Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:25].[CH3:26][C:27]1[CH:39]=[CH:38][C:30]2[N:31]=[C:32](S(C)(=O)=O)[O:33][C:29]=2[CH:28]=1>ClC(Cl)C>[F:25][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:32]1[O:33][C:29]2[CH:28]=[C:27]([CH3:26])[CH:39]=[CH:38][C:30]=2[N:31]=1
Reactant: Cc1ccc2nc(S(C)(=O)=O)oc2c1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)c(F)c2)cc1
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(C)cc4o3)c(F)c2)cc1
Temperature: 85 °C
Yield: 42.7 %

Procedure:
To a solution of methyl (1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate (800 mg, 2.34 mmol, 78% ee) in dichloroethane (15 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (891 mg, 4.22 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 80:20 hexane/EtOAc) to give methyl (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate (472 mg). This ester intermediate was redissolved in 1:1 dioxane/THF (20 mL), a solution of 1 N aqueous NaOH (7.02 mL, 7.02 mol) was added, and the mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation, and water (20 mL) and EtOAc (40 mL) were added to the residue. The aqueous layer was separated, acidified to pH 5 by the addition of 1 N aqueous HCl, and then extracted with EtOAc (2×60 mL). The combined organic phases were washed with saturated NaCl and dried (Na2SO4). The solvent was removed by rotary evaporation and the residue was redissolved in DMF (10 mL) and methanol (20 mL). The crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as an off-white solid (161 mg, 15% yield, 80% ee). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (m, 1 H), 8.00-7.60 (m, 6 H), 7.30 (d, 2 H), 7.00 (d, 1 H), 4.05 (m, 1 H), 3.20 (m, 1 H), 2.40 (s, 3 H), 2.20 (m, 1 H), 1.95 (m, 1 H), 1.80-1.60 (m, 4 H); LC-MS ret. time 3.57 min, m/z 459.3 (MH+).
Reaction SMILES: [N+:1]([C:4]([N+:29]([O-:31])=[O:30])([CH2:11][O:12][CH2:13][O:14][CH2:15][C:16]([N+:26]([O-:28])=[O:27])([N+:23]([O-:25])=[O:24])[CH2:17][CH2:18][C:19](OC)=[O:20])[CH2:5][CH2:6][C:7](OC)=[O:8])([O-:3])=[O:2].O>B.C1COCC1>[N+:1]([C:4]([N+:29]([O-:31])=[O:30])([CH2:11][O:12][CH2:13][O:14][CH2:15][C:16]([N+:23]([O-:25])=[O:24])([N+:26]([O-:28])=[O:27])[CH2:17][CH2:18][CH2:19][OH:20])[CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2]
Reactant: COC(=O)CCC(COCOCC(CCC(=O)OC)([N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])C(CCCO)(COCOCC(CCCO)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dimethyl 4,4,10,10-tetranitro-6,8-dioxatridecane-1,13-dioate (28.8 g) was dissolved in 139 mL of BH3.THF with ice-cooling and under a nitrogen atmosphere. The solution was stirred at room temperature for 3 days, after which time 27 mL of water was added slowly and the mixture was heated at 60° C. for 5 minutes. After cooling, the mixture was poured into 200 mL of water, and the product was extracted with ether. The ether solution was washed with aqueous sodium bicarbonate solution, then with water, and dried (MgSO4) After removal of the solvent, the crude product was recrystallized from dichloromethane. Yield: 19.9 g (79%); M.P. 72.5°-3.5° C. 1H NMR spectrum (CDCl3 /TMS): δ 4.76 (s, 2H); 4.41 (s, 4H); 2.69 (m, 4H); 1.59 (m. 4H).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1/[CH:30]=[CH:31]\[C:32]#[N:33]>>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:11]2[CH:10]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:31]=[C:32]([NH2:33])[N:12]2[N:13]=1
Reactant: N#C/C=C\c1ccccn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccc(F)cc2F)n1)c1ccccc1
Product: Nc1cc(-c2ccccn2)cc2nc(-c3ccc(F)cc3F)nn12

Procedure:
The title compound, MS m/e (%): 324(M+H+,100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole and (E)/(Z)-3-pyridin-2-yl-acrylonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: COc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Yield: 27.9 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 298 mg of 4-methoxyindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 107 mg of 2-[2-(4-methoxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a salmon pink powder, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[O:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:12]=2)[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[N:3]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.N12CCCN=C1CCCCC2.N1C=CC=CC=1>CO>[NH3:3].[CH3:8][OH:9].[CH2:16]([O:15][C:13]([C:10]1[O:9][C:8]([CH2:7][N:6]2[C:5]3[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=3[N:3]=[C:2]2[N:22]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:12][CH:11]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reactant: C1CNCCNC1
