Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:13]=[N:12]1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:13]=[N:12]1
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccccn3)cn2)c(F)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Nc1ccc(-n2cc(-c3ccccn3)cn2)c(F)c1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
900 mg of 2-(1-(2-fluoro-4-nitrophenyl)-1H-pyrazol-4-yl)pyridine (24f) was dissolved in 25 mL ethyl alcohol (95%), and then the mixture was heated to reflux. HCl (4N, 660 μL) was added to the mixture, and then Fe powder (886.5 mg) was added in batches over 15 minutes, under stirring and refluxing. TLC monitoring was performed to determine completion of the reaction, after which the mixture was cooled down to room temperature and buffered to pH 9-10 with a saturated Na2CO3 solution. Then, the iron sludge in the mixture was removed by vacuum filtration. The filtrate was rotary evaporated, dissolved with water (20 mL), and then extracted with ethyl acetate for three times. The combined organic phase was washed with diluted hydrochloric acid (5%) until the organic phase was free of fluorescence. Then, the combined water phase was buffered to be basic (pH>7) with a saturated sodium bicarbonate solution. The resultant solution was extracted with ethyl acetate for three times. The combined organic phase was dried and rotary evaporated to obtain 540 mg of a light brown solid, with a yield of 67.2%. Thus obtained crude product can be directly used for the next step without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CCCCCCC.C[CH2:37][O:38]C(C)=O>CC(OC)(C)C>[CH2:17]([N:16]1[C:13]2[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[N:10]=[C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:14]=2[NH:15][C:37]1=[O:38])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(C)=O
Reactant: Nc1c(NCc2ccccc2)cc(C(F)(F)F)nc1NCc1ccccc1
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Product: O=c1[nH]c2c(NCc3ccccc3)nc(C(F)(F)F)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N2,N4-Dibenzyl-6-trifluoromethyl-pyridine-2,3,4-triamine (9.02 g, 24.2 mmol) was dissolved in TBME (180 ml) and CDl (19.6 g, 121 mmol) was added. The reaction mixture was stirred at room temperature for 72 h. Water (100 ml) was added to the reaction mixture and the layers were separated. The aqueous was extracted with EtOAc (200 ml). The combined organics were washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to give the crude (25 g). Column chromatography through silica eluting with 30:70→60:40 Heptane:EtOAc gave the title compound (2.64 g) as a white fluffy solid.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:36])[NH:11][C:12]1([C:15](=[O:35])[NH:16][C:17]2([C:20]3[CH:25]=[C:24]([CH2:26][NH:27]C(OC(C)(C)C)=O)[CH:23]=[CH:22][N:21]=3)[CH2:19][CH2:18]2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[ClH:1].[CH2:2]([O:9][C:10](=[O:36])[NH:11][C:12]1([C:15](=[O:35])[NH:16][C:17]2([C:20]3[CH:25]=[C:24]([CH2:26][NH2:27])[CH:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]2)[CH2:13][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C2(NC(=O)C3(NC(=O)OCc4ccccc4)CC3)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccnc(C2(NC(=O)C3(NC(=O)OCc4ccccc4)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4M HCl solution in 1,4-dioxane (15 mL) was added to (1-{1-[4-(tert-Butoxycarbonylamino-methyl)-pyridin-2-yl]-cyclopropylcarbamoyl}-cyclopropyl)-carbamic acid benzyl ester (1.403 g, 2.92 mmol). The resultant mixture was allowed to stir at RT for 6 h. The mixture was concentrated to afford a light brown solid. This solid was washed with diethyl ether and dried in vacuo to afford 1.271 g of {1-[1-(4-Aminomethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-carbamic acid benzyl ester di-hydrochloric acid salt.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CN=C1.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-1-propanol (10.0 g, 66.0 mmol) and imidazole (6.7 g, 98.4 mmol) in N,N-dimethylformamide (50 ml) was cooled to 0-5° C. and treated dropwise with tert-butylchlorodiphenylsilane (21.5 g, 78.2 mmol). The resulting mixture was stirred at 0-5° C. for 2 hours and then quenched by addition of water (400 ml) and toluene (500 ml). The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 95:5) gave 24.8 g (96%) of the title material as a clear oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15].Cl.[NH2:18][OH:19]>C(O)C>[OH:19][NH:18][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH3:7])=[O:16])=[NH:15]
Reactant: NO
Reactant: COC(=O)CCCCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)CCCCC(=N)NO
Yield: 86.9 %

Procedure:
Add sodium carbonate (4.5 g, 42 mmol) to a solution of commercially available 5-cyano-pentanoic acid methyl ester (5.0 g, 35 mmol) and hydroxylamine hydrochloride (2.9 g, 42 mmol) in ethanol (100 mL) at room temperature under nitrogen and heat the mixture at reflux for 5.5 h. Filter the mixture through celite and remove the solvent under reduced pressure to provide crude methyl 5-(N-hydroxycarbamimidoyl)pentanoate (5.3 g, 87% yield), which is carried forward without further purification.
