Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Br)=[CH:7]2.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]=O)[CH2:19][CH2:18]1)[CH2:15][CH3:16].CC(C)([O-])C.[K+]>>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:24][CH2:23][C@H:20]1[CH2:19][CH2:18][C@H:17]([CH2:14][CH2:15][CH3:16])[CH2:22][CH2:21]1)=[CH:7]2
Reactant: CCCC1CCC(CC=O)CC1
Reactant: Fc1ccc2cc(Br)ccc2c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCC[C@H]1CC[C@H](CCc2ccc3c(F)c(F)ccc3c2)CC1

Procedure:
The procedure of Example 14 was followed except that 5,6-difluoro-2-bromonaphthalene was used instead of 6-fluoro-2-bromonaphthalene, 4-propylcyclohexaneethanal was used instead of 4-propylcyclohexanene and isomerization with potassium t-butoxide was not effected to obtain 5,6-difluoro-2-[2-(trans-4-propylcyclohexyl)ethyl]naphthalene.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16])[CH2:30]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Reactant: Nc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1cccc2c1CN(c1c(F)c(NCCO)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 35.5 %

Procedure:
205 mg of 1-cyclopropyl-5-(2-hydroxyethylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3carboxylic acid, 100 mg of 4-aminoisoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 97 mg of the target compound.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:13]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[N:42]=[N:41][N:40]=2)[CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: COc1cc(C(=O)Nc2ccccc2[N+](=O)[O-])ccc1-c1ccccn1
Reactant: [N-]=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(-c2nnnn2-c2ccccc2[N+](=O)[O-])ccc1-c1ccccn1
Temperature: 25 °C

Procedure:
To toluene (1 mL) was added 3-methoxy-4-(pyridin-2-yl)-2′-nitrobenzanilide (97 mg, 0.28 mmol) and phosphorous pentachloride (56 mg, 0.27 mmol), and the mixture heated at reflux for 1 h. The resulting solution was cooled to rt and added to a solution of NaN3 (35 mg, 0.54 mmol) in DMF (2 mL). The mixture was heated at 90° C. for 1 h, cooled to rt, partitioned between EtOAc and water, and the organic layer concentrated. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (0:1 to 1:1) to afford 2-{2-methoxy-4-[1-(2-nitrophenyl)-1H-tetraazol-5-yl]phenyl}pyridine as a yellow solid.
Reaction SMILES: [ClH:1].[C:2]([NH:6][CH2:7][CH:8]([C:10]1[CH:18]=[C:14]([C:15]([NH2:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)[OH:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[ClH:1].[C:2]([NH:6][CH2:7][CH:8]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([CH:18]=1)[C:15]([NH2:17])=[O:16])[OH:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(C(N)=O)c1
Reactant: CCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C(O)CNC(C)(C)C)cc1C(N)=O