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 2-chloro-1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazole (9.50 g, 31.2 mmol) and [1,4]diazepane (6.24 g, 62.3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.6 mL, 37.4 mmol), and pyridine (90 mL). Heat to reflux. After 18 hours, cool to ambient temperature and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with methanol and then 2% concentrated aqueous ammonia/methanol to give 4-(1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane. Combine 4-(1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.0 g, 2.7 mmol) and tetrahydrofuran (10 mL). Add a solution of lithium aluminum hydride (2.7 mL, 1.0 M in tetrahydrofuran, 2.7 mmol). After 18 hours pour the reaction mixture into a beaker, dilute with dichloromethane, and cool to 0° C. With stirring add portionwise, Glauber's salt (Na2SO4.10H2O) until the evolution of gas ceases. Add dichloromethane to about double the volume, add celite, stir to form a thick slurry, and filter. Evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2([CH3:17])[CH3:16])#[CH:2].[CH3:18][O:19][C:20](=[O:48])[CH:21]([C:23]1[CH:28]=[CH:27][C:26](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:25][CH:24]=1)[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[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>[CH3:18][O:19][C:20](=[O:48])[CH:21]([C:23]1[CH:24]=[CH:25][C:26]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([OH:13])[CH:12]=2)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]3([CH3:17])[CH3:16])=[CH:27][CH:28]=1)[CH3:22]
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.04 g, 0.17 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.075 g, 0.26 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel 230–400 mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexane as the mobile phase, the title compound was obtained as a brown oil (0.018 g, 26%).
Reaction SMILES: I.CS[C:4](=[N:18][CH3:19])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:19][NH:18][C:4]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CN=C(Nc1ccccc1N1CCOCC1)SC
Reactant: C1CCNC1
Agent: I
Solvent: CCO
Product: CNC(=Nc1ccccc1N1CCOCC1)N1CCCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydriodide (3.9 g prepared as described in Example 210), pyrrolidine (1 ml) and ethanol (40 ml) was heated under reflux for two weeks to yield an oil which was purified by chromatography on a neutra alumina column eluted with a 1:1 mixture of dichloromethane and hexane and then a 1:9 mixture of methanol and dichloromethane to give N-methyl-N'-(2-morpholinophenyl)pyrrolidine-1-carboxamidine which was converted into its monofumarate salt (m.p. 168°-171° C.) which was recrystallised from propan-2ol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]([OH:11])[C:3]=1[CH3:12].[OH-].[Na+].C([O:19][C:20](=[O:23])[CH2:21]Br)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH3:1][C:2]1[C:3]([CH3:12])=[C:4]([O:11][CH2:21][C:20]([OH:23])=[O:19])[C:5]([CH3:10])=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1c(C)c(O)c(C)c(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C)c(OCC(=O)O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
A mixture of 20 mL of CH2Cl2, 20 mL H2O, 415 mg (1 eq) of tetramethylhydroquinone (D), 200 mg of NaOH, 540 mg (1.1 eq) of t-butylbromoacetate, 760 mg of C were stirred at room temperature, under argon, for 12 hr. Initially, D was not completely soluble, but with time, in 1 hr, it completely dissolved. After 12 hr, acid was added to bring the pH to 7.0, 200 mL of CH2Cl2 was added, and the reaction mixture was extracted with brine (4×200 mL), dried over Na2SO4, and evaporated under reduced pressure to yield crude product. 5 mL of TFA was added to the crude product, and the mixture was stirred for 1 hr. TFA was evaporated and the crude product charged on silica gel (230-400 mesh, CH2Cl2 -EtOAc, 2:1) to yield 270 mg (49%) of product 27.
