Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH:10](N(C)C)N(C)C)[CH3:9]>>[CH3:7][N:8]([CH:10]=[C:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6])[CH3:9]
Reactant: O=C1CCCO1
Reactant: CN(C)C(N(C)C)N(C)C
Product: CN(C)C=C1CCOC1=O
Temperature: 75 °C
Reaction time: 48 h

Procedure:
A mixture of γ-butyrolactone (1 mol) and tris(dimethylamino)methane (1.5 mol) is stirred under dry nitrogen at 75° C. for 2 days to give 3-[(dimethylamino)methylene]dihydro-2(3H)-furanone. A solution containing 3-[(dimethylamino)methylene]dihydro-2(3H)-furanone (1 mol), n-butanethiol (1.1 mol) and para-toluenesulfonic acid (1 mol) in benzene is heated at reflux overnight to give upon aqueous work-up 3-[(butylthio)methylene]dihydro-2(3H)-furanone. After a solution of 3-[(butylthio)methylene]dihydro-2(3H)-furanone (1 mol) in anhydrous diethyl ether is added to a solution of lithium di-n-butylcuprate (1.1 mol) in diethyl ether at -78° C., the resulting mixture is stirred at -78° C. for an additional 0.5 hours and then quenched with methanol. Work-up affords 3-ethylidenedihydro-2(3H)-furanone. Freshly prepared W-2 Raney nickel (about 3 parts) is deactivated by refluxing in benzene for 1 hour, whereupon 3-ethylidenedihydro-2(3H)-furanone is added and the mixture is heated at reflux under nitrogen for 24-48 hours; the reaction is monitored by thin layer chromatography. After complete washing of the Raney nickel with hot benzene, the title compound is obtained.
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:16]1[C:24](=O)[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[CH2:18][CH2:17]1)[CH2:14][CH3:15]>>[CH2:13]([CH:16]1[CH2:17][CH2:18][C:19]2[S:23][CH:22]=[CH:21][C:20]=2/[C:24]/1=[N:11]\[OH:12])[CH2:14][CH3:15]
Reactant: CCCC1CCc2sccc2C1=O
Reactant: O/N=C1\CCOc2ccccc21
Product: CCCC1CCc2sccc2/C1=N\O

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.98, 7.28, 7.15, 7.10, 3.55, 2.99–2.81, 2.21–1.83, 1.59–1.31, 0.95–0.90; (MS/CI) calcd for C10H13NOS+H 195.3, found 195.7.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[C:11]([CH3:29])=[C:12]([NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[CH:13]=[CH:14][CH:15]=2)[CH:3]=1.Cl[C:31]1[N:36]=[N:35][C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:4]3[CH:3]=[C:2]([NH:1][C:31]4[N:36]=[N:35][C:34]([N:37]5[CH2:38][CH2:39][O:40][CH2:41][CH2:42]5)=[CH:33][CH:32]=4)[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=3)[C:11]=2[CH3:29])=[O:28])=[CH:23][CH:22]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: Clc1ccc(N2CCOCC2)nn1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c(=O)n(C)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(N3CCOCC3)nn2)c(=O)n(C)c1
Temperature: 95 °C
Yield: 38 %

Procedure:
A 48-mL seal tube equipped with a magnetic stirring bar was charged with N-[3-(5-amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (3) (0.39 g, 1.0 mmol), 4-(6-chloropyridazin-3-yl)morpholine (0.30 g, 1.5 mmol), Pd2(dba)3 (0.064 g, 0.070 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.058 g, 0.10 mmol), and Cs2CO3 (652 g, 2.0 mmol) in dioxane (10 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane (10 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-33%, MeOH in dichloromethane, to afford 0.210 g (38%) of 4-tert-butyl-N-(2-methyl-3-(1-methyl-5-(6-morpholinopyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)benzamide (4) as a solid: LCMS m/z 553.3365 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1.C([O-])(O)=O.[Na+].[I:16]I.OS([O-])(=O)=O.[Na+]>O>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:16])[CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1
Reactant: II
Reactant: OCc1ccc(O)c(Cl)n1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: OCc1cc(I)c(O)c(Cl)n1
Yield: 62 %

