Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C@H:24]3[CH2:26][C@H:25]3[CH2:27][CH2:28][OH:29])[CH2:20][CH2:19]2)=[N:16][CH:17]=1>C(Cl)Cl.O>[Cl:11][C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C@H:24]3[CH2:26][C@H:25]3[CH2:27][CH:28]=[O:29])[CH2:20][CH2:19]2)=[N:16][CH:17]=1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: O=CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Temperature: -50 °C
Reaction time: 0.03 h

Procedure:
A flame dried flask was charged with DCM (20 ml) and oxalyl chloride (0.90 g, 0.62 mmol) under N2. The vessel was cooled to −50° C. in an acetorntrile:dry ice bath. DMSO (1.1 g, 14.2 mmol) was added drop wise after which the solution was stirred for 2 minutes. A solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol from step 6 of Example 1 (1 g, 3.55 mmol) in DCM (15 ml) was added drop wise and the mixture was stirred for 15 minutes. TEA (2.88 g, 28.4 mmol) was added, the mixture stirred for 15 minutes at −50° C. and then allowed to warm to RT for 1 hour. Water (15 ml) was then added drop wise, the mixture diluted with an additional 50 ml water. The mixture was then place in a separatory funnel, shaken and the layers separated. The aqueous phase was extracted with DCM (2×35 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered, and the volatiles removed in vacuum strip. The product was purified by chromatography on SiO2 eluting with 30% acetone:hexanes. LRMS calc: 279.11; obs: 280.05 (M+1).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:6]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([N+]([O-])=O)[CH:16]=2)=[N:7][N:8]([CH3:14])[C:9]=1[O:10][CH:11]([F:13])[F:12]>CO>[Cl:4][C:5]1[C:6]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([O:2][CH3:1])[CH:16]=2)=[N:7][N:8]([CH3:14])[C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: Cn1nc(-c2ccc(C#N)c([N+](=O)[O-])c2)c(Cl)c1OC(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.9 ml of a 30% strength by weight solution of sodium methylate in methanol was added to a solution of 1.4 g (4.3 mmol) of 4-chloro-3-(4-cyano-3-nitrophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 30 ml of methanol. The mixture was stirred at room temperature for 6 hours and then cooled to 0° C. for about 16 h. The solid reaction product was then isolated. Yield: 0.6 g.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][CH2:37][OH:38])[CH2:31]1.CS(C)=O>CC(O)C>[OH:38][CH2:37][CH2:36][CH:32]1[CH2:33][CH2:34][CH2:35][N:30]([CH2:3][CH:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]=[C:13]([C:15]4[O:19][N:18]=[C:17]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:16]=4[C:26]([F:27])([F:28])[F:29])[O:12][N:11]=3)=[CH:6][CH:5]=2)[OH:1])[CH2:31]1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Reactant: OCCC1CCCNC1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: OCCC1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) in 2-propanol (2 mL) was added 2-(piperidin-3-yl)ethanol (19.41 mg, 0.150 mmol). The reaction mixture was heated to 80° C. DMSO (1 mL) was added to help solubilize. The reaction mixture was stirred overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 MeOH:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 MeOH:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the Example 31 was 13.0 mg, and its purity was 100%. 1H NMR (400 MHz, MeOD) δ ppm 8.18 (2H, d, J=8.03 Hz), 7.52-7.75 (7H, m), 5.01 (1H, ddd, J=8.60, 4.20, 4.02 Hz), 3.54-3.72 (2H, m), 3.13 (2H, br. s.), 2.73 (2H, br. s.), 2.32 (1H, br. s.), 2.11 (1H, br. s.), 1.61-1.92 (4H, m), 1.48 (2H, dd, J=13.68, 6.90 Hz), 1.04 (1H, br. s.). MS (m+1)=529.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1Cl)([O-:21])=[O:20]>CN(C=O)C>[N+:19]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3ccc(Nc4ccc([N+](=O)[O-])cc4[N+](=O)[O-])cc23)CC1
Yield: 53.4 %

Procedure:
A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.05 g, 0.207 mmol) and 2,4-dinitrochlorobenzene (0.75 g, 0.373 mmol) in dry DMF (2 mL) was refluxed 2 hours. The solvent was removed in vacuo and the residue was taken up in methylene chloride. The organic phase was washed with saturated sodium bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was recrystallized from ether to give 0.045g (54%) of the title compound: mp 153°-154° C. Analysis calculated for C21H21N5O4 ; C, 61.91; H, 5.20; N, 17.19. Found: C, 61.42; H, 5.10; N, 16.79.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])[CH3:14]
Reactant: CC(C)=O
Reactant: O=Cc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
To a mixture of 2,4-difluorobenzaldehyde (5.0 ml, 45.7 mmol) and acetone (10.75 ml, 146 mmol) in Water (10 ml), was added 0.25M sodium hydroxide (18.30 ml, 4.57 mmol). The reaction mixture was heated to for 2 h. The mixture was poured into ice water. It was extracted with ethyl acetate (200 ml). The organic layer was dried, filtered, and evaporated to give (E)-4-(2,4-difluorophenyl)but-3-en-2-one as yellow oil. It was used for the next reaction without purification. 1H NMR (CDCl3/400 MHz): δ (ppm) 7.60 (d, 1H), 7.60-7.53 (m, 1H), 6.96-6.86 (m, 2H), 6.73 (d, 1H), 2.39 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:61][CH3:62])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([F:60])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[C@@H:48]([CH3:59])[CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C1COCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:61][CH3:62])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([F:60])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][NH:49][C@@H:48]([CH3:59])[CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
283(b) The partially purified 1,1-dimethylethyl (2S)-4-[(3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate was mixed with THF (1 mL) and TFA (0.2 mL). The mixture was stirred at room temperature for 1 h. Purification was done with a Gilson HPLC using TFA conditions. The desired fraction was collected, concentrated and re-dissolved in MeOH. Filtration though an amine cartridge and solvent concentration then afforded the above named product (10 mg). LC-MS m/z 747 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)#[N:2].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH2:11][O:10][C:9]1[CH:8]=[C:7]([CH:24]=[CH:23][CH:22]=1)[O:6][CH2:5][CH2:4][CH2:3][C:1]1[NH:27][N:26]=[N:25][N:2]=1
Reactant: N#CCCCOc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OCCCc2nnn[nH]2)cc(OCc2ccc3ccccc3n2)c1
Temperature: 140 °C

Procedure:
A mixture of 4.4 g of 2-[3-(3-cyanopropoxy)phenoxymethyl]quinoline 2.6 g of sodium azide and 2.1 g of ammonium chloride in 35 ml of dry dimethylformamide is heated at 140° C. for 18 hours. The reaction mixture is poured onto ice. A solution of 20 ml of 1N sodium hydroxide is added and the solution is extracted twice with ethyl acetate. Concentrated hydrochloric acid is added to acidify the aqueous portion. This is extracted twice with ethyl acetate, dried and evaporated to give 4.5 g of a tan solid. Recrystallization from ethyl acetate gives 1.5 g of pure product of M.P. 147°-149° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]3[CH2:43][CH2:42]3)=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]3[CH2:42][CH2:43]3)=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (311 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][CH:31]=O)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][CH2:31][N:51]4[CH2:52][CH2:53][CH:48]([OH:47])[CH2:49][CH2:50]4)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: O=CCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: OC1CCN(CCn2cc3c(-c4ccc(F)cc4)c(-c4ccncc4)c(-c4ccc(F)cc4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