Reaction SMILES: S1(CCCC1)(=O)=O.[F:8][C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[NH:14][C:15](=[O:22])[CH2:16][CH2:17]S(C)(=O)=O.F[C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][N:30]2[CH3:33])=[C:26]([NH:34][C:35]2[C:36]([O:41][CH3:42])=[N:37][N:38]([CH3:40])[CH:39]=2)[N:25]=1.C(N(CC)C(C)C)(C)C.[OH-].[K+]>O>[F:8][C@@H:9]1[CH2:13][N:12]([C:24]2[N:32]=[C:31]3[C:27]([N:28]=[CH:29][N:30]3[CH3:33])=[C:26]([NH:34][C:35]3[C:36]([O:41][CH3:42])=[N:37][N:38]([CH3:40])[CH:39]=3)[N:25]=2)[CH2:11][C@H:10]1[NH:14][C:15](=[O:22])[CH:16]=[CH2:17]
Reactant: COc1nn(C)cc1Nc1nc(F)nc2c1ncn2C
Reactant: CS(=O)(=O)CCC(=O)N[C@@H]1CNC[C@H]1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S1(=O)CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@@H]1CN(c2nc(Nc3cn(C)nc3OC)c3ncn(C)c3n2)C[C@H]1F
Temperature: 40 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
To a 200 L Hastelloy reactor heated to 40° C. was added sulfolane (22.4 L) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (4.03 kg, 16.9 mol, 1.05 eq) and stirred the resulting mixture until all solids were dissolved. To this solution was added 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (4.47 kg, 16.1 mol, 1.00 eq) and N,N-diisopropylethylamine (8.50 L, 48.7 mol, 3.0 eq) and the mixture heated at 115° C. for 16 hr. The reaction mixture was cooled to 30° C., and a solution of potassium hydroxide (2.26 kg, 40.3 mol, 2.5 eq) in water (44.7 L) was added. After stirring for 4 hr, the reaction mixture was cooled to 20° C., water (44.7 L) was added and the resulting mixture granulated for 12 hr. The crude product was isolated on a Nutsche filter and washed with water (27 L) and then dried under nitrogen on the filter. The reactor was cleaned and then charged with water (35.8 L) and acetone (53.6 L). The crude product cake was charged back into the reactor and heated to 60° C. until all of the solids had dissolved. The batch was then cooled to 40° C. and then transferred into a speck free 100 L reactor via an in-line 10 μm filter. The 200 L reactor, line and filter were rinsed with acetone (5 L) and sent into the 100 L reactor. The batch was concentrated with the jacket temperature set at 70° C. under partial vacuum until the acetone content reduced to 5 wt %, as determined by gas chromatography head space. The batch was then cooled to 20° C. and granulated for 4 hr. The product was filtered, washed with water (18 L) and dried in a vacuum oven at 55° C. for 8 hr. The title compound (3.942 kg, 9.49 mol, 59%) was isolated as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C18H23FN9O2 416.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[CH:16])[CH2:10][C@H:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[O:7].[ClH:35].[CH:36]([C@H:39]1[CH2:44][O:43][CH2:42][CH2:41][NH:40]1)([CH3:38])[CH3:37].[CH:45](NC(C)C)(C)C.C=O>O1CCOCC1.[Cu]Cl>[ClH:35].[ClH:35].[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:45][N:40]2[CH2:41][CH2:42][O:43][CH2:44][C@@H:39]2[CH:36]([CH3:38])[CH3:37])[CH2:10][C@H:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[O:7]
Reactant: CC(C)NC(C)C
Reactant: CC(C)[C@H]1COCCN1
Reactant: C#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Agent: Cl[Cu]
Agent: C=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOC[C@@H]3C(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A mixture of (2R)-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-propargylpiperazine (286 mg), (3S)-3-isopropylmorpholine hydrochloride (118 mg) and N,N-diisopropylamine (92 mg) in dioxane (3 ml) was stirred at room temperature. Paraformaldehyde (22 mg) and copper(I) chloride (10 mg) were added and the whole was stirred for 30 minutes and then heated at 80° C. for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (1:1) as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-isopropylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (190 mg).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2(C(O)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[K+].[K].F[CH:19]1[CH2:21][C:20]1(CC1C=CC=CC=1)[C:22]([OH:24])=[O:23].BrC[C:34]1[CH:39]=[CH:38]C=C[C:35]=1[C:40](=[CH:45][O:46][CH3:47])[C:41]([O:43][CH3:44])=[O:42]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([O:24][C:22]([CH:20]2[CH2:19][CH2:21]2)=[O:23])[C:9]2[CH:8]=[CH:38][CH:39]=[CH:34][C:35]=2[C:40](=[CH:45][O:46][CH3:47])[C:41]([O:43][CH3:44])=[O:42])=[CH:13][CH:14]=1
Reactant: O=C(O)C1(Cc2ccccc2)CC1F
Reactant: O=C(O)C1(Cc2ccc(F)cc2)CC1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: [K+]
Agent: [K]
Agent: [OH-]
Product: COC=C(C(=O)OC)c1ccccc1C(Cc1ccc(F)cc1)OC(=O)C1CC1
Yield: 54 %

Procedure:
A method similar to Example 3 was used and 6.3 g (32 mmol) of 1-(4-fluorobenzyl)-cyclopropanecarboxylic acid were converted with 2.0 g (36 mmol) of potassium hydroxide into the potassium salt of fluorobenzylcyclopropanecarboxylic acid, and said salt was then reacted at 100° C. with 6.3 g (22 mmol) of methyl alpha-(2-bromomethylphenyl)-beta-methoxyacrylate. Yield: 54%; colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=2[CH:13]=1)#[N:2].C[Sn]([N:23]=[N+:24]=[N-:25])(C)C>C1(C)C=CC=CC=1>[NH:23]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[CH:13]=2)=[N:2][N:25]=[N:24]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)cc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
A 500 mL 3-neck round bottom flask equipped with a magnetic stirrer, condenser, thermometer and nitrogen bubbler was charged with 19.1 g (82 mmol) of 2-(2-cyanophenyl)-5-methylbenzofuran, 200 mL of toluene and 25.6 g (124 mmol) of trimethyltin azide. The suspension was heated at reflux for 20 hours, then an additional 10.0 g (48 mmol) of trimethyltin azide was added and heating at reflux was continued for another 24 hours. Additional trimethyltin azide (5.5 g,27 mmol) was added and refluxing continued for 5 hours. The reaction mixture was cooled to room temperature and solids were removed by filtration and washed with hexane and air dried. The solids were partitioned between 400 mL of 2N aqueous sodium hydroxide and 400 mL of ethyl acetate. The layers were separated and aqueous layer was acidified by the addition of 2N hydrochloric acid, then extracted with 100 mL of ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and refrigerated for 48 hours. The crystals that formed were removed by filtration, washed with hexane and air dried to give 12.97 g (47 mmol,57%) of the product as fluffy, white crystals. 1H NMR (200 MHz,CDCl3): 2.38 (s,3H), 6.27 (s,1H), 7.05 (d,8 Hz,1H), 7.25 (m,2H), 7.4-7.7 (m,3H), 7.90 (d,8 Hz,1H).