Procedure:
2-Chloro-6-(hydroxymethyl)-3-pyridinol (11.6 g, 72.7 mmol) and NaHCO3 (18.3 g, 218 mmol) are added to 200 mL water. The mixture is stirred until homogeneous, the flask is placed in an ice bath, iodine (19.4 g, 76.3 mmol) is added, and the reaction is stirred over the weekend at rt. The pH of the mixture is adjusted to 3 with 2N NaHSO4, and the mixture is extracted with 4×50 mL EtOAc. The combined organic layer is dried over anhydrous MgSO4, is filtered, and the filtrate is concentrated in vacuo to a yellow solid. The crude solid is washed with EtOAc to provide 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol as an off-white solid (62% yield), and the filtrate is concentrated to a small volume and is chromatographed over 250 g silica gel (230-400 mesh) eluting with 2.5:4.5:4:0.1 EtOAc/CH2Cl2/hexane/acetic acid. The desiredd fractionawere combined and concentrated to afford additional pure (12% yield). MS (EI) for C6H5ClINO2, m/z: 285(M)+.
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=3[Cl:19])[C:4]=2[C:3]=1[CH3:22].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:26][CH2:25]1>>[Cl:19][C:12]1[C:13]([F:18])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:20]=[CH:21][C:2]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH2:31][CH2:30][N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:34][CH:35]=3)=[C:3]([CH3:22])[C:4]1=2
Reactant: CN1CCN(CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1c(Br)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2
Product: Cc1c(-c2ccc(OCCN3CCN(C)CC3)cc2)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2

Procedure:
The entitled compound can be prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine and 1-methyl-4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenoxy]-ethyl}-piperazine as described in example 25.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH:37]1([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=2[C:51](=O)[CH3:52])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:51]([C:44]2[CH:45]=[C:46]([O:49][CH3:50])[CH:47]=[CH:48][C:43]=2[CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:52]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COc1ccc(C2CCCCC2)c(C(C)=O)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2CCCCC2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 21 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (86 mg, 0.22 mmol) was reacted with Compound 545a (50 mg, 0.22 mmol) in ethanol (3 mL) using 10% w/v KOH in Ethanol (436 μL, 0.66 mmol) to produce the title compound (26 mg, 21% yield).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:10][CH:9]2[N:11](C(OC(C)(C)C)=O)[CH:5]([CH2:6][O:7][CH2:8]2)[CH2:4]1.[Li][CH2:20]CCC.CN(C=O)C.Cl>C1COCC1>[CH:9]12[NH:11][CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][C:3]1[C:10]2=[CH:20][O:1][N:2]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=NO)C2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1onc2c1C1COCC(C2)N1
Reaction time: 0.5 h

Procedure:
To a solution of compound 104b (512 mg, 2 mmol, 1.0 eq) in THF (10 mL) was added n-BuLi (5 mL, 2.0 M, 5.0 eq) dropwise at −50° C. After 30 min, dry DMF (740 mg, 10 mmol, 5.0 eq) in THF (2 mL) was added dropwise, the mixture was stirred for another 2 h from −60° C. to room temperature. To it 12 N HCl (1 mL) was added and refluxed for 2 h. The reaction mixture was concentrated to give 4,10-Dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-diene 104a (332 mg) as an oil. MS: calc'd (MH+) 167, measured (MH+) 167.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:35])[C:11]2[O:17][C:16]3[C:18]([Cl:31])=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:33])(=[O:32])[C:12]=2[CH:34]=1)=[O:7].C(O)(C(F)(F)F)=O.C([BH3-])#N.[Na+]>CO>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:35])[C:11]2[O:17][C:16]3[C:18]([Cl:31])=[CH:19][C:20]([N:22]([CH2:1][CH3:2])[CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:32])(=[O:33])[C:12]=2[CH:34]=1)=[O:7]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCCC3)cc(Cl)c1O2
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN(CCN1CCCCC1)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Reaction time: 2 h

