Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.[Si:14]([O:21][C@H:22]([CH2:27][O:28][CH3:29])[C:23](OC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O>[Si:14]([O:21][C@H:22]([CH2:27][O:28][CH3:29])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][N:11]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: COC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Reactant: Cc1ccc(N)nc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium (2.5M in hexanes) (2.04 mL, 3.26 mmol) was added dropwise to a stirred solution of 5-methylpyridin-2-amine (CAS 1603-41-4) (353 mg, 3.26 mmol) in THF (10 mL) cooled to 10° C. under nitrogen. The resulting solution was stirred at ambient temperature for 10 minutes and then added to a solution of (R)-methyl 2-(tert-butyldimethylsilyloxy)-3-methoxypropanoate C5b (810 mg, 3.26 mmol) in THF (10 mL) at 10° C. The resulting solution was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with saturated ammonium chloride (50 mL), water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. Purification by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane provided (R)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (300 mg). 1H NMR (400 MHz, CDCl3) δ 0.15 (3H, s), 0.16 (3H, s), 0.88 (9H, s), 2.12 (3H, s), 3.46 (3H, s), 3.61-3.65 (2H, m), 4.35-4.42 (1H, m), 7.47 (1H, d), 8.19 (1H, d), 8.20 (1H, s), 8.97 (1H, s), m/z (ESI+) (M+H)+=325; HPLC tR=3.08 min.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([Br:14])[C:11]([OH:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][C:25](Cl)=[O:26]>O1CCCC1>[C:1]([C:4]1[CH:13]=[C:12]([Br:14])[C:11]([O:15][C:25]([O:24][CH3:23])=[O:26])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Br)c(O)c2ncccc12
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1c(Br)cc(C(C)=O)c2cccnc12

Procedure:
26.6 g of 5-acetyl-7-bromo-8-hydroxyquinoline are dissolved in 200 ml of tetrahydrofurane, 11 g of triethylamine are added and 9.5 g of chloroformic acid methyl ester, diluted in 50 ml of tetrahydrofurane, are added dropwise, whilst stirring and cooling. When the exothermic reaction has ended, the triethylamine hydrochloride which has separated out is removed by filtration and the clear filtrate is evaporated.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[F:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42]1[O:43][C:44]2[C:50]([CH3:51])=[CH:49][C:48]([CH3:52])=[CH:47][C:45]=2[N:46]=1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42]4[O:43][C:44]5[C:50]([CH3:51])=[CH:49][C:48]([CH3:52])=[CH:47][C:45]=5[N:46]=4)=[C:26]([F:25])[CH:31]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3F)nc2c1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3F)nc2c1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo [3,4-d]pyrimidin-4-amine (0.200 g, 0.453 mmol) and N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.216 g, 0.566 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a pale yellow powder (0.111 g, 43%). 1H NMR (DMSO-d6, 400 MHz) 1.56-1.83 (m, 4H), 2.15 (s, 3H), 2.22-2.55 (m, 12H), 2.34 (s, 3H), 2.41 (s, 3H), 3.22-3.53 (m, 1H), 4.78-4.83 (m, 1H), 6.81 (s, 1H), 7.10 (s, 1H), 7.45-7.53 (m, 2H), 8.23 (s, 1H), 8.49 (t, 1H), 10.59 (s, 1H); RP-HPLC Rt 11.873 min, 95% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 570 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36]C)=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:33][O:32][C:31]1[C:3](=[O:2])[C:4]([CH3:38])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[C:29](=[O:36])[C:30]=1[O:34][CH3:35]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccncc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccncc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 61.5 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridylmethyloxy)benzoyl]piperidine (0.550 g, 1.06 mmol) was dissolved in a mixed solution of acetonitrile (15 ml) and water (5 ml) and after adding thereto CAN (1.45 g, 2.64 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.320 g, 0.652 mmol, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:25])([F:24])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1.C(N(C(C)C)C(C)C)C.[N-:35]=[N+:36]=[N-:37].[Na+].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:25])([F:24])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([C:21]([N:35]=[N+:36]=[N-:37])=[O:22])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: O=C(O)c1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1
