Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
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: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1

Procedure:
In a manner similar to Example 12, Step (b), (3,4-dichloro-phenyl)boronic acid (1.0569 g, 0.005539 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.3636 g, 0.005019 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.1054 g, 0.0000912 mol) and 2.0 M aqueous sodium carbonate (5.5 mL, 0.011 mol) in toluene (11 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with hexanes-acetone (7:1) 1.432 g of 4-(3′,4′-dichloro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 120-121° C.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=1[C:21](=[O:23])[CH3:22]>C1COCC1>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=1[C:21]1([CH3:8])[CH2:22][O:23]1
Reactant: CC(=O)c1c(F)cc(F)cc1F
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2c(F)cc(F)cc2F)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents were stirred for 10 min. after which the solution of 1-(2,4,6-trifluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored for completion. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]([CH:13]=1)=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH3:28])=[C:9]2[CH:29]=[O:30])=[O:4].P([O-])(O)(O)=[O:32].[Na+].CC(=CC)C.C1COCC1.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.[Cl-].[Na+].O.CC(=O)OCC>[F:27][C:23]1[C:22]([CH3:28])=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:10]1[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:12]2[N:8]([C:9]=1[C:29]([OH:32])=[O:30])[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13]2
Reactant: COC(=O)c1ccn2c(C=O)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COC(=O)c1ccn2c(C(=O)O)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 137.8 %

Procedure:
The compound of step 3 (0.293 g, 0.73 mmol) was suspended in 4 ml of tert-butanol and cooled to 0° C. To this suspension were added a solution of sodium dihydrogenphosphate (0.263 g, 2.19 mmol) in 1 ml of water, a 2 M solution of 2-methyl-2-butene in THF (2.19 ml, 4.38 mmol) and sodium chlorite (0.124 g, 1.09 mmol) in small portions. After stirring at room temperature for 18 h, once more a solution of sodium dihydrogenphosphate (0.263 g, 2.19 mmol) in 2 ml water, a 2 M solution of 2-methyl-2-butene in THF (2.19 ml, 4.38 mmol) and sodium chlorite (0.124 g, 1.09 mmol) were added again and stirring was continued for an additional 48 h. Then 30 ml of a 1:1 mixture of brine and EA were added, the organic phase was separated, and the aqueous phase was extracted with EA. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to give 0.420 g of the crude title compound as a yellow powder which was directly used in the next step.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2CCOCC2)[nH]n1
Yield: 82 %

Procedure:
As described for example 8b, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using 4-aminotetrahydropyran instead of 4-aminomorpholine, to the title compound (100 mg, 82%), which was obtained as a white foam. MS: m/e=401.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15](=[O:23])[CH2:16]P(=O)(OC)OC)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:25][C@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][C:34]2[S:38][C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:35]=2)[C@@H:29]([CH:43]=O)[C@H:28]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:27]1>C1COCC1>[Si:3]([O:10][C@@H:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15](=[O:23])/[CH:16]=[CH:43]/[C@H:29]1[C@H:28]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:27][C@@H:26]([Cl:25])[C@@H:30]1[CH2:31][CH2:32][CH2:33][C:34]1[S:38][C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:35]=1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Reactant: COP(=O)(CC(=O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/C(=O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
To a suspension of 160.3 mg of sodium hydride (60% oil dispersion, 4.00 mmol) in 8 ml of THF at 0° C. was added a solution of dimethyl (S)-6-(tert-butyldimethylsilyloxy)-2-oxoheptylphosphonate 13 (1.41 g, 4.00 mmol) in 4 mL THF. The mixture was stirred at 0° C. for 30 min before a solution of aldehyde 7 (1.10 g, 2.65 mmol) in 4 ml of THF was added dropwise. The syringe containing the aldehyde was rinsed with 2 mL of THF to complete the addition and the mixture was stirred at 25° C. for 2.5 h. The reaction was worked up with addition of saturated aqueous ammonium chloride (50 mL) and the aqueous layer was extracted with ethyl acetate (2×75 mL). The ethyl acetate layers were combined and washed with brine, dried over 30 g of anhydrous sodium sulfate, filtered and concentrated in vacuo. FCC (flash column chromatography) purification (silica gel, 6:1 hex/EtOAc) provided 1.60 g (95%) of enone 14.
Reaction SMILES: Br[C:2]1[C:3]([Cl:26])=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:34]([Sn:38](Cl)([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Cl:26][C:3]1[C:2]([Sn:38]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:7][N:6]=[C:5]2[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=12
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(F)cc2)c2c(Cl)c(Br)cnc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2c(c(-c3ccc(F)cc3)cn2COCC[Si](C)(C)C)c1Cl
Temperature: -25 °C
Reaction time: 2 h
Yield: 121.1 %