Procedure:
Acetaldehyde (0.151 g, 3.4 mmol) was added to a solution of Example 92k (0.330 g, 0.68 mmol) in MeOH (10 mL) at 0° C. TFA (0.08 g, 0.68 mmol) was then added and stirring continued for 2 h. The reaction mixture was brought to room temperature, treated with sodium cyanoborohydride (0.108 g, 1.7 mmol) and allowed to stir for 4 h. It was concentrated, treated with aqueous sodium bicarbonate solution, water and extracted ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography to obtain the title compound. Yield: 0.80 g, (51%); 1H NMR (CDCl3): δ 1.20 (t, 2H, CH2), 1.70 (t, 2H, CH2), 1.80 (t, 4H, 2CH2), 2.70 (s, 3H, CH3), 2.80 (s, 2H, CH2), 2.90 (m, 2H, CH2), 3.40 (q, 2H, CH2), 3.80 (t, 2H, CH2), 3.9 (s, 3H, OCH3), 4.8 (s, 2H, CH2), 6.8 (s, 2H, Ar), 8.10 (s, 1H, Ar), 8.4 (s, 1H, Ar); MS: m/e (ES−) 506 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1I.[N:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:24][CH:23]2[CH2:25][NH2:26])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[NH:26][CH2:25][CH:23]1[CH2:24][CH:22]1[C:19]1[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=1
Reactant: Clc1c(I)ccn2c(CC3CC3)nnc12
Reactant: NCC1CC1c1ccncc1
Product: Clc1c(NCC2CC2c2ccncc2)ccn2c(CC3CC3)nnc12
Yield: 48.4 %

Procedure:
A mixture of 8-chloro-3-(cyclopropylmethyl)-7-iodo-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.150 mmol) and (2-(pyridin-4-yl)cyclopropyl)methanamine (26.7 mg, 0.180 mmol) was reacted in a manner similar to Example 1 to give 8-chloro-3-(cyclopropylmethyl)-N-((2-(pyridin-4-yl)cyclopropyl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine (25.7 mg, 47.5%). 1H NMR (500 MHz, DMSO-d6) δ 8.35 (d, J=6.1 Hz, 2H), 8.23 (d, J=7.6 Hz, 1H), 7.06 (d, J=6.1 Hz, 2H), 6.90 (d, J=7.6 Hz, 1H), 6.42 (t, J=6.1 Hz, 1H), 2.95 (d, J=6.7 Hz, 2H), 1.95 (dd, J=8.7, 4.4 Hz, 1H), 1.48 (br. s., 1H), 1.19-1.09 (m, 2H), 1.09-1.00 (m, 1H), 0.50 (d, J=6.4 Hz, 2H), 0.25 (d, J=4.6 Hz, 2H). LCMS: M+1=354.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](C(O)=O)CC1SC=CC=1)=O)C1C=CC=CC=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:58]([NH2:62])([CH3:61])([CH3:60])[CH3:59]>C1COCC1>[C:58]([NH:62][C:19](=[O:21])[C@H:12]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)N
Reactant: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: O=C(N[C@@H](Cc1cccs1)C(=O)O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)NC(=O)[C@H](Cc1cccs1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.29 h
Yield: 97 %

