Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:3]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cc(Cl)cc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccc(CCO)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: OCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 49.3 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyridine (0.140 g, 0.48 mmol), 4-aminophenethyl alcohol (0.099 g, 0.72 mmol), palladium acetate (0.005 g, 0.024 mmol), rac-BINAP (0.022 g, 0.036 mmol) and cesium carbonate (0.390 g, 1.20 mmol) in dioxane (5 mL) under argon. The reaction mixture was heated to 120° C. under microwave irradiation for 2 h. The reaction mixture was cooled, and absorbed onto silica (5 g). Purification by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) afforded the title compound (0.093 g, 50%) as a pale yellow solid. MW=392.80. M.p. 60-62° C. 1H NMR (DMSO-d6, 500 MHz) δ 9.30 (s, 1H), 7.99-7.96 (m, 1H), 7.91-7.86 (m, 1H), 7.57-7.51 (m, 2H), 7.50 (d, J=2.0 Hz, 1H), 7.30-7.26 (m, 2H), 7.24-7.20 (m, 2H), 7.18 (d, J=2.0 Hz, 1H), 4.64 (t, J=5.0 Hz, 1H), 3.67-3.58 (m, 2H), 2.73 (t, J=7.0 Hz, 2H); ESI MS m/z 393 [M+H]+.
Reaction SMILES: CC(OP(COCCCl)(=O)OC(C)C)C.CS[C:18]1[N:23]=[C:22](SC)[N:21]=[C:20]2[NH:26][N:27]=[CH:28][C:19]=12.C1CCN2C(=NCCC2)CC1.[OH-].[Na+].ClC1C=CC=C(C(OO)=O)C=1.CS(C)(=O)=O.N.Br[Si](C)(C)C>[Pd]>[NH:26]1[C:20]2=[N:21][CH:22]=[N:23][CH:18]=[C:19]2[CH:28]=[N:27]1
Reactant: CSc1nc(SC)c2cn[nH]c2n1
Agent: [Pd]
Agent: CC(C)OP(=O)(COCCCl)OC(C)C
Agent: CS(C)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Product: c1ncc2cn[nH]c2n1

Procedure:
Di-(2-propyl)-2-chloroethoxymethylphosphonate is reacted with 4,6-bismethylmercapto-pyrazolo[3,4-d]pyrimidine (Tetrahedron, 1967, 23: 891) in the presence of DBU to effect attachment at the pyrazole ring nitrogen(s). Displacement of the 4-methymercapto functionality and concommitant monoester hydrolysis is then effected using aqueous sodium hydroxide. Displacement of the remaining 6-methymercapto group is accomplished (after initial oxidation with m-chloroperbenzoic acid to the intermediate methy sulfone) using methanolic ammonia. Bromination at the 3-position is performed according to the procedure described in J. Med. Chem. 1984, 27: 1026-30. Displacement of the 3-bromo group with Fmoc-protected propargylamine is effected using the palladium(0) catalyst described above. The remaining phosphate ester is then deprotected using bromotrimethylsilane. Pyrophosphorylation, deprotection and dye coupling are then performed as described above to yield the fluorescently labeled PME-G-pp analog (pyrazolo[3,4-d]pyrimidine analog).
Reaction SMILES: N[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:13])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C>[Br:13][C:5]1[C:6]2[CH2:7][C:8]([CH3:12])([CH3:11])[O:9][C:10]=2[CH:2]=[CH:3][CH:4]=1
Reactant: CC1(C)Cc2c(Br)ccc(N)c2O1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(Br)cccc2O1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
A stirred solution of 12.3 grams (0.051 mole) of 7-amino-4-bromo-2,3-dihydro-2,2-dimethylbenzofuran and 30 mL of toluene in 200 mL of ethanol was cooled in an ice-bath, and 5.6 mL (0.102 mole) of concentrated sulfuric acid was added slowly, followed by 5.6 grams (0.082 mole) of sodium nitrite. Upon completion of addition, the ice-bath was removed, and the reaction mixture was warmed to 50° C. The reaction mixture temperature was then brought to about 75° C., where it was stirred for 30 minutes. After this time the reaction mixture was heated at reflux for one hour and then was poured into 200 mL of water. The mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.6 grams of 4-bromo-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)C(O)=O)#[N:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CO>[CH3:11][S:10][C:7]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:3][C:1]#[N:2]
Reactant: C1COCCN1
Reactant: CSC(SC)=C(C#N)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CSC(=CC#N)N1CCOCC1
Temperature: 20 °C