Reaction SMILES: C(OCCOCCO)C.[BH4-].[Na+].[C:12]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[C:12]([CH:16]1[CH2:17][CH2:18][CH:19]([OH:22])[CH2:20][CH2:21]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCCOCCO
Solvent: Cc1ccccc1C
Product: CC(C)(C)C1CCC(O)CC1
Temperature: 95 °C

Procedure:
A mixture consisting of 0.52 g (0.0039 mole) of diethylene glycol monoethyl ether and 5 ml of xylene was added dropwise to a mixture consisting of 0.65 g (0.017 mole) of sodium borohydride, 10 ml of xylene and 10 g (0.065 mole) of 4-t-butylcyclohexanone at 95° C. over 30 minutes while agitating the mixture. Subsequently, the mixture was agitated for one hour while maintaining it at 95° C. Next, after the mixture was cooled to room temperature, it was neutralized with dilute sulfuric acid. As a result, 4-t-butylcyclohexanol was quantitatively obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH3:42])[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[S:36]1[CH:37]=[C:33]([CH2:32][N:22]([C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[O:13])[CH3:42])[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 98 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([Cl:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.O.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=[C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=2)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(Cl)nc2cccnc2c1Cl
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(-c2cccc(F)c2)nc2cccnc2c1Cl
Temperature: 25 °C

Procedure:
To a stirred suspension of ethyl 2,4-dichloro-1,5-naphthyridine-3-carboxylate (1.0 g, 3.69 mmol) in acetonitrile:water (7 mL:2 mL) was added Pd (PPh3)4 (0.426 g, 0.369 mmol), 3-fluorophenylboronic acid (0.568 g, 4.06 mmol) and sodium carbonate (0.782 g, 7.38 mmol) and the reaction was heated at reflux for 6 h. After this time the reaction was cooled to rt and partitioned between EtOAc (80 mL) and water (30 mL). The separated organic layer was dried over MgSO4, filtered and concentrated in vacuo. The mixture was purified by column chromatography on silica gel using a gradient from 1:0 to 4:1 of hexane:EtOAc to give ethyl 4-chloro-2-(3-fluorophenyl)-1,5-naphthyridine-3-carboxylate as a white solid: LC-MS (ESI) m/z 331.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1.C([O-])(O)=O.[Na+]>O1CCCC1.O.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methly-2-propanesulfinamide (7.4 g) is added to a solution of 1,4-dioxa-spiro[4.5]decan-8-one (10.0 g) and titanium tetraisopropoxide (37.9 mL) in tetrahydrofuran (130 mL) at room temperature. After stirring the solution at room temperature overnight, it is poured into a stirred saturated solution of NaHCO3 in water. The resulting mixture is filtered over Celite and the remainder in the filter is thoroughly washed with ethyl acetate. The organic phase of the filtrate is separated, washed with brine, and dried (MgSO4). The solvent is evaporated and the residue is chromatographed (cyclohexane/ethyl acetate 1:2→0:1) to give the title compound as a colorless solid. Yield: 7.0 g (42% of theory); TLC [silicagel, cyclohexane/ethyl acetate 1:2]: rf=0.5; Mass spectrum (ESI+): m/z=260 [M+H]+.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][C:21]=1[CH:34]([CH3:38])[CH2:35][CH2:36][OH:37])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.Cl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:37][CH2:36][CH2:35][CH:34]([C:21]1[CH:22]=[C:23]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:25][C:20]=1[O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:38])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CCO)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)c2cc(OCc3ccccc3)ccc2OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