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-])=[C:6]([CH3:9])[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>C(OCC)(=O)C>[C:15]([O:18][CH2:9][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)(=[O:17])[CH3:16]
Reactant: Cc1cccc(Cl)[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cccc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of the 6-chloro-2-methylpyridine-N-oxide prepared in step 1 in 750 mL acetic anhydride was heated at reflux overnight. The reaction was cooled to ambient temperature and poured into saturated aqueous sodium bicarbonate. The mixture was diluted with ethyl acetate and filtered through celite. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated. The residue was azeotroped with benzene to remove any remaining acetic acid. 2-acetoxymethyl-6-chloropyridine was isolated by vacuum distillation (b.p. 105°-110° C./1.3 torr).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(O)CCC>CN(C=O)C.CO>[N:21]1([C:24]2[CH:25]=[CH:26][C:27]([NH:28][C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)=[CH:29][CH:30]=2)[CH2:20][CH2:19][O:18][CH2:23][CH2:22]1
Reactant: CC(=O)Nc1ccc(-c2ccnc(Cl)n2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CO
Solvent: CCCCO
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C

Procedure:
A flask was charged with C1 (500 mg, 2.0 mmol), 4-morpholinoaniline H (540 mg, 3.0 mmol) and nBuOH (10 mL). The flask was immersed in a 180° C. oil bath for 30 minutes. The reaction mixture was cooled to ambient temperature and the black residue dissolved in DMF and MeOH. The product was purified by HPLC with TFA/ACN as eluent. The TFA salt was removed by extracting with sodium hydroxide and ethylacetate to afford the title compound (18).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.OS(O)(=O)=O.[N+:20]([O-])([OH:22])=[O:21]>>[N+:20]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][CH:4]=[C:3]2[C:2]([F:1])([F:13])[F:14])([O-:22])=[O:21]
Reactant: FC(F)(F)c1ccnc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc2c(C(F)(F)F)ccnc12
Yield: 29 %

Procedure:
In a similar fashion using route 11 general procedure 57, 4-trifluoromethyl-quinoline 467 (200 mg, 1.01 mmol) and H2SO4:HNO3 (2:1) gave the title compound (70 mg, 29%) which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[O:25])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:21][C:22](=[O:24])[CH3:23])=[N:19][NH:20][C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B-](F)(F)(F)[F:27].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC(N(C)C)=O.CO>[F:27][C:13]1[C:14]2[NH:20][N:19]=[C:18]([NH:21][C:22](=[O:24])[CH3:23])[C:15]=2[CH:16]=[N:17][C:12]=1[NH:11][C:10]([NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])=[O:25]
Reactant: F[B-](F)(F)F
Reactant: CC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CC(=O)Nc1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)—N-(6-(3-(1-Phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (Example 47; 75 mg, 0.222 mmol) was dissolved in DMA (0.5 mL) and methanol (0.5 mL), charged with powdered Selectfluor® (86 mg, 0.244 mmol), and stirred at room temperature overnight. The reaction was then heated to 65° C. for 2 h. The resulting crude residue was purified by mass-triggered reverse phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)—N-(7-fluoro-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd. for C17H17FN6O2 [M+1]+ 357. found 357. 1H NMR (500 MHz, DMSO-d6) δ 13.83 (s, 1H) 11.15 (s, 1H), 10.79 (s, 1H), 9.86 (s, 1H), 8.28 (d, J=7.3, 1H) 7.34 (m, 4H), 7.34 (m, 1H), 4.88 (m, 1H), 2.20 (S, 3H), 1.43 (d, J=6.9, 3H).