Procedure:
A mixture of 5-(2-tert-butylamino-1-hydroxyethyl) salicylamide, hydrochloride (8.7 g) and anhydrous potassium carbonate (8.25 g) in dimethylformamide (100 ml) were heated at 100° for 1 hour. 1-Bromopentane (4.5 g) in dimethylformamide (25 ml) was added and the mixture was heated at 100° for a further 2 hours. The solvent was removed and the residue was partitioned between water and ethyl acetate. The dried (MgSO4) ethyl acetate solution was evaporated to yield a red oil which was chromatographed on alumina. Eluation with ethyl acetate gave the required benzamide which was obtained as a colourless oil which was converted into its hydrochloride (1.55 g) m.p. 162°-167°. Recrystallisation from ethyl acetate-methanol raised the m.p. to 169°-172°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: OB(O)c1ccncc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
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: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(OC3CCOCC3)nc(Cl)nc21
Temperature: 75 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
To a solution of 2-chloro-5-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), pyridin-4-ylboronic acid (1.1 equiv), tetrakis(triphenylphosphine)palladium(0) (0.1 equiv) in a 5:1 mixture of 1,4-dioxane and water (0.17 M) was added sodium carbonate (2.1 equiv). The reaction was stirred at 75° C. for 3 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90%) ethyl acetate (with 10% 1N ammonia in methanol) in hexane) to give the title compound (50.5% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.06 (s, 9 H) 0.82-0.91 (m, 2 H) 1.74 (dtd, J=12.74, 8.37, 8.37, 3.71 Hz, 2 H) 2.01-2.16 (m, 2 H) 3.50-3.63 (m, 4 H) 3.69-3.83 (m, 2 H) 5.50 (tt, J=7.91, 3.81 Hz, 1 H) 5.59 (s, 2 H) 7.72 (d, J=6.25 Hz, 2 H) 8.12 (s, 1 H) 8.60 (d, J=6.25 Hz, 2 H); MS (ESI) m/z 461.0 [M+1]+
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH3:14])[CH2:3]1.[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:15]([O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH3:14])[CH2:3]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1
Reactant: C[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of the alcohol of step A (0.81 g, 4.0 mmol), benzoic acid (0.74 g, 6.0 mmol) and triphenylphosphine (2.11 g, 8.0 mmol) in toluene (20 mL) was added DIAD (1.67 mL, 8.0 mmol). After being stirred at room temperature for 4 hours, the solution was concentrated. The residue was purified by flash chromatography eluting with 0%, 5% and 20% EtOAc/hexanes provided 1.0 g of the title compound. MS calculated (M+H)+ 308. found 308.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11](I)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C>C1COCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:16]#[C:15][C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:29][CH:30]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cnc(I)cn2)cc1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2cnc(C#Cc3ccc(OCCN4CCCC4)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere 19 mg (0.1 mmol) CuI, 82 mg (0.1 mmol) [1,1′-bis-(diphenylphosphine)-ferrocene]-palladium(II)-chloride are added to a solution of 316 mg (1.0 mmol) 2-(4-chloro-phenyl)-5-iodo-pyrazine and 215 mg (1.0 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine in 50 mL THF and 0.4 mL (3 mmol) triethylamine and the reaction mixture is stirred overnight at RT. To complete the reaction another 100 mg (0.32 mmol) 2-(4-chloro-phenyl)-5-iodo-pyrazine are added and the mixture is again stirred overnight. It is evaporated down i. vac., the residue is combined with 10% Na2CO3 solution, extracted exhaustively with DCM, the combined organic phases are washed three times with water and dried over MgSO4. This is filtered through activated charcoal, evaporated down i.vac. and the residue is purified by chromatography (silica gel, gradient: EtOAc to EtOAc/MeOH/NH3 9:9:1).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]([O:34]C)=[O:33])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH:36]=1.CO>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]([OH:34])=[O:33])=[O:26])=[CH:21][CH:20]=4)=[CH:17][CH:18]=3)=[N:9][C:8]=2[CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4s3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4s3)cc2)cc1
Temperature: 60 °C
Yield: 81.4 %

