Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[O:13][CH2:12][CH:11]([OH:14])[CH:10]([OH:15])[CH2:9][CH2:8]2)=[C:5]([N+:16]([O-])=O)[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([NH:68][C:69]1[S:73][C:72]([C:74]2[C:79]([F:80])=[CH:78][CH:77]=[CH:76][C:75]=2[F:81])=[N:71][C:70]=1[C:82](O)=[O:83])=O)(C)(C)C>CO.C(Cl)Cl.Cl.O1CCOCC1.[Pd]>[NH2:68][C:69]1[S:73][C:72]([C:74]2[C:79]([F:80])=[CH:78][CH:77]=[CH:76][C:75]=2[F:81])=[N:71][C:70]=1[C:82]([NH:16][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[CH:7]1[CH2:8][CH2:9][C@@H:10]([OH:15])[C@@H:11]([OH:14])[CH2:12][O:13]1)=[O:83]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(O)C(O)CO1
Agent: [Pd]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC[C@@H](O)[C@@H](O)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
A solution of 7-(2-methyl-4-nitro-pyrazol-3-yl)oxepane-3,4-diol (Intermediate 10) (165 mg, 0.64 mmol) in MeOH (13 mL) was passed through the H-Cube (full H2 mode, 80° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure. To a solution of the resulting amine in DCM (10 mL) was added DIPEA (0.33 mL, 1.92 mmol), PyBOP (499 mg, 0.96 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (249 mg, 0.70 mmol). The mixture was stirred at room temperature for 18 hr, diluted with DCM (5 mL) and washed with water (3×5 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-10% MeOH/EtOAc) gave a pink solid. This solid (65 mg, 0.11 mmol) was dissolved in a solution of HCl in dioxane (4 M, 8.6 mL) and MeOH (2 mL) and stirred at room temperature for 18 hr. The solvents were removed under reduced pressure. Purification via preparative HPLC gave 111 as an off-white solid (28 mg, 9% over three steps). 1H NMR (400 MHz, CDCl3) δ 9.75 (br s, 1H), 8.17 (s, 1H), 7.39-7.32 (m, 1H), 7.10-7.00 (m, 2H), 6.25 (br s, 2H), 5.14-5.10 (m, 1H), 4.23 (dd, J=13.7, 4.0 Hz, 1H), 3.90-3.85 (m, 1H), 3.79 (s, 3H), 3.75-3.56 (m, 2H), 2.12-2.00 (m, 3H), 1.76-1.70 (m, 1H). OH protons not observed. LCMS (ES+) m/z 466 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24]#[N:25])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[C@@H:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1.C(OC(N1CCO[C@@H](C2C=CC(N)=CC=2[F:47])C1)=O)(C)(C)C>>[ClH:2].[C:24]([C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([CH3:23])[N:20]=1)[C:16]([NH:15][C:5]1[CH:6]=[CH:7][C:8]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[C:3]([F:47])[CH:4]=1)=[O:26])#[N:25]
Reactant: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(Cl)c2)cc(C#N)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2F)C1
Agent: Cl
Product: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(F)c2)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methyl-isonicotinic acid (described in example 112) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 83) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[C:38]([CH3:50])[CH:37]=3)[C:12]3[C:13]([F:35])=[CH:14][C:15]([O:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:51])=[N:6]1)([CH3:4])[CH3:3].C(Cl)Cl.C(O)(C(F)(F)F)=O.[OH-].[K+]>C(Cl)(Cl)Cl.O>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[C:38]([CH3:50])[CH:37]=3)[C:12]3[C:13]([F:35])=[CH:14][C:15]([O:20][CH2:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:51])=[N:6]1)([CH3:1])[CH3:3]
Reactant: COc1c(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OCC2CCNCC2)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Reaction time: 1 h
Yield: 100 %

Procedure:
To 1,1-dimethylethyl 4-{[(3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-yl)oxy]methyl}piperidine-1-carboxylate (178 mg, 0.26 mmol) was added CH2Cl2 (3 mL). The solution was cooled with an ice bath and TFA (0.5 mL) was added slowly. After 1 h, the reaction mixture was diluted with CHCl3 and water was added. The mixture was then basified with 1 M KOH (aq) and partitioned. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to provide 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-8-[(piperidin-4-ylmethyl)oxy]-3H-pyrazolo[3,4-c]isoquinoline (159 mg, 0.26 mmol, 100% yield) as a yellow sticky solid. 1H NMR (400 MHz, CDCl3): δ 7.51-7.33 (m, 7H), 6.98 (d, 1H), 6.81 (d, 1H), 5.16 (s, 2H), 4.03 (d, 2H), 3.89 (s, 3H), 3.55 (d, 2H), 3.04-2.95 (m, 2H), 2.88 (s, 3H), 2.37 (s, 3H), 2.26 (m, 1H), 2.16 (d, 2H), 1.85 (s, 9H), 1.88-1.80 (m, 2H); MS (EI) for C36H41FN4O3: 597 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:6]=O.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[F:17])[CH2:29][CH2:28]2)[CH:8]=[CH:9][C:10]=1[O:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: COc1cc(C=O)ccc1OC(=O)N(C)C
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(CN2CCN(c3ccccc3F)CC2)ccc1OC(=O)N(C)C
Yield: 78 %

Procedure:
To a solution of 3-methoxy-4-(dimethylaminocarbonyloxy)benzaldehyde (1.50 g) in 1,2-dichloroethane (14 ml) was added 1-(2-fluorophenyl)piperazine (1.21 g) in 1,2-dichloroethane (13 ml) and sodium triacetoxyborohydride (2.14 g), with stirring. The reaction mixture was stirred for 4 hrs at ambient temperature, poured into saturated sodium carbonate solution (75 ml) and extracted with dichloromethane. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatographed (silica gel), eluting with dichloromethane, followed by 0.1, 0.2, 0.4, 0.5, 1, and 2% methanol:dichloromethane. The appropriate fractions were combined and concentrated to afford 2.03 g (78%) of product. Recrystallization from ethyl acetate gave the analytical sample, mp 130-133° C.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:24]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl.CN(C)CCCN=C=NCC.[K+].[Br-]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH:24]1([CH2:36][CH2:37][C:38]([C:1]2[C:6](=[O:7])[S:5][CH2:4][C:2]=2[OH:3])=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CSC(=O)C1
Reactant: O=C(O)CCC1CCCCCCCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCC1CCCCCCCCCCC1)C1=C(O)CSC1=O
Reaction time: 0.08 h

Procedure:
To a solution of 0.80 g of thiotetronic acid in 20 ml of dry dimethylformamide at 0° C. is added 1.1 ml (836 mg, 8.3 mmol) of triethylamine and 0.31 g (2.5 mmol) of dimethylaminopyridine. After stirring for 5 minutes, 2.0 g (8.3 mmol) of 3-cyclododecylpropanoic acid is added followed by 1.6 g (8.3 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride. After 10 minutes the ice bath is removed and the reaction mixture is allowed to stir overnight at room temperature. The reaction mixture is then poured into 1N hydrochloric acid and extracted 3 times with ethyl acetate. The organic layers are combined, washed with brine, filtered and evaporated to give a brown oil. The oil is subjected to flash chromatography using acidic silica gel and hexane/ethyl acetate (9:1) as the mobile phase to give an off white solid: m.p. 60°-62° C.; IR (KBr) 2940, 1700, 1630, and 1590 cm1 : NMR (CDCl3) δ 1.33 (bs, 22H), 1.49 (bs, 1H), 1.58 (m, 2H), 2.96 (m, 2H), 3.77 and 3.98 (singlets, 2H); MS (EI) M+338.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[C:9]([F:10])=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[C:6]([N+:20]([O-:22])=[O:21])[C:5]=1[NH2:23].[CH3:25][N:26]1[CH:31]=[CH:30][C:29](OS(C(F)(F)F)(=O)=O)=[CH:28][C:27]1=[O:40].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[C:9]([F:10])=[C:8]([C:29]2[CH:30]=[CH:31][N:26]([CH3:25])[C:27](=[O:40])[CH:28]=2)[CH:7]=[C:6]([N+:20]([O-:22])=[O:21])[C:5]=1[NH2:23]
Reactant: COC(=O)c1c(N)c([N+](=O)[O-])cc(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: Cn1ccc(OS(=O)(=O)C(F)(F)F)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Product: COC(=O)c1c(N)c([N+](=O)[O-])cc(-c2ccn(C)c(=O)c2)c1F
