Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]([O:8]C)=O.[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([N:35]([CH3:37])[CH3:36])[S:32][C:31]=2[CH:38]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:34]2[C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:38][C:31]=3[S:32][C:33]=2[N:35]([CH3:37])[CH3:36])=[O:8])[CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(CN2CCCC2)c(OC)c1
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Product: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Yield: 80 %

Procedure:
Following essentially the procedure of Example 208, Part B, the title compound was prepared from methyl 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzoate (Example 139, Part B) and 6-benzyloxy-2-dimethylaminobenzo[b]thiophene in 80% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:8])[CH2:5][CH:6]=[CH2:7].Br[CH2:10][CH:11]=[CH2:12]>CN(C)C=O>[CH2:12]([O:8][CH:4]([CH3:3])[CH2:5][CH:6]=[CH2:7])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: C=CCC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(C)CC=C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.3 %

Procedure:
A 500-mL four neck round-bottom flask was purged and maintained with an inert atmosphere of nitrogen, then a suspension of sodium hydride (14.0 g, 350 mmol, 2.01 equiv, 60%) in N,N-dimethylformamide (100 mL) was added. The mixture was cooled to 0° C., then a solution of pent-4-en-2-ol (15.0 g, 174 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) was added drop-wise and the mixture was stirred for 20 min at 0° C. The mixture was cooled to −20° C. and a solution of 3-bromoprop-1-ene (20.9 g, 172 mmol, 0.99 equiv) in N,N-dimethylformamide (100 mL) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight, then carefully quenched with H2O (500 mL). The aqueous was extracted with ethyl acetate (4×100 mL) and the combined organics was washed with brine (2×200 mL), dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a yellow oil (13.3 g, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COc1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cccc(OCCn2cc([N+](=O)[O-])cn2)c1
Temperature: 80 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (220 mg, 1.90 mmol) in MeCN (9.5 mL), 1-(2-bromoethoxy)-3-methoxybenzene (495 mg, 2.14 mmol) dissolved in MeCN (1.5 mL) and Cs2CO3 (697 mg, 2.14 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo to obtain 1-(2-(3-methoxyphenoxy)ethyl)-4-nitro-1H-pyrazole which was used in the next step without further purification. LC-MS conditions A: tR=0.85 min, [M+H]+=no ionization.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=[O:13])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CC(C)=O.C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3](=[O:13])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(/C=C/c1ccc(O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A solution of (E)-1,1,1-trifluoro-4-(4-hydroxyphenyl) 3-buten-2-one (0.105 g, 0.49 mmol) in acetone (6 ml) was treated with powdered potassium carbonate (0.3 g) and tert-butyl bromoacetate (0.20 g, 1.02 mmol) and stirred at 22° C. for 3 h. The reaction mixture was then diluted with toluene, washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on silica gel (elution toluene-ethyl acetate 2%) and gave 0.150 g (94%) of the title material as yellow needles: mp 112-113° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:39])([C:37]#[CH:38])[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31].N(CC)CC>[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.CCN(CC)CC>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:38]#[C:37][C:29]([CH3:28])([CH3:39])[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C#CC(C)(C)C(=O)OCCCC
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCNCC
Product: CCCCOC(=O)C(C)(C)C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Yield: 17.6 %

Procedure:
A microwave vial was charged with (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.12 mmol), butyl 2,2-dimethylbut-3-ynoate (40 mg, 0.23 mmol), CuI (2.2 mg, 0.012 mmol), PdCl2(PPh3)2 (5 mg, 0.008 mmol), Et3N (2 mL) and Et2NH (0.2 mL). The mixture was sparged with N2 for 10 min and heated at 100 C for 2 h. The mixture was concentrated, redissolved in EtOAc (90 mL), washed with 5% aq HCl (20 mL) and brine (20 mL), and dried over Na2SO4. Removal of the solvent left an oil (75 mg) which was purified by prep HPLC to afford butyl 4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2,2-dimethylbut-3-ynoate (11 mg, 19%). LC-MS Method 1 tR=2.13 min, m/z=520, 462.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]1[CH:35]=[C:34]([CH:36]2[CH2:38][CH2:37]2)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH:36]1([C:34]2[N:33]=[CH:32][N:31]=[C:30]([N:20]3[CH2:21][CH2:22][C:16]4[C:15]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[N:14][C:13]([C:10]5[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=5)=[N:18][C:17]=4[CH2:19]3)[CH:35]=2)[CH2:38][CH2:37]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Clc1cc(C2CC2)ncn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cc(C4CC4)ncn2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0597 g, 0.156 mmol), 4-chloro-6-cyclopropylpyrimidine (0.046 g, 0.30 mmol), N,N-Diisopropylethylamine (0.0570 mL, 0.327 mmol), and dry N,N-Dimethylformamide (0.84 mL, 11 mmol) were combined, the reaction was microwaved on 200 watts, 120° C. for 20 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.37 (s, 1H), 8.21 (d, J=8.8, 2H), 7.50 (d, J=8.8, 2H), 6.91 (s, 1H), 6.21 (t, J=5.5, 1H), 4.70 (s, 2H), 3.88 (s, 2H), 3.73 (d, J=4.5, 4H), 3.48 (d, J=4.3, 4H), 3.16-3.08 (m, 2H), 2.75 (s, 2H), 2.01-1.91 (m, 1H), 1.06 (t, J=7.2, 3H), 1.02-0.88 (m, 4H). LC/MS-m/z+501.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:22])[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[OH:10].[C:23]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)(O)=[O:24].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:21][C:6]1[CH:5]=[N+:4]([O-:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[O:10][C:30](=[O:31])[C:29]1[CH:32]=[CH:33][C:26]([CH:23]=[O:24])=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)cc2)cc1OC
Yield: 76 %

Procedure:
A solution of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-pyridine 1-oxide (0.688 g, 2 mmol), 4-carboxybenzaldehyde (0.300 g, 2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.767 g, 4 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1 mmol) in anhydrous DCM (30 mL) was stirred at RT for 17 hours. The reaction mixture was partitioned between saturated NaHCO3 (20 mL) and DCM (10 mL) and filtered through a phase separator cartridge. The cartridge was washed thoroughly with DCM and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography eluting with 2:3 DCM:EtOAc to afford the title compound as a white solid (0.724 g, 76%).
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([O:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1nccnc1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
A mixture of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (100 mg, 0.37 mmol), 2-methoxy-phenol (47 mg, 0.37 mmol) and Cs2CO3 (242 mg, 0.74 mmol) in DMSO (10 mL) was stirred at 90° C. overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude compound, which was purified by column chromatography to afford pure product (13) (80 mg, 0.22 mmol, yield 61%) as solid. ESI-MS (M+1): 358 calc. for C19H23N3O4 357.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.O[CH2:9][NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>FC(F)(F)C(O)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([NH:10][CH2:9][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:18])[CH:13]=1
Reactant: Sc1ccncc1
Reactant: O=C(NCO)c1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCSc1ccncc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a mixture of 1.11 g (10 mmol) of 4-mercaptopyridine and 1.52 g (10 mmol) of N-(hydroxymethyl)nicotinamide, 30 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off and 30 ml of ethanol was added to the residue. The solvent was distilled off and water was added to the residue. The mixture was neutralized with saturated aqueous sodium bicarbonate, followed by extraction with chloroform. After washing with saturated saline, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=5:1) to give 390 mg of the desired compound (15.9% yield, yellow solid).
