Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].[CH3:7][O:8][C:9](=[O:54])/[C:10](/[C:52]#[N:53])=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=3[O:40][CH3:41])[CH:23]=[C:22]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH:21]=2)=[C:14]([O:50][CH3:51])[CH:13]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:51][O:50][C:14]1[CH:13]=[C:12](/[CH:11]=[C:10](\[C:52]#[N:53])/[C:9]([O:8][CH3:7])=[O:54])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=2[O:40][CH3:41])[CH:25]=1)[O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:4][C:3](=[O:5])[C:2]([CH3:1])=[CH2:6]
Reactant: C=C(C)C(=O)O
Reactant: COC(=O)/C=C/c1ccc(OCc2cc(COc3ccc(/C=C(\C#N)C(=O)OC)cc3OC)cc(OCCCCCCCl)c2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCCCCOc1cc(COc2ccc(/C=C/C(=O)OC)cc2OC)cc(COc2ccc(/C=C(\C#N)C(=O)OC)cc2OC)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
0.32 ml (2 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) in 2 ml N,N-dimethylformamide (DMF) were added dropwise to a solution of 0.2 ml (1.9 mmol) 2-methylacrylic acid in 2 ml DMF. After addition of 2 mg phenothiazine, 60 mg tetrabutylammonium iodide and 1.1 g (1.6 mmol) (E)-3-[4-[[3-[(6-chlorohexyl)oxy]-5-[[2-methoxy-4[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]benzyl]oxy]-3-methoxyphenyl]-2-cyanoacrylic acid methyl ester in 7 ml DMF the resulting mixture was stirred at 80° C. for 20 hours. The reaction mixture was poured into an ice cold 1 M HCl solution. The aqueous phase was extracted three times with ethyl acetate. The organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfate, filtered and concentrated by vacuum evaporation. The crude product was filtered through a thin silica gel layer. (eluent: ethyl acetate). The filtrate was evaporated to dryness and recrystallized from ethanol to yield 0.35 g (30%) of 2-methylacrylic acid 6-[3-[2-methoxy-4-[2-cyano-(E)-2-(methoxycarbonyl)vinyl]phenoxymethyl]-5-[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxymethyl]phenoxy]hexyl ester as slightly yellow crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.[Si:34]([O:41][C@@H:42]([C@H:46]([O:74][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:77])[CH3:76])[C@@H:47]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[C@@H:48]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:49][O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:43][NH:44][CH3:45])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:44]([CH3:45])[CH2:43][C@@H:42]([O:41][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[C@H:46]([O:74][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:76])[CH3:77])[C@@H:47]([O:66][Si:67]([C:70]([CH3:71])([CH3:72])[CH3:73])([CH3:69])[CH3:68])[C@@H:48]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:60])[CH3:61])[CH2:49][O:50][Si:51]([C:54]([CH3:55])([CH3:56])[CH3:57])([CH3:53])[CH3:52])=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Reactant: CNC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of acid 225 (220 mg, 0.474 mmol, scheme 54), amine 242 (309 mg, 0.474 mmol) and DIPEA (0.331 mL, 1.895 mmol) in DMF (5 mL) was added HATU reagent (270 mg, 0.710 mmol). The mixture was stirred overnight at room temperature then partitioned between ethyl acetate and water. The organic layer was collected, washed with water, 1M NaOH, and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-15%, SNAP 10 g cartridge) to afford title compound 243 (250 mg, 0.254 mmol, 54% yield) as a white solid. MS: 985.4 (MH+).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:23](=O)[C:24]#[C:25][CH2:26][CH2:27][CH2:28][N:29]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]4=[O:39])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:11]=[N:10]1.C(=O)(O)O.[NH2:45][C:46]([NH2:48])=[NH:47]>COCCO>[NH2:48][C:46]1[N:47]=[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH:24]=[C:23]([C:22]2[C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:12]4[CH:11]=[N:10][N:9]([CH3:8])[CH:13]=4)[CH:15]=3)[NH:20][CH:21]=2)[N:45]=1