Procedure:
Into a 500 ml flask was placed 8.06 g of the subtitled compound of Example A, N-(Benzyloxycarbonyl)-3-(2-thienyl)-L-alanine, in 130 ml of THF. The compound was cooled to 0° C. N-Methylmorpholine (4.23 ml) was added, followed by isobutylchloroformate (4.04 ml) over two minutes. The mixture was stirred for 15-20 minutes, and 3.74 ml of t-butylamine was added. The bath was removed, and the mixture was stirred at room temperature for two hours. The mixture was concentrated on rotovap, and the residue was taken up in ethyl acetate. The residue was washed successively with H2O, HCl, and saturated NaHCO3 solution. The organics were separated and dried with Na2SO4, filtered, and concentrated to an oil. The oil was dissolved in 100 ml hot hexane and cooled in a refrigerator overnight to give a solid. The hexane was decanted, followed by drying to yield a solid of 9.25 g N-(carbobenzyloxy)-3-(2-thienyl)-L-alanine-tert-butylamide (97% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2N)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].[I-:24].[K+]>Cl.O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[I:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2ccc(OCc3ccccc3)cc12
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Ic1cccc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution of 7-benzyloxy-naphthalen-1-ylamine (6.98 g, 28.02 mmol) in concentrated hydrogen chloride (30 mL), water (30 mL) and tetrahydrofuran (30 mL) is cooled with an ice-salt (sodium chloride) bath. A solution of sodium nitrite (2.32 g, 33.6 mmol) in water (20 mL) is then added in a dropwise manner over a 15-minute period of time and the reaction temperature is kept under 5° C. The mixture is stirred for another 30 minutes before potassium iodide (9.3 g, 56.04 mmol) in water (30 mL) is added. The resulting mixture is stirred for three hours at room temperature before being extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (Hexanes/CH2Cl2 =25/1-20/1) to give 7-benzyloxy-1-iodo-naphthalene (6.26 g, 61%); MS m/z (M+Na+) 361.00.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[NH:10][C@H:11]([CH2:36][OH:37])[CH2:12][CH2:13][C:14](=[O:35])[NH:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:44](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>CN(C=O)C.CC(OC)(C)C>[CH2:1]([O:8][C:9](=[O:38])[NH:10][C@H:11]([CH2:36][O:37][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:12][CH2:13][C:14](=[O:35])[NH:15][C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC[C@@H](CO)NC(=O)OCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 71 %

Procedure:
Intermediate B1, prepared above, was dissolved in DMF (10 mL). Imidazole (2.69 g, 39.5 mmol, 2.3 equiv) and tert-butyldimethylsilyl chloride (2.86 g, 19.0 mmol, 1.1 equiv) were added. The reaction mixture was stirred overnight, then diluted with MTBE (500 mL) and washed sequentially with 2.5% KHSO4, H2O, NaHCO3, H2O, and brine (100 mL each). The organic phase was dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (gradient elution, 25→40% EtOAc in hexanes) to provide the title intermediate (7.6 g, 71%) as a white amorphous solid: IR (cm−1) 3307, 1708, 1660, 1496, 1249; 1H NMR (CDCl3) δ-0.01-0.05 (m, 6H), 0.89 (s, 9H), 1.76-1.93 (m. 2H), 2.29-2.40 (m, 2H), 3.56-3.77 (m, 3H), 5.03-5.16 (m, 3H), 7.00 (s, 1H), 7.18-7.39 (m, 20 H); Anal. C38H46N2O4Si: C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([OH:22])=[N:10]2)=[CH:5][CH:4]=1.Br[CH2:24][C:25]#[C:26][CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([O:22][CH2:24][C:25]#[C:26][CH3:27])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Reactant: CC#CCBr
Product: CC#CCOc1nc(-c2ccc(OC)cc2)n(-c2ccc(OC)cc2)n1
Yield: 40.8 %