Procedure:
2-Cyano-3,3-bis-methylsulfanyl-acrylic acid (the compound of formula (F), 35 g, 0.18 mol) was dissolved in 250 mL of methanol. Morpholine (the compound of formula (O), 28 mL, 0.32 mol) and triethylamine (25 mL, 0.18 mol) were added to the solution while the temperature was maintained at approximately 20° C. The reaction was warmed slightly to a temperature of between 25-27° C. and this temperature was maintained overnight. The solvents were then removed under reduced pressure taking care not to heat the reaction mixture. The resulting crude material was filtered through a short silica gel column eluting with MeOH:CH2Cl2=1:5 to afford the 3-methylsulfanyl-3-morpholin-4-yl-acrylonitrile of formula (P).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=O)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:38](=[NH:43])(OCC)[CH3:39].C(N(CC)CC)C>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[NH:43][C:38]([CH3:39])=[N:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nnc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)[nH]1
Temperature: 200 °C

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.025 g, 0.048 mmol), ethyl acetimidate hydrochloride (6.6 mg, 0.053 mmol), triethylamine (11 mg, 0.11 mmol), and MeCN (0.15 mL) was heated in a microwave reactor at 200° C. for 1 h. The reaction was partitioned between water and DCM, and the product was extracted with DCM. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatograph, elution with mixtures of EtOAc in hexanes to provide the title compound. LC/MS: m/e 543.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.12 (1H, s), 7.92 (1H, s), 7.57 (1H, d, J=6.8 Hz), 7.20-7.60 (3H, m), 6.87-6.93 (3H, m), 4.40-5.20 (3H, br), 2.53 (3H, s), 1.22 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.[N:30]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1>CO>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:25][CH:26]([CH3:27])[CH3:28])[NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:36][C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[CH:9][C:8]=1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccncc1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N)cc1-c1cccc2ccccc12
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(NCc2ccncc2)cc1-c1cccc2ccccc12

Procedure:
This compound was synthesized via the reductive amination of N-[4-amino-2-naphth-1-ylbenzoyl]leucine methyl ester and pyridine-4-carboxaldehyde in methanol to afford, after purification, a white solid. 1H NMR (DMSO-d6) δ 0.71 (d, J=5.45 Hz, 3H), 0.82 (d, J=5.13 Hz, 3H), 1.20-1.27 (m, 2H), 1.29-1.32 (m, 1H), 3.72 (s, 2H), 3.79 (s, 1H), 4.15 (m, 1H), 4.41 (d, 2H, CH2), 5.52 (d, 1H, NH), 6.67-6.75 (dd, 1H), 6.89 (d, 1H), 7.23 (m, 2H), 7.25-7.35 (m, 8H), 8.55 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH:19]([CH2:23][OH:24])[CH2:18]2)=[C:13]([CH3:25])[N:12]([CH2:26][C:27]2[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:28]=2[F:37])[C:11]1=[O:38])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:56][C:57]1[O:58][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:60][CH:61]=1>ClCCl>[C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:56][C:57]3[O:58][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:60][CH:61]=3)[CH:19]([CH2:23][OH:24])[CH2:18]2)=[C:13]([CH3:25])[N:12]([CH2:26][C:27]2[C:32]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:30]=[CH:29][C:28]=2[F:37])[C:11]1=[O:38])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cc1c(N2CCNC(CO)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)C(CO)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.5 %

Procedure:
To a solution of {(R)-2-[3-(2-fluoro-6-trifluoromethyl-benzyl)-5-(3-hydroxymethyl-piperazin-1-yl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (0.028 mmol) in dichloromethane (2 mL) were added N,N-diisopropylethylamine (10 μl, 0.056 mol) and 2-bromomethyl-5-trifluoromethyl-furan (7.6 mg, 0.034 mmol) in the order, followed by stirring at room temperature for 6 hrs. After concentration of the solution, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/2/1) and dried in a vacuum to afford 17 mg of a white oil (yield 77%).
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]2=[O:18])[C@H:13]([OH:24])[C@@H:12]1[OH:25])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].[Cl-].[Mg+2].[Cl-].C(N(CCCC)CCCC)CCC>CN(C)C=O>[CH:22]1[C:20](=[O:21])[NH:19][C:17](=[O:18])[N:16]([C@@H:14]2[O:15][C@H:11]([CH2:10][O:9][P:1]([O:4][P:5]([O:8][P:1]([OH:4])([OH:3])=[O:2])([OH:7])=[O:6])([OH:2])=[O:3])[C@@H:12]([OH:25])[C@H:13]2[OH:24])[CH:23]=1
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.5 %

