Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([CH:76]=O)=[CH:72][CH:71]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:73]3[CH:74]=[CH:75][C:70]([O:69][CH3:68])=[CH:71][CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(C(C)c5ccccn5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 16 h
Yield: 49 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.12 mmol), DMF (0.85 mL), ethanol (0.15 mL), 1M Na2S2O4 (3 eq, 0.42 mmol, 0.42 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.14 mmol, 18 mg). After 16 h, concentration in vacuo and preparation by preparative tlc (EtOAc—CH2Cl2-MeOH, 50:50:2) gave the product (29 mg, 48%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.38 (d, J=6.8 Hz, 3H, CHCH3), 2.60 (s, br, 2H, piperazine NCH2), 2.70 (br s, 2H, piperazine NCH2), 3.64 (s, br, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.9 Hz, 2H, methoxyphenyl), 7.25-7.28 (m, 1H, pyridine H-5), 7.50 (d, J=7.9 Hz, 1H, pyridine H-3), 7.79 (td, J=7.7, 1.5 Hz, 1H, pyridine H-4), 8.12 (d, J=8.9 Hz, 2H, methoxyphenyl), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.53 (d, J=4.2 Hz, 1H, pyridine H-6), 13.37 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[OH-].[Na+].[CH:14](=O)[CH3:15]>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]=[CH:14][CH3:15])=[CH:6][CH:5]=1
Reactant: CC=O
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC=NNc1ccc(OC)cc1
Temperature: 0 °C

Procedure:
Combine (4-methoxyphenyl)-hydrazine hydrochloride salt (10 g, 57 mmol), sodium hydroxide solution (50 mL, 1M), and extract with toluene. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Combine the residue and toluene (50 mL) and cool to 0° C. Add acetaldehyde (3.5 mL, 63 mmol) dropwise as a solution in toluene (10 mL). When the addition is complete, warm to ambient temperature. After 1 hour at ambient temperature evaporate under a stream of nitrogen to give N-(4-methoxyphenyl)-N'-ethylidene hydrazine.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)#[N:2].C(Cl)([Cl:14])=O>C(#N)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(C(=O)Cl)cc1
Yield: 97.9 %

Procedure:
p-Cyanobenzoic acid (14.7 g) and acetonitrile (300 ml) were mixed and stirred vigorously while the solvent was refluxed, and phosgene gas (30 g) was introduced to the mixture over four hours. After dry nitrogen gas was introduced to the reaction mixture for one hour, acetonitrile was removed under ambient pressure, and was further removed under reduced pressure through distillation, to thereby obtain 16.2 g of p-cyanobenzoyl chloride (yield 98%, based on p-cyanobenzoic acid). The p-cyanobenzoyl chloride obtained had a purity of 99%.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][Cl:27]>CC(C)=O>[Cl:27][CH:26]([O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1)[CH3:25]
Reactant: O=c1c2ccccc2sc2c(O)ccc(O)c12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Cl)Oc1ccc(O)c2sc3ccccc3c(=O)c12
Yield: 66.4 %

Procedure:
A solution of 120 mg of 1,4-dihydroxythioxanthone in 100 ml of acetone is stirred for 0.5 h at room temperature with 138 mg of potassium carbonate. A solution of 80 mg of 1-bromo-2-chloroethane in 5 ml of acetone is then added and the mixture refluxed for 24 h. The heterogeneous mixture is cooled, filtered, concentrated under reduced pressure and purified by silica gel column chromatography using a 1:1 mixture of hexanes and ethyl acetate to produce 100 mg of a yellow-red crystals (65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1COCC1.C([Li])CCC.[I:28]I>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[I:28]
Reactant: II
Reactant: CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCc1ccc(-c2cc(F)c(I)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 3,5-difluoro-4′-propylbiphenyl (T-4) (18.0 g) and THF (200 ml) were added, and cooling was carried out to −74° C. Thereto, a n-butyllithium (1.57 M) n-hexane solution (56.4 ml) was added dropwise in a temperature range of −74° C. to −70° C., and stirring was carried out for another 1 hour. Subsequently, a THF (150 ml) solution of iodine (24.6 g) was added dropwise in a temperature range of −75° C. to −70° C., and stirring was carried out for 6 hours while returning to room temperature. The resultant reaction mixture was poured into ice water (400 ml), and mixing was carried out. Toluene (300 ml) was added to separate layers into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was sequentially washed with an aqueous solution of sodium thiosulfate and water, and drying over anhydrous magnesium sulfate was carried out. The resultant solution was concentrated under reduced pressure, and a residue was purified by means of column chromatography (silica gel; heptane), and further purified by recrystallization from Solmix A-11, and thus 3,5-difluoro-4-iodo-4′-propylbiphenyl (T-5) (21.4 g) was obtained. The yield based on compound (T-4) was 77%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])OC(C)(C)C)[CH3:14])[CH:3]=1.Cl.[C:24](OCC)(=O)C>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[CH3:24])[CH3:14])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc(Cl)c([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (1.35 g) was added 4 M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.00 g). 1H NMR (300 MHz, CDCl3) δ 1.27 (3H, d, J=6.4 Hz), 1.98 (3H, s), 4.33-4.55 (3H, m), 5.65 (1H, d, J=6.1 Hz), 6.94 (1H, s), 8.86 (1H, s).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:18][CH2:17][CH2:16][C@H:2]1[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:4].O.O.C(O)(=O)C(O)=O>CO.[Pd]>[NH:1]1[CH2:18][CH2:17][CH2:16][C@H:2]1[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:4]
Reactant: CCCCCCCCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: CCCCCCCCCCNC(=O)[C@@H]1CCCN1
Yield: 118.8 %