Reactant: [N-]=[N+]=[N-]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC(=O)c1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a stirred solution of 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carboxylic acid (3.5 g, 8.55 mmol), N-ethyl-N-isopropylpropan-2-amine (6.63 g, 51.3 mmol) and sodium azide (5.56 g, 86 mmol) in anhydrous DMF (60 mL), PyBOP (5.34 g, 10.27 mmol) was added in portions at ambient temperature over 5 min. The reaction was stirred for an additional 30 min and diluted with EtOAc (200 mL). The reaction was then poured into a 10% aqueous citric acid (200 mL), and the organic phase was separated and washed with citric acid solution (2×100 mL), saturated NaHCO3 (3×100 mL), and saturated NaCl solution. The aqueous phases were back extracted with EtOAc (200 mL) and the organic phases were combined, dried with MgSO4, filtered, and concentrated to dryness via rotary evaporation. The resulting residue was triturated in 1:1 Et2O/hexane, and the solid was collected by filtration and dried in vacuum over P2O5 to provide the title compound, 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carbonyl azide 45K (3.2 g, 7.37 mmol, 92%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (dd, J=9.85, 1.77 Hz, 1 H) 7.88 (d, J=9.60 Hz, 1 H) 8.00-8.05 (m, 1 H) 8.56 (d, J=9.60 Hz, 1 H) 8.98 (s, 1 H) 9.14 (s, 1 H). ESI-MS:m/z 434.0 (M+H)+. ESI-MS:m/z 406.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[C:4]([CH3:19])[C:3]=1[CH3:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=3)=[O:30])=[C:3]([CH3:20])[C:4]=2[CH3:19])[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1c(N)ccc(Oc2ccnc(N)c2[N+](=O)[O-])c1C
Product: Cc1c(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)ccc(Oc2ccnc(N)c2[N+](=O)[O-])c1C
Yield: 86 %

Procedure:
Method H3 was used with 4-(4-amino-2,3-dimethylphenoxy)-3-nitropyridin-2-amine and 4-chloro-3-trifluoromethyl-phenyl isocyanate to afford the title compound (625 mg, 86%) as a yellow powder. 1H-NMR (δ, ppm, DMSO-d6): 2.07 (s, 3H, CH3), 2.19 (s, 3H, CH3), 5.77 (d, 1H, HPy,5, J=5.7 Hz), 6.98 (d, 1H, Harom, J=8.7 Hz), 7.14 (s, 2H, NH2,Py), 7.57 (d, 1H, Harom, J=8.7 Hz), 7.62 (m, 1H, Harom), 7.96 (d, 1H, HPy,6, J=5.7 Hz), 8.12 (m, 1H, Harom), 8.21 (s, 1H, NHurea1), 9.38 (s, 1H, NHurea3). LC-MS (m/z): 496 (M+H, 100).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1.II.[CH2:29]([O:31][C:32](=[O:35])[CH2:33]Cl)[CH3:30]>O.C1(C)C=CC=CC=1>[C:32]([CH2:33][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([O:31][CH2:29][CH3:30])=[O:35]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: II
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde (250 g, 2.05 M), potassium carbonate (565 g, 4.09 M), toluene (2.5 L), p-toluenesulfonic acid (39 g, 0.21 M) and iodine (2 g, catalytic) were taken in a 5 L 4-neck round bottom flask with mechanical stirrer and a Dean-Stark condenser. Ethylchloroacetate (251 g, 2.05 M) was added and the reaction was refluxed for 6-8 hours, under azeotropic removal of water, while monitoring the reaction on TLC. After the completion of tile reaction, water was added and the organic layer separated while the aq. layer was extracted with toluene (2×500 ml). The combined organic layers were washed with brine and concentrated wider vacuum to yield 4-((carboethoxy)methoxy)benzaldehyde as an oily material (395 g, Y=93%, P=99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]([OH:17])(=[O:16])[CH2:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:10])[CH:3]=1)[NH:9][C:14]([CH2:13][CH2:12][C:11]([OH:17])=[O:16])=[CH:15]2
Reactant: Nc1c(F)cc(Br)cc1I