Procedure:
1.30 g (2.85 mmol) of 5-bromo-4-chloro-3-(4-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine and 750 mg (17.69 mmol) of anhydrous vacuum dried lithium chloride were dissolved under nitrogen in 50 mL of anhydrous THF. The resulting solution was cooled to −25° C. and 2.0 mL (4 mmol) of a 2 M solution of iso-propyl-magnesium chloride in anhydrous THF was added dropwise. The resulting mixture was allowed to stir at −25 to −5° C. for 2 h. 2.0 mL (7.4 mmol) of tri-n-butyltin chloride was added slowly to the resulting mixture. Upon complete addition the reaction mixture was allowed to stir for 18 h, allowing to warm to ambient temperature. The resulting reaction mixture was distributed between diethyl ether and a saturated aqueous solution of ammonium chloride. The aqueous phase was separated and extracted twice with diethyl ether. The combined organic phases were dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate and hexanes to afford 2.298 g (3.45 mmol, 121%) of 4-chloro-3-(4-fluoro-phenyl)-5-tributylstannanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine as a colorless oil. 1H-NMR [500 MHz, d6-DMSO] δ: 8.13 (s, 1H), 7.77 (s, 1H), 7.49-7.45 (m, 2H), 7.27-7.22 (m, 2H), 5.66 (s, 2H), 3.55 (t, 2H), 1.63-1.47* (m, 6H), 1.34-1.08* (m, 12H), 0.89-0.80* (t, 9H), −0.12 (s, 9H) [*: compound contaminated with other tri-n-butyl tin side product(s) in shift ranges indicated, appearing as distinct sets of peaks with equal integration to desired product]; MS [MH+] m/z: 665+667.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(O)(C)C.C(Cl)Cl>[NH:16]([C:13]1[N:14]=[CH:15][C:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:18][CH2:17][C:11]=2[N:12]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccccc3)ncc2C1
Temperature: 100 °C
Yield: 59 %

Procedure:
A mixture of 6-t-Butoxycarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamine, Intermediate 3 (996 mg, 3.98 mmol), bromobenzene (0.42 mL, 3.98 mmol), Cl-BrettPhos-Pd/BrettPhos 1 mol/1 mol admixture (133 mg, 0.0995 mmol) and cesium carbonate (1.82 g, 5.57 mmol) in t-BuOH (30 mL) was heated at 100° C. for 16 hours. Upon cooling to ambient temperature, the reaction mixture was diluted with CH2Cl2 and the insolubles were filtered off (celite). The filtrate was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 7:3 hexanes:EtOAc) to obtain a yellow glass (770 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(C)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1cc(C)c([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C

Procedure:
A 2.00 g portion of 2-methoxy-4-methylbenzoic acid was dissolved in 10 ml of sulfuric acid. With stirring at 0° C., 0.88 ml of concentrated nitric acid was added thereto dropwise. After 4 hours of stirring at room temperature, and ice water was added. The thus formed crystals were collected by filtration, dried under a reduced pressure and then purified by column chromatography (chloroform:methanol=30:1) to give 1.32 g of 2-methoxy-4-methyl-5-nitrobenzoic acid as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[CH:16]=[C:15]([C:34]([F:37])([F:36])[F:35])[CH:14]=1>>[CH3:33][O:32][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[CH:16]=[C:15]([C:34]([F:36])([F:37])[F:35])[CH:14]=[C:13]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)[N:18]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Nc3ccc(C(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-trifluoromethylaniline and (6-chloro-4-trifluoromethyl-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a yellowish solid (Yield=61%). MS ISP (m/e): 508.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.65 (d, 1H), 7.65-7.45 (AA′BB′-System, 4H), 7.21 (d, 1H), 7.13 (d, 1H), 6.98 (dxd, 1H), 6.90 (s, 1H), 6.83 (s, 1H), 6.75 (s, 1H), 6.54 (s, 1H), 6.50 (s, 1H), 3.72 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[O:16]1[CH2:40][CH:17]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]3[O:39][CH2:38]3)=[CH:31][CH:30]=2)([CH3:28])[CH3:27])=[CH:22][CH:21]=1>CO>[CH2:1]([N:5]([CH2:40][CH:17]([OH:16])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH:37]([OH:39])[CH2:38][N:5]([CH:6]3[CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][C:10]([CH3:12])([CH3:13])[CH2:11]3)[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:33][CH:34]=2)([CH3:27])[CH3:28])=[CH:24][CH:25]=1)[CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Solvent: CO
Product: CCCCN(CC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)CN(CCCC)C3CC(C)(C)NC(C)(C)C3)cc2)cc1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 5 h