Procedure:
A 0.154 M dimethylformamide solution of uridine 5′-diphosphate (UDP) tributylamine salt (584 μL, 90.0 μmol) and a 0.45 M dimethylformamide solution of anhydrous magnesium chloride (200 μL, 90.0 μmol) were added to a 0.15 M dimethylformamide solution of cUTP tributylamine salt (500 μL, 75.0 μmol), and the mixture was stirred at room temperature for 72 hours. The resultant reaction mixture was analyzed through HPLC (262 nm). As a result, Up5U (i.e., target product) was found to be produced from UTP at a synthesis yield of 50.5%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH2:21]([N:28]1[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][C:29]1=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:34]([C:31]3[CH:32]=[CH:33][N:28]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:29](=[O:37])[CH:30]=3)=[O:35])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccn(Cc2ccccc2)c(=O)c1
Temperature: 25 °C

Procedure:
In a 20 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (50 mg, 0.176 mmol), 1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (40.3 mg, 0.176 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) (81.8 mg, 176 mmol) and N,N-diisopropylethylamine (0.092 mL, 0.527 mmol) were combined with CH2Cl2 (5.00 mL). The reaction mixture was stirred at room temperature, and the crude product was purified using preparative reverse-phase HPLC. MS calcd. for C29H23ClN3O3 [(M+H)+] 496.1, obsd. 496.0.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:55])[N:28](COCC[Si](C)(C)C)[CH:29]=[C:30]([C:32](=[O:46])[NH:33][C:34]2[CH:35]=[N:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:38]=2)[CH:31]=1)=O)(C)(C)C>CO>[CH2:39]([N:37]1[CH:38]=[C:34]([NH:33][C:32]([C:30]2[CH:31]=[C:26]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][C:13]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[O:18])=[CH:14][CH:15]=4)[C:27](=[O:55])[NH:28][CH:29]=2)=[O:46])[CH:35]=[N:36]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)cc(-c2cc(C(=O)Nc4cnn(Cc5ccccc5)c4)cn(COCC[Si](C)(C)C)c2=O)n3C(=O)OC(C)(C)C)CC1
Solvent: CO
Product: CN1CCN(C(=O)c2ccc3[nH]c(-c4cc(C(=O)Nc5cnn(Cc6ccccc6)c5)c[nH]c4=O)cc3c2)CC1

Procedure:
The title compound was prepared according to the experimental used in Example 1, Step 5 with intermediate (3h), 2-[5-(1-benzyl-1H-pyrazol-4-ylcarbamoyl)-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methylpiperazine-1-carbonyl)-indole-1-carboxylic acid tert-butyl ester. After the usual work up the crude product was taken up in methanol (1 mL) and loaded onto a 5 g SCX column. The column was flushed with methanol and then eluted with ammonia solution 7N in methanol. The eluent was concentrated in vacuo and the residue further purified by preparative HPLC at pH 4 to afford the title compound as a brown solid, 13 mg, 10%. LC/MS RT=1.52 Min (270 nm), m/z=536 [M+H]. Total run time 3.75 min (short pos). 1H NMR (d6 DMSO): δ 2.21 (s, 3H), 2.33 (br m, 4H), 3.53-3.56 (br m, 4H) 33 (s, 2H), 7.13 (dd, 1H), 7.31 (m, 6H), 7.53 (d, 1H), 7.61 (s, 2H), 8.10 (s, 1H), 8.14 (d, 1H), 8.58 (d, 1H), 10.31 (s, 1H), 11.72 (s, 1H), 12.5 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:14][C:12]([CH3:15])([CH3:13])[CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(Br)c1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1c(Br)cccc1C#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-bromo-2-fluoro-benzonitrile (40.0 g, 0.200 mol) and tetrahydrofuran (200 mL) was chilled to 0° C. and stirred for 5 min. A solution of potassium tert-butoxide (130 mL, 0.210 mol) was added dropwise at 0° C. and the reaction was allowed to warm to RT with stirring over 90 min. The reaction was quenched with water (200 mL) and 2 M Na2CO3 (100 mL) and extracted with EtOAc (3×200 mL). The organic layer was dried over Na2SO4 and the solvent was removed by rotary evaporation to provide the title compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:11]1([C:17]([C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:23]3[CH:24]=[C:19]([C:17]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:18])[CH:20]=[CH:21][CH:22]=3)[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Reactant: Brc1cnc2[nH]ccc2c1
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: O=C(c1cccc(-c2cnc3[nH]ccc3c2)c1)N1CCOCC1
Temperature: 110 °C
Reaction time: 15 h
Yield: 83.7 %