Reactant: C#CCCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CCc1cc2cc(Br)cc(F)c2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To a solution of (4-bromo-2-fluoro-6-iodophenyl)amine (D159) (2 g), 4-pentynoic acid (0.62 g) and copper(I) iodide (0.60 g) in DMF (4 mL) stirred under nitrogen at room temperature was added bis(triphenylphosphine)palladium(II) chloride (0.222 g), then triethylamine (2.2 mL) was added in a portion. The reaction mixture was stirred at 80° C. in microwave reactor for 2 hrs. The solid in the mixture was filtered, the filtrate was diluted with EtOAc (30 mL), washed with brine (80 mL) and water (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford 3-(5-bromo-7-fluoro-1H-indol-2-yl)propanoic acid (D160) (700 mg) as a yellow solid. MS (ES): C11H9BrFNO2 requires 285; found 286.0 (M+H+). δH (CDCl3, 400 MHz): 2.75 (2H, t), 3.07 (2H, t), 5.45 (1H, s), 7.05 (1H, d), 7.41 (1H, s).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.C(O)C>[C:8]1(/[CH:7]=[CH:3]/[C:4](=[O:5])/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1

Procedure:
(3) Hill and Barbaro, Experiments in Organic Chemistry. Contemporary Publishing Co. of Raleigh, Inc., Raleigh, 1996. 5 g of sodium hydroxide, dissolved in 25 ml of water and 25 ml of 95% ethanol, was cooled to 20 to 25° C. 2.9 g (50 mmol) of acetone and 10.6 g (100 mmol) of benzaldehyde were added, and a yellow precipitate formed. After 20 minutes the solution was filtered, and the solid was recrystallized from ethyl acetate to afford 10.1 g (86.3%) of bright-yellow platelets: mp 111.9-112.5° C. (lit. mp 112° C., Hill and Barbaro, supra). 1H NMR (250 MHz) δ 7.79-7.73 (d, 1H), 7.65-7.61 (m, 4H), 7.44-7.41 (t, 6H), 7.13-7.07 (d, 1H) ppm.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH3:42][N:43]([CH2:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=1)[CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:55][C:54]4[CH:53]=[CH:52][C:51]([CH2:50][N:43]([CH3:42])[CH:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)=[CH:57][CH:56]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3CCC)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCCN3CCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.3 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (180 mg) in THF (10 ml) were added a drop of DMF and then thionylchloride (0.04 ml) at 0° C. After stirring at room temperature for 30 minutes under a nitrogen atmosphere, the mixture was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (118 mg), and triethylamine (1.08 g) in tetrahydrofuran (15 ml) at 0° C. After stirring at room temperature for 1.5 hours under a nitrogen atmosphere, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solutions, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate:methanol=8:1) to obtain yellowish amorphous 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (Compound 2, 64 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=O)[CH:12]=2.[N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[S:23][C:22]=1[NH2:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[S:23][C:22]=1[NH:30][C:18]([C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[NH:10]2)=[CH:15][CH:14]=1)=[O:20]
Reactant: Nc1nc2cccnc2s1
Reactant: O=C(O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(Nc1nc2cccnc2s1)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 150 °C

Procedure:
A mixture of 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid (362 mg, 1.18 mmol), thiazolo[5,4-b]pyridin-2-ylamine (179 mg, 1.18 mmol), EDCI (340 mg, 1.77 mmol) and HOBT (176 mg, 1.30 mmol) in THF (10 mL) was heated in a microwave apparatus at 150° C. for 3 h. The insolubles were filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed using a 30-70% gradient of heptane/ethyl acetate to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 12.95 (s, broad, 1H), 12.00 (s, broad, 1H), 8.51 (dd, J=4.7, 1.4 Hz, 1H), 8.34 (s, 1H), 8.16 (d, J=7.7 Hz, 1H), 7.88 (dd, J=8.5, 1.4 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.3 Hz, 2H), 7.54 (m, 2H), 6.66 (m, 1H). MS (m/z) 439.0 (M+1), Retention time=1.41 min (Method 10). Anal. Calcd.: C, 57.41; H, 2.75; N, 12.75. Found: C, 57.29; H, 2.73; N, 12.54.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[N:23]=[C:24]([CH3:27])[S:25][CH:26]=1>>[CH3:27][C:24]1[S:25][CH:26]=[C:22]([NH:21][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[N:23]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncc(C)c1