Procedure:
To 150 ml of methanol were added 21.2 g of 4-butylamino-2,2,6,6-tetramethylpiperidine and 17.0 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane; the mixture was then refluxed, with stirring, for 5 hours. After completion of the reaction, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel eluted with a 5:1 by volume mixture of ethyl acetate and triethylamine. The desired compound was obtained in the form of a white powder having an Rf value of 0.63 on thin layer chromatography on silica gel developed with a 5:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1Cl.[CH3:23][C:24]([CH3:30])([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)(O)[O-].[Na+]>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][C:24]([CH3:30])([CH3:29])[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=CC=CC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)C=CC=Cc1cncc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 100 °C
Yield: 20.5 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine (600 mg, 1.59 mmol) in acetonitrile (5.0 mL) and triethylamine (4.5 mL) was added 5,5-dimethyl-1,3-hexadiene (228 mg), palladium acetate (39 mg) and tri-o-tolylphosphine (205 mg). After being heated in a sealed tube at 100° C. overnight, the resulting mixture was cooled to room temperature. Minimum amount of saturated sodium bicarbonate was added to free the amine hydrochloride salt, and the mixture was extracted with EtOAc, dried (MgSO4), and concentrated. The residue was chromatographed on a silica gel column, eluting with EtOAc:hexane 1:3 to afford the title compound (126 mg, 42% yield). MS (CI/NH3) m/z 307 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 1.55 (s, 9H), 2.24-2.42 (m, 2H), 3.88 (t, J=7.5, 2H), 4.13 (dd, J=3, 7.5, 1H), 4.29-4.41 (m, 1H), 5.97 (d, J=15, 1H), 6.22 (dd, J=9, 15, 1H), 6.67-6.78 (m, 2H), 7.45 (br s, 1H), 8.95 (d, J=3.0, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].C(N(CC)CC)C.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[O:23])=[CH:20][CH:19]=1
Reactant: CCOC(CN)OCC
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CNC(=O)c1ccc(Br)cc1)OCC
Reaction time: 6 h
Yield: 66.1 %

Procedure:
To a stirred solution of aminoacetaldehyde diethyl acetal (6.66 g, 50.0 mmol) in CH2Cl2 (100 ml) was added triethylamine (5.06 g, 50.0 mmol), 4-bromobenzoyl chloride (10.97 g, 50.0 mmol), and the mixture was stirred for 6 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate. The solution was washed with 0.5N HCl aqueous solution, water, saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with ethyl acetate-hexane to give title compound (10.45 g, 66% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:23].[O:24]([CH2:31][CH:32]1[NH:37][CH2:36][CH2:35][NH:34][CH2:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[F:23][C:3]1[CH:2]=[CH:11][C:10]([N:9]2[C:12]3[C:17](=[CH:16][C:15]([F:18])=[C:14]([N:34]4[CH2:35][CH2:36][NH:37][CH:32]([CH2:31][O:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:33]4)[CH:13]=3)[C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8]2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(Cl)c(F)cc2c1=O
Reactant: c1ccc(OCC2CNCCN2)cc1
Solvent: c1ccncc1
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(N3CCNC(COc4ccccc4)C3)c(F)cc2c1=O
Yield: 33.6 %

Procedure:
A mixture of 0.6 g of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.03 g of 3-(phenoxymethyl)piperazine and 5 ml of pyridine was reacted as described in Example 81, giving 295 mg of the desired product, mp 204°-207° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=1.[I:17]I>O1CCCC1>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([I:17])[CH:13]=[CH:12][N:11]=1
Reactant: Fc1cccnc1Cl
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1c(I)ccnc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 105.3 %

