldehyde, 2-(4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethanal. To a suspension of the aldehyde (0.160 g, 0.347 mmol) and diethylamine (0.127 g, 1.74 mmol) in 1.0 ml of DCM was added acetic acid (0.0198 mL, 0.347 mmol) and the reaction mixture was heated at 40 C for 1 hour. Finally sodium cyanoborohydride (0.0350 g, 0.556 mmol) was added in portions. The reaction mixture was heated at 40° C. for 45 minutes with complete conversion to product as determined by LCMS. The cooled reaction mixture was diluted with DCM, washed with water and saline, and concentrated to a solid which was purified by RP-HPLC to give 484. MS: (ESI+)=518.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH2:25][CH2:26][CH2:27][CH:28]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(N(CC)CC)C>O1CCOCC1.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]>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:23]3[O:24][CH2:25][CH2:26][CH2:27][CH:28]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nc2c(OC)ccc(C3=CCCCO3)c2s1

Procedure:
From (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester with tributyl-(5,6-dihydro-4H-pyran-2-yl)-stannane, bis(dibenzylideneacetone)palladium, trifurylphosphine and triethylamine in dioxane. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:27]=[C:28]([CH:45]=[C:46]([F:48])[CH:47]=1)[O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[C:46]([F:48])[CH:47]=[C:26]([F:25])[CH:27]=4)=[CH:35][CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc(Oc3cc(F)cc(F)c3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (250 mg, 0.56 mmol, 1.00 equiv), 2-[4-(3,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (226 mg, 0.68 mmol, 1.20 equiv), tetrakis(triphenylphosphane)palladium (39 mg, 0.03 mmol, 0.06 equiv), dioxane (50 mL), sodium carbonate (149 mg, 1.41 mmol, 2.50 equiv), and water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath and then concentrated under vacuum. The resulting solution was extracted with dichloromethane and the organic layers combined, dried and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.237 g (81%) of tert-butyl (2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:20][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: CN(C)CCCOc1ccccc1C=O
Solvent: Cc1ccccc1
Product: CCCCN=Cc1ccccc1OCCCN(C)C
Yield: 92.1 %

Procedure:
2-(3-Dimethylaminopropoxy)bezaldehyde (32.5 g) is reacted with 11.5 g of n-butylamine in 150 ml of toluene following the procedure described in Example 1, part A, to yield 37.9 g of oil product, boiling point 124°-128° C/0.1-0.2 mm of Hg.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[CH2:15][C@H:14]([CH2:16]O)[C@@H:13]([OH:18])[C@H:12]1[OH:19].S(Cl)([Cl:22])=O.[OH-].[NH4+]>CN(C)P(N(C)C)(N(C)C)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[CH2:15][C@H:14]([CH2:16][Cl:22])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=S(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](CCl)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
(±)-(1R*,2S*,3R*,5R*)-3-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)-1,2-cyclopentanediol (J. Am. Chem. Soc. 1969, 91, 3075) (0.94 g, 3.54 mmol) was stirred in hexamethylphosphoramide (13 ml) with cooling (ice bath) while thionyl chloride was added. The mixture was stirred under nitrogen at 25° C. for 18 hours. Ice water (50 ml) was added to the cooled mixture. The resulting solution was neutralized with concentrated ammonium hydroxide. The white precepitate was filtered off and dissolved in refluxing methanol (125 ml). Concentrated ammonium hydroxide (10 ml) was added and the solution allowed to cool slowly to 25° C. over 1 hour. The methanol was evaporated and the residual solid slurried in cold water and filtered to give title compound as an off-white powder (0.92 g, 92%); mp 188°-189° C. dec.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]([CH:39]=O)[CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:31]3[CH:30]=[N:29][C:38]4[C:33]([CH:32]=3)=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cnc2ccccc2c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cnc5ccccc5c4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and quinoline-3 carbaldehyde. MS (ESI) m/z 518.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[C:21]([F:28])[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[CH:22]=[C:21]([F:28])[N:20]=1
Reactant: OB(O)c1cc(F)nc(F)c1
Reactant: Fc1ccc(-c2nn3ccccc3c2Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3ccccc3c2-c2cc(F)nc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.1 %

Procedure:
A solution of 3-bromo-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine (from Example le, 570 mg, 1.96 mmol), 2,6-difluoro-4-pyridyl-boronic acid (340 mg, 2.15 mmol) and dichlorobis(triphenylphosphine)palladium (137 mg, 0.196 mmol) in DMF (10.0 mL) was placed in a pre-heated oil bath at 110° C. To the reaction was added, in a dropwise manner, 2M sodium carbonate (2.00 mL, 4.00 mmol). The reaction was allowed to stir for 45 min before cooling to room temperature and filtering through a Celite 545 pad. The Celite filter was washed with ethyl acetate and the filtrate was concentrated to dryness at 50° C. under vacuum. The residue was dissolved in methylene chloride and dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated and purified by silica gel chromatography to yield the title compound (160 mg, 0.492 mmol, 25%). 1H NMR (CDCl3) δ 8.53(d, 1H, J=6.8 Hz), 7.67(d, 1H, J=8.8 Hz), 7.53(dd, 2H, J=5.6, 8.0 Hz), 7.31(t, 1H, J=7.6 Hz), 7.11(t, 2H, J=8.4 Hz), 6.93(t, 1H, J=6.8 Hz), 6.75(s, 2H). MS (ES+ve): 326 (90, M+).