Temperature: 90 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of 2-amino-5-bromo-6-fluoro-3-nitro-benzoic acid methyl ester (1.0 g, 3.4 mmol) in dioxane (25 mL), under nitrogen atmosphere, was added bispinacoladaboron (1.3 g, 5.1 mmol), dichloro[1,1′-bis(diphenylphosphine)ferrocene]palladium (II) dichlormethane adduct (0.125 g, 0.17 mmol), and potassium acetate (1.0 g, 10.2 mmol). The resulting mixture was heated at reflux for 18 hours, cooled to room temperature, diluted with ethyl acetate (50 ml) and filtered through Celite®. The resulting solid was triturated with hexanes (40 ml) three times to afford 0.515 g of 2-amino-6-fluoro-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester. To a mixture of 2-amino-6-fluoro-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester in ethylene glycol dimethyl ether (10 ml) was added trifluoro-methanesulfonic acid 1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl ester (0.39 g, 1.5 mmol), lithium chloride (0.25 g, 6.0 mmol), sodium carbonate (1.1 ml, 2.2 mmol of 2M), and tetrakistriphenylphosphine palladium (0.18 g, 0.15 mmol). The resulting mixture was heated to 90° C. and allowed to stir for 18 hours. After cooling and concentration in vacuo, the residue was purified by chromatography (Silica Gel 0.5% methanol/dichloromethane to 2% methanol/dichloromethane) to provide the title compound (0.275 g, 25%). 1H NMR (500 MHz, CDCl3) δ 3.58 (s, 3H), 4.03 (s, 3H), 6.30 (d, 1H), 7.32 (d, 1H), 8.45 (br s, 2H), 8.53 (d, 1H)
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].O1CCCC1.[NH2:18]/[C:19](=[N:36]\[OH:37])/[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22][CH2:21]1>ClCCl>[O:2]=[C:1]1[O:37][N:36]=[C:19]([C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24][CH2:25]2)[NH:18]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[Si](C)(C)CCOC(=O)N[C@H]1CC[C@H](/C(N)=N/O)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)N[C@H]1CC[C@H](c2noc(=O)[nH]2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Carbonyldiimidazole (1.24 g, 7.43 mmol) was added to a tetrahydrofuran (20 ml) solution of the compound (1.12 g, 3.71 mmol) obtained in Step 5 above under ice cooling and the resulting mixture was stirred at 50° C. for 24 hours. The reaction mixture was diluted with dichloromethane:methanol [10:1 (v/v)] and washed with 10% aqueous citric acid solution and saturated sodium bicarbonate solution in that order and then the organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=9:1→13:7→dichloromethane:methanol=49:1→19:1 (v/v)] to give 757 mg (62%) of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)=[O:25])=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>>[NH:29]1[CH2:30][CH:26]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:1][C:2]3[N:7]=[C:6]([C:8]4[N:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]5=[N:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)=[CH:19][CH:20]=2)=[O:25])[CH:27]=[N:28]1
Reactant: O=C(c1ccc(Br)cc1)c1cn[nH]c1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1)C1C=NNC1
Yield: 8 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo-[1,2-a]pyridin-3-yl)pyrimidine and (4-bromophenyl)(1H-pyrazol-4-yl)methanone following the general method of Example 1 using potassium tert-butoxide as the base. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 95:5, as the eluent affording 0.020 g (8% yield) of the title compound as a yellow solid: mp (decomp.) 229-232° C.; MS (TSP) m/z 382 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 10.27 (d, J=6.9 Hz, 1 H), 10.21 (s, 1 H), 8.76 (s, 1 H), 8.62 (d, J=5.4 Hz, 1 H), 8.30 (br s 2H), 8.03 (m, 5 H), 7.89 (m, 1 H), 7.62 (m, 2 H), 7.29 (m, 1 H).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CO[C:39]1N=CC(N)=C[CH:40]=1>>[NH2:8][C:3]([C:4]1[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)[CH2:13][CH2:14]2)[CH:7]=[CH:39][CH:40]=1)=[O:2]