Procedure:
In an oven-dried flask, to a solution of 2.0 M of lithium diisopropylamide in tetrahydrofuran (6.0 mL) in tetrahydrofuran (30 mL, 400 mmol) at −78° C. was added 2-chloro-3-fluoropyridine (1.000 mL, 10.06 mmol). The resulting mixture was stirred at −78° C. for 2 hours. Iodine (3.899 g, 15.36 mmol) was then added as a solution in 5 mL tetrahydrofuran and the reaction was maintained −78° C. for an additional 2.5 hours. The reaction was then quenched with saturated aqueous NH4Cl and warmed to room temp. The reaction mixture was poured into ethyl acetate and washed sequentially with 10% aqueous Na2S2O3 and brine, dried over MgSO4, filtered, and evaporated in vacuo to yield 2.7279 g (100%) of 2-chloro-3-fluoro-4-iodopyridine. LCMS (ESI): M+H=258.0; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=4.9 Hz, 1H), 7.71-7.59 (m, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[N:17]2)[CH:11]=1.NC1C=NC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:57][C:58]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][C:59]=1[O:60][CH:61]1[CH2:65][CH2:64][NH:63][CH2:62]1>CN(C=O)C.O>[F:57][C:58]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][C:59]=1[O:60][CH:61]1[CH2:65][CH2:64][N:63]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[N:17][N:16]([C:12]3[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=3)[CH:20]=2)=[O:22])[CH2:62]1
Reactant: Fc1ccc(F)c(OC2CCNC2)c1
Reactant: O=C(O)CNC(=O)c1cn(-c2cccnc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)C1)c1cn(-c2cccnc2)nn1
Reaction time: 0.03 h
Yield: 37.2 %

Procedure:
DIPEA (156.8 mg, 1.2 mmol) was added to a stirred solution of [(1-pyridin-3-yl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine, and subsequently, application of Step 3 of the General Scheme) (75 mg, 0.3 mmol) in DMF (3 mL) followed by HOBt (45 mg, 0.33 mmol) and EDCI (116 mg, 0.6 mmol). After 2 minutes of stirring, 3-(2,5-difluoro-phenoxy)-pyrrolidine hydrochloride (prepared by the method used for the synthesis of Intermediate 72) (71.5 mg, 0.3 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and precipitate was collected to afford 48 mg (37.2% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[3-(2,5-difluoro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 429.14, 92.32%. 1H NMR (300 MHz, DMSO-d6): δ 9.5 (s, 1H), 9.2 (d, 1H), 8.75 (d, 1H), 8.6 (m, 1H), 8.4 (m, 1H), 7.7 (q, 1H), 7.3-7.2 (m, 2H), 6.9-6.7 (m, 1H), 5.3-5.1 (d, 1H), 4.25-4.1 (m, 2H), 4.0-3.5 (m, 4H), 2.3-2.2 (m, 1H), 2.2-2.05 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH2:16][NH:17]C(OC(C)(C)C)=O)[O:13][N:12]=2)=[CH:3]1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH2:16][NH2:17])[O:13][N:12]=2)=[CH:3]1
Reactant: Cn1cc(-c2noc(CNC(=O)OC(C)(C)C)n2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2noc(CN)n2)c2ccccc21
Temperature: 25 °C

Procedure:
1-Methyl-3-[5-t-butoxycarbonylaminomethyl-1,2,4-oxadiazol-3-yl]indole (300mg) was dissolved in CH2Cl2 (10 ml) at 0° C., trifluoroacetic acid (0.5 ml) was then added and the reaction mixture allowed to warm to room temperature over 30 mins. The reaction mixture was stirred at room temperature for twelve hours before evaporation at reduced pressure. The residue was recrystallised from cold CH2Cl2 to afford white crystals (150 mg) mp 178° C.; Found C, 48.74; H, 3.74; N 15.97 C14H13N4O3F3 requires C, 49.13; H, 3.83; N, 16.37%; δH (360 MHz, DMSO), 3.92 (3 H, s, NMe), 4.58 (2 H, s, CH2N), 7.24-7.35 (2 H, m, H-5, H-6), 7.60 (1 H, d, J=7, H-4), 8.07 (1 H, d, J=7, H-7), 8.10 (1 H, s, H-2); M/Z 228 (M+, free base 70%), 171(100), 156(80).