Reactant: N=C(N)N
Reactant: Cn1cc(-c2cnc3[nH]cc(C(=O)C#CCCCN4C(=O)c5ccccc5C4=O)c3c2)cn1
Agent: O=C(O)O
Solvent: COCCO
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cnc3[nH]cc(-c4cc(CCCN5C(=O)c6ccccc6C5=O)nc(N)n4)c3c2)cn1

Procedure:
8.5 0.92 ml (6.7 mmol) of triethylamine is added to a solution of 116 mg (0.265 mmol) of 2-{6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-6-oxohex-4-ynyl}isoindole-1,3-dione and 70 mg (0.39 mmol) of guanidine carbonate in 4 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 6 hours. After cooling, the mixture is evaporated, and the residue is purified by preparative HPLC, giving 2-(3-{2-amino-6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrimidin-4-yl}propyl)isoindole-1,3-dione as brown solid; ESI 479, EMD 1183586.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH:28]=O>C(O)C.N1CCCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:28][C:20]1[NH:19][C:27]2[C:22]([CH:21]=1)=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 104.5 %

Procedure:
A mixture of 5-tert-butoxycarbonylamino-2-oxindole (124 mg), indole-2-carbaldehyde (87 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (4 mg) in ethanol (2 mL was heated in a sealed tube at 90° C. for 3 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in oven for overnight to give 196 mg of 5-tert-butoxycarbonylamino-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one as a bright orange solid. It was then dissolved in trifluoroacetic acid/dichloromethane mixture (2 mL each) and stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was dissolved in water and basified with saturated sodium bicarbonate solution. The solid was collected by vacuum filtration, washed with water and dried in vacuum oven for overnight to give 129 mg of 5-amino-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one as a brown solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([OH:15])[CH2:5][P:6]([CH2:11][CH2:12][CH2:13][CH3:14])(=[O:10])[O:7]CC.[OH-].[Na+:24]>C(O)C.O>[NH2:2][CH2:3][C:4]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)([OH:15])[CH2:5][P:6]([CH2:11][CH2:12][CH2:13][CH3:14])(=[O:7])[O-:10].[Na+:24]
Reactant: CCCCP(=O)(CC(O)(CN)c1ccc(Cl)cc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCP(=O)([O-])CC(O)(CN)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 1.2 g of ethyl 3-amino-2-(4-chlorophenyl)-2-hydroxy-propyl(n-butyl)phosphinate hydrochloride in 5 ml of ethanol is treated with 0.24 g of sodium hydroxide dissolved in 3 ml of water. The solution heated to 60° for 20 hours. After this time the solution is cooled to room temperature and washed 2-times with 50 ml each of dichloromethane and once with 50 ml of diethyl ether. The aqueous phase is evaporated to dryness. The residue is suspended in n-propanol, heated to 80° C. for 10 minutes and filtered. The n-propanol is removed in vacuo to afford a white solid. Chromatography on reverse-phase silica gel followed by drying in vacuo at 80° yields sodium 3-amino-2-(4-chlorophenyl)-2-hydroxy-propyl(n-butyl)phosphinate; m.p. 215°-215.5°; 1H-NMR spectrum (D2O): δ=7.4 ppm (4H, s), 2.91 ppm (2H, ABq), 2.22 ppm (2H, ABq,d), 1.37-1.0 ppm (6 H, m), 0.75 ppm (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(OCC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCc1cccnc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1cccnc1
Temperature: 60 °C
Yield: 62.9 %

Procedure:
To a solution of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.2 g, 0.71 mmol) in N,N′-dimethylformamide is added 3-(aminomethyl)pyridine (0.073 mL, 0.71 mmol). The reaction mixture is heated at 60° C. under N2. After reaction is completed, diethyl ether is added, and the red precipitate is isolated and washed with methanol, ether, and hexane respectively to afford 0.16 g (63.2% yield) of orange solid: mp 299-300° C.; 1H NMR (DMSO-d6) δ 11.09 (s, 1H), 10.69 (m, 1H), 8.74 (d, J=9 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J=3 Hz, 1H), 8.10 (s, 1H), 7.84 (m, 2H), 7.42 (m, 1H), 7.31 (d, J=9 Hz, 1H), 3.40 (d, J=4.8 Hz, 2H); MS (ESI) m/z 355.7 and 357.7 (M−H)−1, Analysis for C16H12BrN3O2, Calcd: C, 53.70; H, 3.38; N, 11.70. Found: C, 53.45; H, 3.23; N, 11.74.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.2 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A), morpholine-3-carboxylic acid hydrochloride (1 g, 6 mmol) and triethylamine (1.21 g, 12 mmol) in ethanol (40 mL) was stirred at 25° C. for 12 hours under N2. The mixture was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=25/1) to give the title compound as a yellow solid (1.5 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[N:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccncc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccncc1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamine. LCMS (MH+): m/z=440.0, tR (minutes, Method F)=2.43
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(OCC2CO2)c2c1CCCC2
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(O)COc1ccc(C=O)c2c1CCCC2
Temperature: 45 °C

Procedure:
To 4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydronapthaldehyde (2.4 gms) is added tert.-butylamine (15 ml.). The resulting solution is heated at 45° C. for 15 hours. The excess tert.-butylamine is removed at reduced pressure (20 mm). To the residue is added 30 ml. 6 N hydrochloride acid, and the resulting mixture is refluxed for three hours. The acidic mixture is poured into a saturated solution of sodium carbonate which is heated on a steam bath with nitrogen bubbling through it. The basic mixture is extracted with chloroform, which is dried over anhydrous sodium sulfate, filtered and concentrated to give 2.3 g of 4-(3-tert.butylamino-2-hydroxypropoxy)-5,6,7,8-tetrahydronapthaldehyde as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH2:10])[CH3:9].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:28]1[NH:33][C:32](=[O:34])[N:31]([CH:35]([CH3:37])[CH3:36])[C:30](=[O:38])[CH:29]=1>CN1C(=O)CCC1.CS(C)=O>[CH:35]([N:31]1[C:30](=[O:38])[CH:29]=[C:28]([NH:10][C@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH3:9])[NH:33][C:32]1=[O:34])([CH3:37])[CH3:36]
Reactant: Cc1ccccc1[C@H](C)N
Reactant: CC(C)n1c(=O)cc(Cl)[nH]c1=O
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: Cc1ccccc1[C@H](C)Nc1cc(=O)n(C(C)C)c(=O)[nH]1
Temperature: 130 °C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
To a stirred solution of (1S)-1-(2-methylphenyl)ethan-1-amine (310 mg, 2.29 mmol, 1.50 equiv) in NMP (1 mL) was added proton sponge (491.4 mg, 2.30 mmol, 1.50 equiv) and 1.3 (288 mg, 1.53 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at 130° C. in an oil bath, cooled to room temperature, and then diluted with DMSO (2 mL). The solids were filtered and the filtrate was purified by Flash-Prep-HPLC with the following conditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: H2O/0.05% TFA, Mobile Phase B: CH3CN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min. This afforded 50 mg of crude product which was subsequently separated by chiral preparative HPLC with the following conditions: Column, Chiralpak IC, 2*25 cm, Sum; mobile phase, hexanes and ethanol (9:1, 15 min). This resulted in 35.6 mg (8%) of the title compound as a white solid. LC/MS: m/z (ES+) 288 (M+H)+. 1H-NMR (300 MHz, DMSO-d6): δ ppm 9.76 (br s, 1H), 7.28 (d, J=7.2 Hz, 1H) 7.24-7.14 (m, 3H), 6.48 (d, J=6.3 Hz, 1H), 4.95-4.86 (m, 1H), 4.60 (quin, J=6.9 Hz, 1H), 4.19 (s, 1H), 2.34 (s, 3H), 1.37 (d, J=6.6 Hz, 3H), 1.27 (d, J=6.9 Hz, 6H).