Tosyl chloride (11.1 g., 58.1 mM) is added to a solution of 3-(2,5-dibenzyloxyphenyl)-1-butanol (20.7 g., 57 mM) in pyridine (90 ml.) at -45° C. The reaction mixture is held at -35° C. for 18 hours and is then diluted with cold 2 N hydrochloric acid (1500 ml.) and extracted with ether (5×250 ml.). The combined extracts are washed with saturated sodium chloride solution (4×250 ml.) and then dried (Na2SO4). Concentration of the dried extract affords the product which may be purified by standard methods, if desired.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])=[C:14]3[NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([CH2:33][NH:34]C(=O)OC(C)(C)C)[CH2:29][CH2:28]2)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:34][CH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:26][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:4]4[CH:5]=[C:6]([O:9][CH3:10])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=4)[CH:12]=3)[N:17]=[CH:16][C:15]=2[C:21]([CH:23]2[CH2:24][CH2:25]2)=[O:22])[CH2:28][CH2:29]1
Reactant: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](CNC(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](CN)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure A-2, tert-butyl {trans-4-[6-(3-chloro-4-hydroxy-5-methoxyphenyl)-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}methylcarbamate (0.123 mmol) was reacted with TFA (2 mL) to afford the desired product (28 mg, 47% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD+TFA-d) δ 9.35 (s, 1H), 8.49 (s, 1H), 8.30 (d, J=8.7 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.33 (s, 1H), 7.26 (s, 1H), 4.0 (s, 1H), 3.99 (s, 3H), 2.90-2.81 (m, 3H), 2.47-2.41 (m, 2H), 2.10-1.98 (m, 2H), 1.83-1.64 (m, 3H), 1.37-1.17 (m, 6H); ESI MS m/z 480 [C27H30ClN3O3+H]+; HPLC>99% (AUC), tR=11.15 min.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]1([C:13]#[CH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CC)CC)C.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.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:14]#[C:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C(#Cc1cccs1)c1ccccc1
Yield: 57.5 %

Procedure:
1 g (0.00142 mol) of bis-(triphenylphosphine)palladium chloride, 5 g (0.0262 mol) of copper iodide and 8.5 g (0.0324 mol) of triphenylphosphine were added in succesion to a solution of 163 g (1 mol) of 2-bromothiophene and 127.5 g (1.25 mol) of phenylacetylene in 850 ml of triethylamine at 25° C. Stirring was carried out for twelve hours under a nitrogen atmosphere at 80° C., after which the mixture was filtered and the filtrate was evaporated down under reduced pressure. 600 ml of methylene chloride were added to the residue and the solution was washed with three times 200 ml of water, dried over Na2SO4 and evaporated down under reduced pressure, after which 200 ml of n-pentane were added. The crystals thus obtained were filtered off under suction and dried. 106 g (57.6% of theory) of 1-(2-thienyl)-2-phenylacetylene were obtained as pale yellow crystals of melting point 49°-59 ° C. (Active Ingredient Example 1.001).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.C(N(CC)CC)C.FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C(Cl)Cl>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][N:29]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:14])[F:15])[C:5]=12
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(CC(F)(F)F)C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 17.2 %

Procedure:
To a mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (20 mg, 0.04 mmol) and triethylamine (20 μL, 0.14 mmol) in methylene chloride (0.3 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 mg, 0.049 mmol). The resulting mixture was stirred at 40° C. for 3 h. The solvents were evaporated and the crude material purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3.4 mg (20%) of the desired product. The product was isolated as a racemic mixture. LCMS calculated for C22H23F5N7O (M+H)+: m/z=496.2; Found: 496.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][C@@H:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:16][C:10]1[N:9]=[C:8]([O:17][C@@H:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCl)c2n1
Reactant: C1CCNCC1
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(3-chloropropyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26]([OH:28])=O)[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:52][CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=1>C(OCC)(=O)C.CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)([CH3:29])[C:26](=[O:28])[NH:52][CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)=[CH:18]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: NCCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1ccccn1