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Reactant: COc1ccc(N)cn1
Product: NC(=O)c1cccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
N-(2-[((3R)-1-{1-[3-(aminocarbonyl)phenyl]piperidin-4-yl)pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, substituting 3-aminobenzamide for 6-methoxypyridin-3-amine. The crude product was purified by preparative HPLC. MS m/z: 518 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cn1nccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 67.8 %

Procedure:
In the same manner as in Example 259 and using 1-methyl-1H-pyrazole-5-carboxylic acid (100 mg, 0.79 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (89 μL, 1.0 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (180 mg, 68%) was obtained as a white solid. melting point 253° C.
Reaction SMILES: Cl.[C:2]([N:5]1[C:14]2[C:9](=[C:10]([O:28][CH2:29][CH2:30][CH3:31])[C:11]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:12][CH:13]=2)[CH2:8][CH2:7][C@@H:6]1[CH3:32])(=[O:4])[CH3:3]>O1CCOCC1.C(OCC)C>[CH3:32][C@H:6]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:10]=2[O:28][CH2:29][CH2:30][CH3:31])[N:5]1[C:2](=[O:4])[CH3:3]
Reactant: CCCOc1c(C2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Reaction time: 3 h

Procedure:
A solution of hydrogen chloride (4.0 N in 1,4-dioxane, 1.4 mL, 5.6 mmol) was added to a solution of (S)-tert-butyl 4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate (480 mg, 1.1 mmol) in 1,4-dioxane (3 mL). The reaction was stirred for 3 hours resulting in a white precipitate. The reaction solution was diluted with diethyl ether (10 mL) and the precipitate was collected by filtration. The filtrate was further washed with diethyl ether (10 mL), collected and dried in vacuo affording the hydrochloride salt of the title compound as a white powder. The salt was free based via neutralization in ethyl acetate with saturated aqueous sodium carbonate solution until a pH=7.5 was achieved. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo affording (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (356 mg, 97%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96-1.06 (m, 6H), 1.11-1.26 (m, 1H), 1.38-1.61 (m, 4H), 1.66-1.89 (m, 2H), 2.20 (s, 3H), 2.16-2.28 (m, 2H), 2.52 (m, 2H), 2.67-2.80 (m, 2H), 2.83-2.94 (m, 1H), 2.99 (br d, J=12.02 Hz, 2H), 3.58-3.72 (m, 2H), 4.40-4.63 (br d, J=6.75 Hz, 1H), 7.03 (br s, 2H). MS (ESI, pos. ion) m/z 331 [M+H]+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:16])[CH2:13][O:14][CH3:15])[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]=2[C:23]=1[F:24].Cl[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.CCN(C(C)C)C(C)C>CC(O)CC>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:16][C:26]3[N:34]=[CH:33][N:32]=[C:31]4[C:27]=3[N:28]=[CH:29][N:30]4[CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH2:13][O:14][CH3:15])[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:8]=2[C:23]=1[F:24]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: COC[C@H](N)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: COC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Temperature: 90 °C

Procedure:
To a solution of (R)-1-(6,7-difluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethylamine dihydrochloride (0.20 g, 0.68 mmol) in 2-butanol (5 mL) was added 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (0.195 mg, 0.81 mmol) and DIPEA (233 μL, 1.36 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give the title compound as an off white solid (290 mg, 84%). LCMS (Method C): RT=3.48 min, [M+H]+=506.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][NH:12][C:13](=[O:28])[NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:26]O)[C:21](OCC)=[O:22])[N:19]=1.OS([O-])(=O)=O.[Na+].Cl>CO.C1COCC1>[NH2:26][CH:20]([C:18]1[N:19]=[C:15]([NH:14][C:13]([NH:12][CH2:11][C:10]2[CH:29]=[CH:30][CH:31]=[C:8]([F:7])[CH:9]=2)=[O:28])[S:16][CH:17]=1)[CH2:21][OH:22]