In a volumetric flask, 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetaldehyde (0.08 g, 0.2 mmol, obtained in example 94), sodium triacetoxyborohydride (0.08 g, 0.4 mmol), 4-hydroxypiperidine (0.02 g, 0.2 mmol) and 1,2-dichloroethane (3 mL) were introduced under argon atmosphere. The mixture was stirred overnight at room temperature. It was concentrated and a mixture of water and EtOAc were added. The phases were separated. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using increasing polarity mixtures of EtOAc-MeOH as eluent, to afford 19 mg of the title compound (yield: 20%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:10]=[C:9]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:27][N:28]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)[CH3:29]>>[CH3:27][N:28]([CH3:29])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([O:13][CH:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[N:10]=3)=[CH:21][CH:22]=2)=[O:38])=[CH:32][CH:31]=1
Reactant: Nc1ccc(-c2nc(OC3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: CN(C)c1ccc(NC(=O)Nc2ccc(-c3nc(OC4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1

Procedure:
1-[4-(dimethylamino)phenyl]-3-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}urea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding 4-(N,N-dimethyl amino)phenylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 519.61.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[CH2:19][OH:20])=[N:16][C:15]([O:21][CH3:22])=[CH:14][CH:13]=2)C1C=CC=CC=1>[Pd].CO>[OH:20][CH2:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH3:22])[N:16]=2)[N:11]=[CH:10][C:9]=1[OH:8]
Reactant: COc1ccc2ncc(OCc3ccccc3)c(CO)c2n1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2ncc(O)c(CO)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
10% Palladium on activated carbon (140 mg, 0.13 mmol, 0.1 eq) is added at room temperature to a stirred solution of (3-benzyloxy-6-methoxy-[1,5]naphthyridine-4-yl)-methanol (390 mg, 1.32 mmol, 1.0 eq) in methanol (30 mL). The resulting mixture is stirred under hydrogen flow (4 bars) at room temperature for 1 hour. The catalyst is then removed by filtration and the solution is concentrated to afford 4-hydroxymethyl-6-methoxy-[1,5]naphthyridin-3-ol as a white solid (220 mg, 81% yield).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=C[C:11]=2N=N1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[CH:43]=[C:44]([C:51]([N:53]([CH3:55])[CH3:54])=[O:52])[CH:45]=[C:46]([CH:50]=3)[C:47](O)=[O:48])[CH:40]=2)[N:35](COCC[Si](C)(C)C)[N:34]=1.C(N)C.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:12]([NH:8][C:47](=[O:48])[C:46]1[CH:50]=[C:42]([C:39]2[CH:40]=[C:41]3[C:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])=[N:34][NH:35][C:36]3=[N:37][CH:38]=2)[CH:43]=[C:44]([C:51]([N:53]([CH3:55])[CH3:54])=[O:52])[CH:45]=1)[CH3:11]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(C(=O)O)cc(C(=O)N(C)C)c3)cc12
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc(C(=O)N(C)C)cc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
In a microwave vial O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexa-fluorophosphate (34.8 mg, 0.9 mmol) was added to a solution of 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-iso-phthalamic acid (50 mg, 0.09 mmol), ethyl amine (69 μL, 0.14 mmol), and di-iso-propyl ethyl amine (47.8 μL, 0.27 mmol) in tetrahydrofuran (1 mL). The vial was sealed and the solution irradiated to 100° C. for 10 min in a microwave reactor. The solvent was then removed on under reduced pressure. Trifluoroacetic acid (1 mL) was then added to the residue and the mixture stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure and the residue purified by preparative high pressure liquid chromatography to give N-ethyl-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N′,N′-dimethyl-isophthalamide (5.30 mg, 13% yield). 1H-NMR (500 MHz, Dimethyl sulfoxide-d6) δ 1.15 (t, J=14 Hz, 3H) 2.97 (s, 3H); 3.03 (s, 3H)); 3.29 (dq, J=5.5 Hz, J=7 Hz, 2H); 3.84 (s, 3H); 7.11 (t, J=7.5 Hz 1H); 7.23 (d, J=8 Hz 1H) 7.48 (t, J=7.5 Hz, 1H); 7.67 (d, J=8 Hz 1H); 7.86 (s, 1H); 7.94 (s, 1H); 8.25 (s, 1H); 8.45 (s, 1H); 8.69 (t, J=5.5 Hz, 1H); 8.94 (s, 1H); 13.88 (s, br, 1H) MS: m/z 444.0 (M+H+).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][S:13][CH:14]=2)=[CH:6][CH:5]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Br>O>[O:19]1[CH2:18][CH:17]1[CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[N:12][S:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2csnn2)cc1