Procedure:
5.0 g (12.9 mmoles) of Z-Pro-NH-C10H21 and 2.02 g (16 mmoles) of oxalic acid dihydrate are dissolved in 100 ml of methanol, 0.8 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for 2 hours. The reaction mixture is heated, the catalyst is filtered off, and the filtrate is evaporated. The crystalline residue is triturated with ether and then filtered off to obtain 3.9 g (88%) of H-Pro-NH-C10H21.(COOH)2 ; m.p.: 152°-154° C., Rf3 =0.16.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=1[CH3:22].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][S:6][C:2]=2[C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[C:15]([CH3:22])[CH:16]=1)#[N:21]
Reactant: CCOC(=O)CCc1csc(Br)c1-c1ccc(C#N)cc1C
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2scc(CCC(=O)O)c2-c2ccc(C#N)cc2C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of ethyl 3-(5-bromo-4-(4-cyano-2-methylphenyl)thiophen-3-yl)propanoate (35 mg, 0.09 mmol), 4-methoxyphenylboronic acid (16 mg, 0.10 mmol), Na2CO3 (19 mg, 0.18 mmol), Pd(PPh3)2Cl2 (6 mg, 0.009 mmol) in a mixture of dioxane and H2O (5 mL, 4:1) was stirred at 100° C. overnight under nitrogen. The mixture was neutralized to pH=5, and extracted with EtOAc. The organic layer was concentrated, and purified by preparative TLC to give 3-(4-(4-cyano-2-methylphenyl)-5-(4-methoxyphenyl)thiophen-3-yl)propanoic acid (30 mg, yield 86%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][OH:22])[O:12]1.C[Si](Cl)(C)C.[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.N>N1C=CC=CC=1.O>[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[C@H:11]2[C@H:15]3[C@H:14]([O:18][C:17]([CH3:19])([CH3:20])[O:16]3)[C@@H:13]([CH2:21][OH:22])[O:12]2)=[O:34])=[CH:31][CH:30]=1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(N)ncnc21
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(NC(=O)c3ccc(Br)cc3)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (0.400 g, 1.30 mmol) was dried by co-evaporation with pyridine, then suspended in dry pyridine (6.5 mL). TMSCl (0.330 mL, 2.60 mmol) was added and the mixture was stirred for 15 min. 4-Bromobenzoylchloride (0.342 g, 1.56 mmol) was added to the mixture and stirred for 2 h. The solution was cooled to 0° C. and 1 mL of H2O was added. After 5 min a 29% NH3 aq solution (0.847 mL) was added and the reaction mixture was stirred for 30 min while warming to r.t. The mixture was then concentrated and the residue was diluted with H2O (40 mL). The product was extracted with EtOAc (60 mL) and concentrated. The crude material was purified by flash chromatography (65 to 100% EtOAc/hexanes) to afford the title compound (0.305 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([CH2:22][N:11]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18](=[O:19])[NH2:20])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)c1ccc(CN([C@@H]2CCCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 61 %

Procedure:
The titled compound (90 mg) was prepared in 61% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and methyl 4-(bromomethyl)benzoate according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.83 (m, 4 H), 7.64 (d, 2 H, J=8.0 Hz), 7.42 (d, 2 H,J=8.0 Hz), 7.28 (s, 1 H), 6.61 (s, 1 H), 4.64 (AB2,2 H,Δv=20,Jab=72 Hz), 3.85 (m, 4 H), 2.79 (m, 1 H), 2.42 (m, 1 H), 1.78 (m, 1 H), 1.63 (m, 2 H), 1.28 (m, 3 H), 0.90 (m, 1 H); MS m/e 464.98 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.CCN(CC)CC.[C]=O.CO.C[CH2:44][O:45][C:46](C)=[O:47]>[Pd](Cl)Cl>[CH3:44][O:45][C:46]([C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:4][C:5]([CH3:21])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[N:7]=1)=[O:47]
Reactant: CCOC(C)=O
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl[Pd]Cl
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Yield: 63 %