Reactant: Cc1nc(N)cs1
Product: Cc1cncc(Nc2ccc(C)nc2C(=O)Nc2csc(C)n2)c1

Procedure:
The title compound, was prepared from 6-Methyl-3-(5-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid ethyl ester and 4-Amino-2-methylthiazole in accordance with the general method of Example 78, step 2 to yield the final compound as a light-yellow solid, MS (ISP): m/e=340.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:56])C(=O)C1.O.O[Li].O>CC#N.C1COCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[C:36]([Cl:56])[N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Temperature: 70 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (20 mg, 0.031 mmol, 1 equiv) in MeCN (1 mL) was added NCS (4 mg, 0.031 mmol, 1 equiv). After 1 h, the reaction was concentrated in vacuo. The crude chloride was taken up in 9:1 MeOH:water (1.1 mL) and LiOH.H2O (39 mg, 0.918 mmol, 30 equiv) was added. A few drops of THF were added to aid solubility. The reaction was heated to 70° C. for 1.5 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 60-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (10 mg, 48%). 1H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.36 (s, 1H), 7.16-7.08 (m, 3H), 6.02-5.67 (m, 1H), 4.60 (d, J=3.3 Hz, 1H), 3.96 (d, J=10.6 Hz, 2H), 3.52 (d, J=8.4 Hz, 1H), 3.42-3.30 (m, 1H), 2.44 (s, 3H), 2.40-2.31 (m, 2H), 2.29 (s, 3H), 2.05-1.51 (m, 10H), 1.20 (br. s., 3H), 1.19 (s, 9H), 1.03 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 673.3.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][NH2:31].[BH4-].[Na+]>CO>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][NH:31][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: NCCc1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCc2ccc(F)cc2F)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.300 g, 1.10 mmol), 2-(2,4-difluorophenyl)ethylamine (0.343 g, 2.184 mmol) and 3 Å molecular sieves in a vial. Add methanol (4.4 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 2% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give 6-(4-{[2-(2,4-difluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamide. Dissolve the compound in methanol (5.0 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound: TOF MS ES+ 414.2 (M+H)+, HRMS calcd for C22H22N3O3F, 414.1629 (M+H)+, found 414.1613, time 0.52 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.14% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.6 min, 100% purity.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH:5]([CH3:6])[CH2:4][CH2:3][CH2:2]1.[OH-:9].[K+].Cl>C(O)C.O>[OH:9][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: CC1CCCC(=O)O1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCO
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 82.8 %

Procedure:
To a solution of 12.0 g of ε-hexanolactone in 20 ml of ethanol was added a solution of 11.7 g of potassium hydroxide in 20 ml of water under ice-cooling and the reaction mixture was stirred for 2.5 hours at 40° C. After reaction, the reaction mixture was adjusted to pH 9 by adding 1N-HCl solution and washed with ethyl acetate (twice). The aqueous layer was concentrated under reduced pressure and the residue was adjusted to pH 1 by adding 1N-HCl solution and extracted by ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give 11.5 g of 6-hydroxyhexanoic acid. A mixture of 1 g of 6-hydroxyhexanoic acid obtained above, 0.72 mg of sodium bicarbonate in 20 ml of water was stirred for 15 minutes. After reaction, the solvent was removed and the resulting residue was washed with acetonitrile to give 1.24 g of sodibm 6-hydroxyhexanoic acid. Then, 276 mg of this compound was dissolved in 2.7 ml of dimethylformamide and to this solution was added 161 mg of methoxymethyl chloride and the reaction mixture was stirred for 1.5 hours at room temperature. After adding 10 ml of ethyl acetate to the reaction mixture, the organic layer was washed with saline, saturated sodium bicarbonate aqueous solution and saline respectively and dried over magnesium sulfate. The solvent was removed to give 190 mg (59%) of methoxymethyl 6-hydroxyhexanoate [Compound (15)].