Reaction SMILES: C[O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])\[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1/[C:7](/[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:24])=[O:2]
Reactant: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C\C=C\C(=O)O)c2ccccc2OC)cc1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
In the manner described in Example 99, (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester (4.3 g) was saponified in a refluxing mixture of methanol (35 mL) and 1N NaOH (35 mL). After 1 hour the reaction was worked up in the usual fashion and the crude acid was crystallized from 2-propanol to afford 3.6 g of (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid, mp 210.5°-211.5° C.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[BH4-].[Na+].O>CO>[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cccc(C=O)n2)OCCO1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(c2cccc(CO)n2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a ice-cold solution of 6-(2-methyl-[1,3]dioxolan-2-yl)-pyridine-2-carbaldehyde (713 mg, 3.69 mmol) in MeOH (10.0 mL) was added NaBH4 (180 mg, 4.57 mmol in four equal portion). The reaction mixture was then stirred for 1 h at rt. Water was added and the mixture was extracted with EA followed twice with EA-MeOH 9:1. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid. LC-MS-conditions 02: tR=0.46 min; [M+H]+=196.49.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Product: Fc1ccc(OCCCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 53 %

Procedure:
Following the combined procedures of Examples 14 and 16, 4-[bis(4-fluorophenyl)methyl]piperidine and 4-(3-chloropropoxy)-1-fluorobenzene were reacted and worked up by chromatography in Example 16, to give the free base in 53% yield as a yellow oil after drying in vacuo at 80° C. overnight.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3](O)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH2:28]>C(Cl)Cl>[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH:28][C:3](=[O:4])/[C:2](/[CH3:1])=[CH:6]/[CH3:7]
Reactant: C/C=C(\C)C(=O)O
Reactant: COC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C/C=C(\C)C(=O)NCC(=O)OC
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
(E)-2-methyl-2-butenoic acid (300 mg, 3.00 mmol) was dissolved in CH2Cl2 (6 mL) and N-methyl morpholine (396 μL, 3.60 mmol) was added to the solution. The reaction mixture was cooled to −15° C. Isobutyl chloroformate (389 μL, 3.00 mmol) was added and stirred at −15° C. for 15 min. Glycine methyl ester hydrochloride (377 mg, 3.00 mmol), CH2Cl2 (4 mL), and N-methyl morpholine (330 μL, 3.00 mmol) were added to the solution. After stirring at −15° C. for 15 min, the reaction mixture was warmed to 24° C. and stirred for 16 h. CH2Cl2 (60 mL) was added to the reaction mixture and the organic layer was washed with 1 N aq HCl (3×20 mL) and 5% aq NaHCO3 (3×20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The crude product was purified by silica gel column chromatography using 30% and 40% EtOAc/CH2Cl2 to give 11 (219 mg, 43% yield). 1H-NMR (400 MHz, CDCl3) δ 6.47 (m, 1H), 6.37 (bs, 1H), 4.05 (d, J=4.8 Hz, 2H), 3.73 (s, 3H), 1.83 (m, 3H), 1.73 (m, 3H); 13C-NMR (100 MHz, CDCl3) δ 170.8, 169.4, 131.8, 131.2, 52.4, 41.6, 14.0, 12.3; HRMS (ESI) calcd for C8H14NO3 [M+H]+172.0974, found 172.0974.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]1>>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Yield: 46.7 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (160 mg, 0.537 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (537 mg, 2.68 mmol) were processed as described in Example 1, Step J. The crude material was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-80% CH3CN/water gradient; 25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(cyclopropane-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (120 mg, 47% yield) as solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.57 (d, 1H), 9.61 (s, 1H), 8.14 (s, 1H), 7.52 (br s, 1H), 6.85 (br s, 1H), 3.61-3.48 (m, 1H), 3.25-3.13 (m, 3H), 3.09-3.01 (m, 1H), 1.87-1.80 (m, 1H), 1.77-1.65 (m, 3H), 1.45-1.32 (m, 1H), 1.29 (s, 9H), 0.77 (d, 4H); LCMS (APCI+) m/z 478, 480 (M+H)+, Retention time=3.59 minutes (Method 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH2:11][C:12]([OH:14])=O.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]([NH2:49])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]([CH3:48])[CH:45]=[CH:46][N:47]=3)[S:42][C:35]=12.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([NH:49][C:12](=[O:14])[CH2:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]([CH3:48])[CH:45]=[CH:46][N:47]=3)[S:42][C:35]=12