Procedure:
1,5-bis(4-methoxyphenyl)-3-(2-butynyloxy)-1H-1,2,4-triazole (96 mg, 40.8% yield) was prepared from 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol and 1-bromo-2-butyne by the similar manner described for Example 18.
Reaction SMILES: CC(C)(OC([N:7](C(OC(C)(C)C)=O)[C:8]1[C:13]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[C:12]([O:20][C:21]2[C:26]([F:27])=[CH:25][C:24]([NH:28][C:29]([C:31]3[C:36](=[O:37])[C:35]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)=[CH:34][N:33]([CH3:45])[CH:32]=3)=[O:30])=[C:23]([F:46])[CH:22]=2)[CH:11]=[CH:10][N:9]=1)=O)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[C:13]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[C:12]([O:20][C:21]2[C:26]([F:27])=[CH:25][C:24]([NH:28][C:29]([C:31]3[C:36](=[O:37])[C:35]([C:38]4[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=4)=[CH:34][N:33]([CH3:45])[CH:32]=3)=[O:30])=[C:23]([F:46])[CH:22]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Cn1cc(C(=O)Nc2cc(F)c(Oc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3-c3cnn(C)c3)cc2F)c(=O)c(-c2ccc(F)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3-c3cnn(C)c3)cc2F)c(=O)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of N-(4-(2-[bis[(1,1-dimethylethoxy)carbonyl]amino]-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (0.115 g, 0.15 mmol) in CH2Cl2 (5 mL) was treated with TFA (0.35 mL, 4.62 mmol) and the solution was stirred at RT for 3 h. The solvent was removed in vacuo and the residue was partitioned between satd NaHCO3 solution (30 mL) and EtOAc (30 mLl). The aqueous layer was extracted with EtOAc (25 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide as off-white solid (82 mg, 97% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.49 (dd, J=12.6 Hz, 7.3 Hz, 1H), 8.15 (d, J=2.3 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J=5.8 Hz, 1H), 7.69 (m, 2H), 7.59 (d, J=0.8 Hz, 1H), 7.41 (dd, J=11.2 Hz, 7.4 Hz, 1H), 7.27 (t, J=8.9 Hz, 2H), 6.00 (d, J=5.8 Hz, 1H), 5.69 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H); MS (ESI) m/z: 547.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([F:30])[CH:18]=2)=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[Li+].[OH-].O>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([F:30])[CH:18]=2)=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(F)c(NCc2cc(F)cc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Ethyl 2-[2,4-difluoro-3-[[3-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (385 mg, 0.89 mmol, 1.0 eq) in THF (4 mL) was added an aqueous solution of LiOH (2M aqueous solution, 3 mL, 6 mmol, 6.7 eq). The reaction was stirred at room temperature for 1 h. Water was added and the THF removed in vacuo. The aqueous residue was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude material obtained was recrystallised from DCM/petroleum ether, collected by filtration and dried in vacuo to give (I(n)) (60 mg, 17%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:15][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH2:3]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[OH:1][CH:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:5]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(=O)C2)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(CC(O)C2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (507 mg, 2.4 mmol) in MeOH (5.0 mL) was added NaBH4 (182 mg, 4.8 mmol) at 0° C. under N2. It was stirred at 0° C. for 30 min. The solution was concentrated by evaporator in vacuo to give crude solid. A saturated solution of NaHCO3 (30 mL) was added. The aqueous mixture was extracted with DCM (4×30 mL). The combined organic solution was dried over anhydrous Na2SO4 and then concentrated by evaporation in vacuo to afford tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (511 mg, 100%) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[CH:8]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:23]([C:15]1[CH:16]=[C:17]2[C:22](=[C:13]([C:9]3[CH:8]=[C:7]([CH2:6][CH:5]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:4][OH:3])[CH:12]=[CH:11][CH:10]=3)[CH:14]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(Cc1cccc(-c2cc(C(C)C)cc3cccnc23)c1)c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cc(-c2cccc(CC(CO)c3ccncc3)c2)c2ncccc2c1
Temperature: 21 °C
Reaction time: 1 h

Procedure:
To a solution of Example 66 (15 mg, 0.035 mmol) in THF (mL) at 0° C. was added LiAlH4 (1M, THF, 0.35 mL, 0.35 mmol) dropwise. The resulting reaction mixture was stirred 1 h at 0° C., 1 h at 21° C., and then quenched with water and neutralized using 1N HCl. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with ethanol/ethyl acetate, 1:9) provided the title compound.