Reactant: BrCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(-c2csnn2)ccc1OCC1CO1

Procedure:
To a solution of 0.112 g. of sodium hydroxide in 10 ml. of water is added 0.499 g. of 4-(4-hydroxyphenyl)1,2,3-thiadiazole and to the resulting solution is added dropwise, under stirring, 0.66 ml. of epibromohydrin, in a 5 minute period. The reaction mixture is stirred for 48 hours and extracted several times with ethyl acetate. The combined organic extracts are washed with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness under vacuo. The semisolid residue is crystallized from methylene chloride-hexane to yield the pure 4-[4(2,3-epoxypropoxy)phenyl] 1,2,3-thiadiazole.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[N:28](COCC[Si](C)(C)C)[CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH2:5]1)#[N:2].[F:39][C:40]([F:44])([F:43])[CH2:41][NH2:42]>>[C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:42][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:16])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)O)cn5)C4)c3)ccnc21
Reactant: NCC(F)(F)F
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2cnc(C(=O)NCC(F)(F)F)cn2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 34, Step 3 starting from 5-{3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylic acid and 2,2,2-trifluoroethanamine. LCMS (M+H)+: m/z=482.1.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[N:44]([C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[C:50]#[N:51])=[C:45]=[O:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][N:40]([C:45]([NH:44][C:47]2[CH:54]=[CH:53][CH:52]=[C:49]([C:50]#[N:51])[CH:48]=2)=[O:46])[CH2:39][CH2:38]1
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(NC(=O)N2CCN(c3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) and 3-isocyanatobenzonitrile as the starting materials in 35% yield. LCMS for C30H28ClN8O (M+H)+: m/z=551.0. 1H NMR (300 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.34 (s, 1H), 8.95 (s, 1H), 8.14 (s, 1H), 7.97-7.96 (m, 2H), 7.79-7.75 (m, 2H), 7.48-7.37 (m, 2H), 7.13-7.03 (m, 3H), 6.89-6.82 (m, 2H), 3.63 (br s, 4H), 2.99 (s, 4H), 2.84 (brs, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[Si:10]([O:17][C@@H:18]1[C@H:22]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@@H:20]([NH2:32])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(O)C>[Si:10]([O:17][C@@H:18]1[C@H:22]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[CH2:21][C@@H:20]([NH:32][C:2]2[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=2)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2ncnc(Cl)c2F)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 77.6 %

Procedure:
A solution of 4,6-dichloro-5-fluoropyrimidine (102 mg, 0.61 mmol), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentanamine (200 mg, 0.56 mmol), and triethylamine (0.16 mL, 1.11 mmol) in ethanol (2.00 mL) was heated in a sealed tube under microwave irradiation at 140° C. for 1 h. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography (0 to 15% ethyl acetate/hexanes) to afford the title compound (213 mg, 70%) as a light yellow solid. LC/MS: Rt=2.60 min, ES+ 490.5 (AA standard).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][S:22]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 4-hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine (2.96 g, 14.8 mmol) (obtained as described in Reference Example 51(1)) in methylene chloride (90 ml) were added methanesulfonyl chloride (1.15 ml, 14.8 mmol) and triethylamine (2.07 ml, 14.8 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes, and then stirred for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was recrystallized from a solution of n-hexane:ethyl acetate (1:1) to afford 4-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)piperidine (3.31 g, yield 87%) as pale yellow crystals.