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
To a solution of the acid (27) (75 mg, 0.36 mmol) and HOBt (54 mg, 0.40 mmol) in DMF (6 mL), was added amine 9 (135 mg, 0.40 mmol). After stirring for 5 min, EDC (84 mg, 0.42 mmol) was added and the reaction mixture was stirred for additional 4 hrs at room temperature. The reaction mixture was poured into NaHCO3 solution, extracted with EtOAc; the organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (Aquasil C-18 column, gradient MeOH/water from 60:40 to 95:5) to afford 28a (105 mg, 55% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.80 (s, 1H), 9.62 (s, 1H), 8.66 (d, 1H), 8.33 (s, 1H), 8.04 (d, 1H), 7.90 (d, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.54-7.49 (m, 2H), 7.06 (m, 2H), 6.89 (m, 2H), 4.03 (s, 3H), 3.84 (s, 3H), 3.66 (s, 2H). MS (m/z): 532.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([OH:18])=O)=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[N:26]1[CH2:31][CH2:30][C@@H:29]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C@H:28]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:27]1>>[NH2:1][C:2]1[C:3]([C:16]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[N:26]2[CH2:31][CH2:30][C@@H:29]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C@H:28]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:27]2)=[O:18])=[N:4][C:5]([C:8]2[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: Nc1ccc(-c2c(F)cccc2F)nc1C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2nc(-c3c(F)cccc3F)ccc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
3-amino-6-(2,6-difluorophenyl)picolinic acid and tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate were coupled following method 11 (example 249), to yield tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate after HPLC purification. Alternatively, tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)-piperidin-3-ylcarbamate could be obtained starting with tert-butyl (3R,4R)-1-(3-(3-amino-6-bromo-picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-yl-carbamate and 2,6 difluorophenylboronic acid following the Suzuki procedure outlined in method 14. The TBDMS deprotection of tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-yl-carbamate was performed with 6N HCl, THF, methanol (1:2:1) at room temperature for 2 h. After volatile materials were removed, the crude material was stirred in 30% TFA in dichloromethane for 2 hours. After volatile materials were removed in vacuo, purification and lyophilization yielded 3-amino-N-(4-((3R,4R)-3-amino-4-hydroxy-piperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)picolinamide. HPLC. LCMS (m/z): 441.2 (MH+); LC Rt=2.03 min.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A mixture of 3-nitropyrrole (500 mg, 4.46 mmol), cesium carbonate (3.63 g, 11.2 mmol, 2.5 equiv), 1-chloro-2-dimethylaminoethane (835 mg, 5.8 mmol, 1.3 equiv) and DMF (5 mL) was stirred for 16 h at rt. The reaction mixture was quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with DCM/MeOH (9:1, v/v). The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM→DCM/MeOH, 97:3) to afford 656 mg of the title compound as a yellow oil. Title compound: ESI-MS: 184.1 [M+H]+; TLC: Rf=0.38 (DCM/MeOH, 9:1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11](OC)=[O:12])[CH:8]=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[N:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1cccc(OCC(F)(F)F)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a stirred solution of methyl 6-(2,2,2-trifluoroethoxy)picolinate (0.40 g, 1.69 mmol, Step-2) in tetrahydrofuran (17 mL) is added slowly lithium aluminum hydride (0.096 g, 2.53 mmol) at 0° C. The resulting mixture is stirred at room temperature for 1 hour. The reaction mixture is carefully quenched with 25% aqueous ammonia solution at 0° C. Then the mixture is diluted with dichloromethane (50 mL) and celite is added to the mixture. After stirring at room temperature for 1 hour, the mixture is filtrated through a pad of celite, and the filtrate is concentrated in vacuo to give 0.32 g (92% yield) of the title compound as a white solid. This material is used for the next reaction (Step-4) without further purification.