Reactant: CCOC(=O)C(=NO)c1csc(NC(=O)NCc2cccc(F)c2)n1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CO
Product: NC(CO)c1csc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
LiAlH4 (10 mL, 10 mmol, 1 M in THF) was added to a THF (20 mL) solution of ethyl 2-(2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)-2-(hydroxyimino)acetate (1.05 g, 2.86 mmol). The mixture was stirred for a day at 50 C. Upon cooling the mixture to 0 C, Na2SO4x10H2O (9.2 g, 28.6 mmol) was added carefully. The suspension was stirred for two days at ambient temperature which was followed by the addition of NaHSO4 (1.2 g, 28.6 mmol) and MeOH (20 mL). The mixture is further stirred for an hour then HCl (5 mL, 2 M in ether) was added. Stirring was continued for another hour. Filtration, evaporation of the filtrate and Flash chromatography afforded 1-(4-(1-amino-2-hydroxyethyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea. 1H NMR (400 MHz, MeOH): δ 7.28 (m, 1H), 7.09 (d, 1H), 7.01 (d, 1H), 6.92 (td, 1H), 6.81 (s, 1H), 4.42 (s, 2H), 4.10 (m, 1H), 3.84 (dd, 1H), 3.72 (dd, 1H). MS (ES+): M/Z 311 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:32])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C:26](=[O:31])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C(#N)C.C(=O)=O>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:4][C:5]1([CH3:32])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C@H:26]([OH:31])[C:27]([O:29][CH3:30])=[O:28])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])O
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC1(C)CCN(c2c([C@H](O)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Temperature: -15 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a stirred yellow solution of ethyl 5-(4-(allyloxy)-4-methylpiperidin-1-yl)-6-(2-methoxy-2-oxoacetyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate (0.86 g, 1.94 mmol, 1 equiv) in toluene (19 mL) was added (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.54 g, 1.94 mmol, 1 equiv). The reaction was cooled to −40° C. (acetonitrile/dry ice bath) and a solution of 50% catechoborane in toluene (0.93 mL, 3.88 mmol, 2 equiv) was added over 10 min. The reaction mixture was stirred at −15° C. for 2 h. Upon completion, the reaction was diluted with EtOAc (30 mL) and sat. NaHCO3 (10 mL). The mixture was stirred vigorously for 30 min. The organic phase was washed with saturated aqueous NaHCO3 (2×5 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% MeOH/DCM) to afford desired product (0.86 g, 100%) as an off-white solid. LCMS (ESI, M+1): 446.25.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28]COC)=[CH:24][CH:23]=3)[N:19]=[C:18]3[N:32](C4CCCCO4)[N:33]=[C:34]([CH3:35])[C:17]=23)[C:10]([CH3:43])([CH3:42])[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:42][C:10]1([CH3:43])[CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:19]=[C:18]3[NH:32][N:33]=[C:34]([CH3:35])[C:17]=23)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COCOc1ccc(-c2cc(CNC3CCN(C(=O)OC(C)(C)C)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CNC3CCNCC3(C)C)c12
Reaction time: 48 h
Yield: 81.2 %

Procedure:
60 mg of 4-{[6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-amino}-3,3-dimethyl-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 1.2 ml of 1,4-dioxane and treated with 1.5 ml of hydrochloric acid (4 M in dry dioxane). After standing at rt for 48 h the volatiles were removed in vacuo, The residue was triturated with dioxane and the resulting solid was isolated by suction. 30 mg (74%) of the title compound were obtained.