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:8][CH:7]=1.[F:38][C:39](B(O)O)([F:41])[F:40]>>[Br:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:21]([CH:26]=1)[C:20]([NH:19][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:6]2[CH:11]=[CH:10][C:9]([C:39]([F:41])([F:40])[F:38])=[CH:8][CH:7]=2)=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:37])=[O:36]
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2O)cc1)C(=O)OC
Reactant: OB(O)C(F)(F)F
Product: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Yield: 40.9 %

Procedure:
5-Bromo-2-heptyloxy-benzoic acid (0.231 g, 0.738 mmol) and the (2S)-Amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g, 0.738 mmol) were then combined as per general procedure A with HBTU (0.335 g, 0.885 mmol) and diisopropylethylamine (0.285 g, 2.21 mmol) to yield the (2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g). The methyl ester of the title compound was the prepared from (2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.080 g, 0.140 mmol) and the trifluoromethylboronic acid (0.050 g, 0.281 mmol) as per general procedure F, which was further hydrolyzed as per general procedure C to give the title compound (0.020 g). 1H-NMR(400 MHz, CDCl3): 1.14(t, 3H), 1.53 (m, 8H), 1.92(m, 2H), 3.6(m, 2H), 4.21(m, 2H), 5.21(m, 1H), 7.12(d, 1H), 7.22(m, 2H), 7.36(d, 1H), 7.5(d, 2H), 7.58(m, 2H), 7.66(m, 1H), 7.78 (m, 6H), 8.62 (S, 1H), 8.9 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([CH:23]3[CH2:25][CH2:24]3)[C:20]([OH:22])=O)=[C:11]2[C:10]([C:26]([O:28][CH3:29])=[O:27])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:40]2[CH:41]=[CH:42][CH:43]=[N:44][C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:39]1([NH:44][C:20](=[O:22])[C@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=[C:10]([C:26]([O:28][CH3:29])=[O:27])[C:11]=23)[CH:23]2[CH2:24][CH2:25]2)[CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C3CC3)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C3CC3)c12
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-2-cyclopropylacetic acid was added THF (2 mL), followed by HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C25H34N4O5, 471; found, 471.5.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][C@H:26]([CH3:28])[O:25][C@H:24]([CH3:29])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:35]=[CH:36][C:31]([N:30]3[C:11]4=[N:12][C:13]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([N:22]6[CH2:23][C@H:24]([CH3:29])[O:25][C@H:26]([CH3:28])[CH2:27]6)[CH:17]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:32][CH:33]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: C[C@@H]1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)C[C@H](C)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(N)CCC6)cc5)c4n3)c2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[cis-2,6-dimethylmorpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (29.0 mg, 0.0449 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixute and stirred at room temperature for 2 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (27.9 mg, 94.7%) as pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.[NH2:9][C:10]1[C:15](Br)=[N:14][C:13]([Br:17])=[CH:12][N:11]=1.O>O1CCCC1>[Br:17][C:13]1[N:14]=[C:15]([O:8][CH2:7][CH:3]2[CH2:6][CH2:5][CH2:4]2)[C:10]([NH2:9])=[N:11][CH:12]=1
Reactant: OCC1CCC1
Reactant: Nc1ncc(Br)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(Br)nc1OCC1CCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
Sodium hydride (0.96 g, 23.7 mmol) was added in portions to a solution of cyclobutanemethanol (2.2 mL, 23.7 mmol) in tetrahydrofuran (30 mL) at 0° C., the reaction mixture was stirred at room temperature for 45 minutes. A solution of 2-amino-3,5-dibromopyrazine (3.0 g, 11.9 mmol) in tetrahydrofuran (10 mL) was added and the reaction mixture was heated at 50° C. for 16 hours. The reaction mixture was cooled to room temperature and water (2 mL) was added, the whole was then concentrated in vacuo to give a brown oil. The crude product was purified by flash column chromatography (100% dichloromethane) to give 5-bromo-3-cyclobutylmethoxy-pyrazin-2-ylamine as a pale yellow solid, 3.19 g (100% yield). LC@215 nm; Rt 2.11: 93%, m/z (ES+): 259 (M+H).
Reaction SMILES: [C:1]12([NH:11][C:12]#[N:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1>ClC1C=CC=CC=1>[C:1]12([NH:11][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])=[NH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1ccccc1N
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1ccccc1NC(=N)NC12CC3CC(CC(C3)C1)C2

Procedure:
A suspension of adamantan-1-ylcyanamide (151 mg, 0.857 mmol) and o-toluidine hydrochloride (186 mg, 0.857 mmol) in dry chlorobenzene was heated between 100°-130° C. for 4.5 hrs. The chlorobenzene was evaporated in vacuo with heating and the residue (285 mg) taken up in 18 ml of water. A gummy, insoluble material was discarded. On adjusting the aqueous extract to pH 9-9.5, a precipitate formed (194 mg, 71%). Two recrystallizations from EtOH/H2O gave the analytical sample; mp 160°-161°, 1H (CD3OD) 1.742 (s, 6 H), 2.050 (d, 6H, J=2.4 Hz), 2.029 (s, 3 H), 6.956 (j, 1 H, J=8.1 Hz), 7.056 (t, 1H, J=8.1Hz), 7.168 (t, 1H, J=7.5 Hz), 7.213 (d, 1H, J=7.5 Hz). Anal. Calcd for C18H25N3:C, 76.28; H, 8.89; N, 14.83. Found: C, 76.25; H, 8.86; N, 14.60.