Procedure:
A solution of 1 N aqueous sodium hydroxide solution (1 mL) was added to trans-methyl 2-({4′-[(5-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate (55 mg, 0.12 mmol) in THF (2 mL). Methanol was added until the mixture became homogeneous, and the resulting solution was heated at 60° C. for 1 h. The reaction was concentrated under reduced pressure to remove excess solvents, and the residue was partitioned between water and chloroform/isopropanol (4:1). The aqueous layer was adjusted to pH 2 by addition of aqueous phosphoric acid solution, with stirring. The organic layer was then separated, dried (Na2SO4), and concentrated under reduced pressure. The residue was suspended in acetone, and the resulting solid was collected by filtration and dried in vacuo to provide the title compound (45 mg, 84%). 1H NMR (300 MHz, acetone-d6) δ 10.40-10.10 (br s, 1H), 8.15 (d, 2H), 8.01 (d, 2H), 7.87-7.82 (m, 5H), 7.41 (dd, 1H), 7.05-6.95 (m, 1H), 4.26-4.17 (m, 1H), 3.43-3.34 (m, 1H), 2.31-2.23 (m, 1H), 1.98-1.70 (m, 5H); LC-MS m/z 461.3 (MH+), retention time 3.56 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:44]3[CH2:43][CH2:42][CH:41]([N:38]4[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]4)[CH2:46][CH2:45]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (200 mg, 0.35 mmol) in DMF (4 mL) was added 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride (170 mg, 0.77 mmol), DIEA (134.4 mg, 1.04 mmol), HATU (160 mg, 0.42 mmol). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (25.0% up to 34.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 25.0% in 2 min); Detector, UV 254/220 nm. This resulted in 74.3 mg (32%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide formate as a off-white solid. LCMS (Method 20) [M+H]+=628.2, RT=2.20 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.36-9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.25-5.21 (m, 2H), 4.36-4.29 (m, 1H), 3.98-3.79 (m, 1H), 3.10-3.00 (m, 1H), 2.69-2.51 (m, 1H), 2.49-2.32 (m, 8H), 2.18 (s, 3H), 1.91-1.86 (m, 2H), 1.47-1.41 (m, 1H), 1.39-1.25 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:34][C:35]#[N:36])=[N:47][CH2:46][C:45]2[CH:48]=[CH:49][C:42]([O:41][CH3:40])=[CH:43][CH:44]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Reactant: COc1ccc(CN)cc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCc2ccc(OC)cc2)NC#N)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and 4-methoxybenzylamine.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(N1C(O[C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=CC(C2C=CC=C(C(NS(CC(F)(F)F)(=O)=O)(C)C)C=2)=N1)C.[O:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][NH2:51]>CN(C=O)C>[O:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][NH:51][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:18]=[CH:19][CH:20]=1
Reactant: NCC1CCCO1
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1CCCO1)c1ccccc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
(1-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (52 mg, 0.12 mmol, 1.2 equiv) and diisopropylethylamine (38 mg, 0.29 mmol, 3 equiv) were added to a stirring solution of 4-({1-ethyl-3-[3-(2-{[(2,2,2-trifluoroethyl)sulfonyl]amino}propan-2-yl)phenyl]-1H-pyrazol-5-yl}oxy)benzoic acid (50 mg, 0.10 mmol, 1 equiv) in DMF (1 mL). 1-(tetrahydrofuran-2-yl)methanamine (20 mg, 0.20 mmol, 2 equiv) was then added and the mixture was stirred at 22° C. for 16 hours. The mixture was purified directly by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, and lyophilized to give 4-({1-ethyl-3-[3-(2-{[(2,2,2-trifluoroethyl)sulfonyl]amino}propan-2-yl)phenyl]-1H phenyl]-1H-pyrazol-5-yl}oxy)-N-(tetrahydrofuran-2-ylmethyl)benzamide (38% yield). Calc'd (M+1)+: 595.2. Found: 595.1
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26](B3OC(C)(C)C(C)(C)C3)=[CH:27][CH:28]=2)[N:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)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>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=5)=[N:23]4)=[CH:28][CH:27]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccn4)nc3c2)OC1(C)C
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: O
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccn5)nc4c3)c12
Temperature: 80 °C