Procedure:
A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (3 g, 15 mmol), 3-(morpholine-4-carbonyl)phenylboronic acid (4 g, 18 mmol), sodium bicarbonate (4 g, 46 mmol), and tetrakis(triphenylphosphine)palladium(0) in dioxane/water (100 mL/20 mL) was stirred at 110° C. for 15 hours. The mixture was then poured into ice water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (3.86 g, 84% yield) as yellow solids. MS: m/z 308.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1.[NH2:15][C:16]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:20][N:19]=[C:18]2[S:29][CH:30]=[CH:31][C:17]=12>>[NH2:15][C:16]1[N:21]([C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:12]([C:9]3([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:11][CH2:10]3)=[O:13])=[CH:26][CH:27]=2)[CH2:20][N:19]=[C:18]2[S:29][CH:30]=[CH:31][C:17]=12
Reactant: NC1=c2ccsc2=NCN1c1ccc(N)cc1
Reactant: O=C(Cl)C1(c2cc(F)ccc2F)CC1
Product: NC1=c2ccsc2=NCN1c1ccc(NC(=O)C2(c3cc(F)ccc3F)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 469, using 1-(2,5-Difluoro-phenyl)-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine as the diamine of choice. MS(ES) m/e 423 [M+H]+.
Reaction SMILES: [CH2:1]1[C:8]2[N:4]([CH:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:10]([C:12]1[N:16]([CH3:17])[C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=1[CH3:23])=[O:11]>C(Cl)Cl>[CH3:17][N:16]1[C:12]([C:10]([C:5]2[N:4]3[C:8](=[CH:7][CH:6]=2)[CH2:1][CH2:2][CH2:3]3)=[O:11])=[C:13]([CH3:23])[CH:14]=[C:15]1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cc1cc(C)c(C(=O)Cl)n1C
Reactant: c1cc2n(c1)CCC2
Solvent: ClCCl
Product: COC(=O)Cc1cc(C)c(C(=O)c2ccc3n2CCC3)n1C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
To a stirred, ice-cooled mixture of 2,3-dihydro-1H-pyrrolizine (0.40 g, 0.0037 m), methyl 5-(chlorocarbonyl)-1,4-dimethylpyrrole-2-acetate (1.1 g, 0.0037 m), and methylene chloride (10 ml) was added dropwise over 3 minutes stannic chloride (0.86 ml, 0.0075 m), and the resulting mixture allowed to stir cold for ca. 30 minutes. The mixture was partitioned between ether and water, and the ether layer washed and dried. It was concentrated in vacuo to a yellow residue which was then eluted on a silica gel chromatograph column with 30% ethyl acetate/hexane to yield 0.35 g of methyl 1,4-dimethyl-5-(2,3-dihydro-1H-pyrrolizin-5-oyl)pyrrole-2-acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[C:9]([CH2:14][CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:11][CH2:12][CH3:13])=[O:10]>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:9](=[O:10])[CH:14]([CH3:15])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:13]
Reactant: O=Cc1ccccn1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)Cc1ccccn1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-pyridinecarboxaldehyde (0.96 mL, 10 mmol, 1.0 eq.) in toluene (17 mL) was added a solution of (carbethoxyethylidene)triphenylphosphorane (6.50 g, 16.1 mmol, 1.6 eq.) in toluene (24 mL). The resulting mixture was stirred at 80° C. for 18 hours. The solvent was removed in vacuo. The residue was suspended in a minimum amount of water and DCM was added. The product was extracted with 5% HCl soln. The aq. phase was cooled down to 0° C. and was basified with solid K2CO3. The product was then extracted with DCM (2×) and the comb. org. layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 45 fractions of 45 mL, Heptane 100% to Heptane+25% AcOEt). To a solution of the resulting α,β-unsaturated ester in THF (21 mL) under N2, palladium on activated carbon (10 wt. %, 33 mg) was added. The flask was carefully evacuated and refilled with H2 (3×). The black suspension was stirred at 45° C. under an H2-atmosphere for 18 hours. The black suspension was filtered through Celite. The Celite was rinsed with THF. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+AcOEt 30%) to yield (±)-2-methyl-3-pyridin-2-yl-propionic acid ethyl ester as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][C@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.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>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:11][C@H:12]1[N:17]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (60 mL), 5-bromo-2-nitropyridine (2.0 g, 10.0 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (2.0 g, 10.0 mmol), and cesium carbonate (6.5 g, 20 mmol). After bubbling nitrogen through the resulting mixture for 10 minutes, tris(dibenzylideneacetone)dipalladium(0) (915 mg, 1.0 mmol) and XantPhos (579 mg, 1.0 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at 100° C. for 15 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 151a (1.6 g, 44%) as yellow solid. MS-ESI: [M+H]+ 323. 1H NMR (500 MHz, DMSO-d6) δ 8.21 (d, J=3.5 Hz, 1H), 8.18 (d, J=9.0 Hz, 1H), 7.45-7.43 (m, 1H), 4.34-4.33 (m, 1H), 3.92-3.99 (m, 1H), 3.80 (d, J=12.5 Hz, 2H), 3.06-3.23 (m, 3H), 1.43 (s, 9H), 1.09 (d, J=6.5 Hz, 3H).