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.400 g, 1.01 mmol) in ethyl acetate (6 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (0.138 g, 1.02 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.198 g, 1.03 mmol). This mixture was stirred 2 hours and 2(2-aminoethyl)pyridine (0.16 mL, 1.3 mmol) was added. After stirring an additional 18 hours, the resulting mixture was diluted with ethyl acetate (20 mL), and washed with aqueous 1N citric acid, aqueous saturated sodium bicarbonate, and brine solutions. The organic phase was dried over MgSO4, concentrated, and purified by flash chromatography (SiO2, 230-400 mesh, ethyl acetate eluant). After concentration, the residue was dried under vacuum at 60° C. for 48 hours to provide 0.365 g (72%) of product; 1H NMR (CDCl3) δ1.40-1.60 (2H, m), 1.56 (3H, s), 1.65-1.95 (12H, m), 2.88 (2H, t, J 6 Hz), 3.39 (2H, d, J 5 Hz), 3.50-3.70 (2H, m), 4.75 (1H, br s), 5.35 (1H, br s), 6.40 (1H, d, J 2 Hz), 7.00-7.20 (4H, m), 7.22-7.35 (2H, m), 7.52-7.60 (2H, m), 8.20 (1H, br s), 8.40-8.45 (1H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[C:27]([CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)(=[O:29])[NH2:28].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[OH-].[Na+]>O1CCOCC1.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:26][C:4]1[N:3]=[C:2]([NH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1)C1CCNCC1
Temperature: 150 °C
Yield: 14.5 %

Procedure:
A mixture of Example 7a (0.100 g, 0.247 mmol), tert-butyl 4-carbamoylpiperidine-1-carboxylate (0.0960 g, 0.421 mmol), cesium carbonate (0.105 g, 0.322 mmol), palladium (II) acetate (2.8 mg, 0.012 mmol), and Xantphos (10.7 mg, 0.019 mmol) in dioxane (3 mL) and DMF (0.1 mL) was degassed and heated at 150° C. for 30 minutes in a Biotage microwave reactor. The solvent was evaporated. The residue was treated with 20% brine and extracted with EtOAc. The organic layer was concentrated, dissolved in dioxane (2.5 mL), and treated with 20% sodium hydroxide (0.50 mL, 0.247 mmol). The mixture was heated at 50° C. for 2 hours. After concentration, the residue was triturated with water and filtered. The solid was purified by reverse-phase HPLC as described in Example 56 to give the title compound (12.7 mg) as trifluoroacetic acid salts. 1H NMR (500 MHz, METHANOL-d4) ppm 1.81-2.07 (m, 2H), 2.10-2.23 (m, 2H), 2.84 (m, 1H), 3.01-3.15 (m, 2H), 3.45-3.57 (m, 2H), 7.30 (dd, J=7.93, 4.88 Hz, 1H), 7.48 (d, J=1.22 Hz, 1H), 8.04 (s, 1H), 8.32 (dd, J=4.73, 1.37 Hz, 1H), 8.48 (dd, J=8.09, 1.37 Hz, 1H), 8.54 (s, 1H). MS (ESI+) m/z 356.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.CN(C=O)C.O[NH:24][C:25](=[NH:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([O:6]/[N:24]=[C:25](\[NH2:27])/[CH3:26])=[O:5]
Reactant: O=C(O)c1c(F)cccc1I
Reactant: CC(=N)NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C/C(N)=N/OC(=O)c1c(F)cccc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
To a heterogeneous mixture of 2-fluoro-6-iodobenzoic acid (1.51 g, 5.66 mmol) at 0° C. in DCM (28 mL) was added oxalyl chloride (0.635 mL, 7.36 mmol) followed by DMF (0.15 mL). Gas evolution commenced immediately and after 5 min the ice bath was removed. When gas evolution had ceased and the mixture was homogeneous an aliquot was removed and quenched with MeOH. Formation of the methyl ester was confirmed by HPLC and the mixture was concentrated in vacuo. The viscous liquid was dissolved in fresh DCM (28 mL) and treated with solid N-hydroxyacetamidine (503 mg, 6.79 mmol) in several portions followed by TEA (1.2 mL, 8.49 mmol) at 0° C. After stirring for 14 h at ambient temperature the mixture was washed with saturated aqueous NaHCO3 solution. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 100% EtOAc/Hex) afforded the desired product as a colorless oil (1.57 g, 86%). MS (ESI) mass calculated for C9H8FIN2O2, 321.96; m/z found, 323.0. 1H NMR (500 MHz, CDCl3): 7.70-7.65 (m, 1H), 7.15-7.11 (m, 2H), 4.87 (br s, 2H), 2.06 (s, 3H).