Procedure:
The mixture of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-ylamine (62.8 mg 0.200 mmol), 2-pyridin-2-yl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline(79.1 mg, 1.2 eq.), Pd(PPh3)4 (14.0 mg, 6% eq.) and Na2CO3 (53.0 mg, 2.5 eq.) in DMF (5 ml)/H2O (1 ml) was flushed with N2 for 30 min at rt and heated at 80° C. for 16 h under N2. After that time, the reaction mixture was treated with H2O (20 ml), and was then extracted with CH2Cl2 (2×25 ml). The extracts were washed with H2O (2×20 ml), and dried over MgSO4. After the solid was filtered off and the solvent was removed in vacuo, the crude yellow oil (105 mg) was purified by MS directed purification system to obtain a yellow solid of 3-cyclobutyl-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine; 1H NMR (CDCl3, 400 MHz) δ 2.05-2.09 (m, 1H), 2.15-2.22 (m, 1H), 2.48-2.56 (m, 2H), 2.62-2.72 (m, 2H), 3.85 (quintet, 1H, J=8.4 Hz), 5.27 (s, 2H), 7.09-7.10 (d, 1H, J=4.8 Hz), 7.15-7.16 (d, 1H, J=4.8 Hz), 7.36-7.39 (m, 1H), 7.86-7.90 (m, 1H), 7.97(m, 2H), 8.31-8.33 (d, 1H, J=8.8 Hz), 8.43 (s, 1H), 8.59-8.61 (d, 1H, J=8.8 Hz), 8.67-8.69 (d, 1H, J=7.6 Hz), 8.75-8.76 (d, 1H, J=4.0 Hz); MS(ES+): 393.4 (M+1), tR(polar-5 min)=2.2 min.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]([CH3:11])=[C:7]([O:9][CH3:10])[CH:8]=1.[C:15]([O-:18])(=[O:17])[CH3:16].[Na+]>C(O)(=O)C.O>[C:15]([O:18][CH2:2][C:3]1[C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]([CH3:11])=[C:7]([O:9][CH3:10])[CH:8]=1)(=[O:17])[CH3:16]
Reactant: COc1cc(CCl)c(OC)c(C)c1C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(COC(C)=O)c(OC)c(C)c1C
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of intermediate C (5 g, 0.023 mole) and anhydrous sodium acetate (7.1 g, 0.086 mole) in glacial acetic acid (35 ml) was refluxed for 20 hours. The reaction mixture was cooled to room temperature, diluted with 50 ml of water and extracted with dichloromethane. The organic extracts were washed with saturated sodium bicarbonate solution, dried, and concentrated to yield a dark syrup, which eventually crystallized to give 5.1 g of crude 5-acetoxymethyl-1,4-dimethoxy-2,3-dimethylbenzene (intermediate D).
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12]C(C)(C)C)=[O:11])=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Cl)cnc1N
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Nc1ncc(Cl)cc1/C=C/C(=O)O
Yield: 76.9 %

Procedure:
t-Butyl (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoate (2 g, 7.8 mmol), was stirred in 3 ml of trifluoroacetic acid at ambient temperature for 1 hour. The reaction mixture was diluted with toluene, evaporated to dryness, and the residue triturated with diethyl ether to yield the title compound as a pale yellow solid (1.89 g, 6.0 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10](C=O)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.[O-]C#N.[Zn+2].[O-]C#N>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#C[O-]
Agent: [Zn+2]
Product: N#Cc1ccc(Br)cn1
Temperature: 135 °C

Procedure:
2,5-Dibromopyridine (10 mmol), Pd(Ph3P)4 (0.3 mmol) and zinc cyanate (10 mmol) are mixed in DMF (12 mL) and purged with N2. The mixture is heated in a microwave reactor at 135° C. for 15 minutes, poured into saturated NH4Cl solution, and extracted with EtOAc. The combined extracts are washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (9:1 hexanes/EtOAc) to give 5-bromo-pyridine-2-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[OH2:33]>C(Cl)Cl>[CH2:14]([NH:13][C:11](=[O:33])[OH:12])[CH3:15].[NH2:1][C:2]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O
Agent: Nc1nc(C(=O)NCC2CC2)nc2c1[nH]c(=O)n2Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Amino-9-benzyl-N-(cyclopropylmethyl)-8-oxo-8,9-dihydro-7H-purine-2-carboxamide (Example 1, 50 mg, 0.15 mmol) was taken up in 2 ml DCM under a nitrogen atmosphere at room temperature and firstly triethylamine (103 μl, 0.74 mmol) and then N-ethyl isocyanate (47 μl, 0.59 mmol) were added in one portion each and the whole stirred at room temperature for 24 h. The mixture was poured into water (5 ml) and extracted with DCM (3×2 ml). The combined organics were dried over MgSO4 and concentrated in vacuo to a yellow residue which was purified by column chromatography using a gradient of 1:1 DCM:EtOAc→EtOAc as the eluant. Combination and evaporation of the appropriate fractions provided the title compound as a white solid (16 mg).