Procedure:
To a degassed solution of 7.00 g (15.5 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) in 180 ml of MeOH/EtOAc 1:1 were added 0.70 g (0.86 mmol) of (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and 5.4 ml=3.92 g (38.7 mmol) of Et3N. This reaction mixture was stirred in an autoclave and in a carbon monoxide atmosphere at 130° C./70 bar for 30 hours. Then, it was evaporated, the residue dissolved in H2O/EtOAc and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 4.61 g (63%) of the title compound as light brown foam. MS: 476.2 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.BrC1C=C([Cl:20])C=CC=1OC.[Li]CCCC.COB(OC)OC>>[Cl:20][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: COc1ccc(Cl)cc1Br
Agent: COB(OC)OC
Agent: [Li]CCCC
Product: COc1ccc(Cl)cc1B(O)O
Yield: 77 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-4-chloroanisole (2.00 g, 9.0 mmol, 1.0 equivuiv), n-BuLi (2.5 M in hexanes; 3.62 mL, 9.0 mmol, 1.0 equivuiv), and trimethylborate (3.0 mL, 26 mmol, 2.9 equivuiv) to afford 1.30 g (77%) of crude 5-chloro-2-methoxyphenylboronic acid as a white semi-solid. This compound was used in the next reaction with no further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:19]=[C:18](F)[C:15]([C:16]#[N:17])=[C:14]([F:21])[CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:19]=[C:18]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:15]([C:16]#[N:17])=[C:14]([F:21])[CH:13]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(F)cc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a 500-mL RBF was added NaH (0.660 g, 27.5 mmol) and THF (100 mL). To this solution was added benzyl alcohol (2.385 mL, 22.94 mmol) in THF slowly via syringe, with external cooling (ice bath) when necessary. After the addition, the reaction mixture was stirred for 1 hour at room temperature. At this time, the mixture was transferred via syringe slowly to a solution of 4-bromo-2,6-difluorobenzonitrile (5 g, 22.94 mmol) in THF at 0° C. The solution was allowed to warm to room temperature and stirred over the weekend. The reaction was poured into water (50 mL), and extracted with EtOAc (3×100 mL). The organic layers were combined and dried over Na2SO4. The dried solution was filtered, and the filtrate was concentrated in vacuo to yield a pale yellow solid which was purified by flash chromatography (gradient elution 0-30% EtOAc in hexanes) to afford the title compound (3.911 g) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6): δ 5.35 (s, 2H), 7.27-7.66 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC)c(I)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Cl)cc(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.7 %

Procedure:
Methyl 3-chloro-5-iodo-4-methoxybenzoate (2.96 g) was dissolved in tetrahydrofuran (23 mL) and water (7 mL), and lithium hydroxide monohydrate (1.52 g) was added to the solution, and then the mixture was stirred at room temperature for 19 hours. After the organic solvent was distilled off, the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.74 g) as a colorless crystal.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)([CH3:14])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 63. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J=8.60 Hz), 6.95-6.85 (m, 4H), 6.79 (d, 2H, J=8.60 Hz), 4.12 (t, 2H, J=6.26 Hz), 3.20 (d, 1H, J=14.08 Hz), 3.11 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.26 Hz), 2.85 (tt, 1H, J=11.73 Hz, J=3.52 Hz), 2.30 (s, 3H), 2.02-1.99 (m, 2H), 1.83-1.78 (m, 2H), 1.72-1.69 (m, 1H), 1.58-1.49 (m, 2H), 1.36 (s, 3H), 1.33-1.22 (m, 3H); HRMS (ES+) m/z exact mass calcd for C28H33NO5F 482.2343, found 482.2347.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=[CH:9]1)=O)(C)(C)C.C(N(CC)CC)C>CO>[C:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCc1cn(C(=O)OC(C)(C)C)cn1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 4-(2-tert-Butoxycarbonylamino-ethyl)-imidazole-1-carboxylic acid tert-butyl ester, were added 100 mL of methanol and 800 mL (5.73 mol) of triethylamine The reaction mixture was allowed to stir at room temperature for four days and concentrated to oil. To the residue were added 40 mL of ether and 80 mL of hexane. This mixture was allowed to stand at room temperature resulting in precipitation of product, as a white solid, which were collected. The yield was 1.7 g (8.0 mmol, 40%) (LC/MS M+H 212.1).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: C1CNCCN1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCNCC4)c(Cl)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To 170 mg of N,N-dimethylformamide were added 50 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of piperazine, and the mixture was stirred at 90° C. for 1 hour. After adding about 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively-to obtain 33 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:10][C@H:11]([OH:37])[C@@H:12]([NH:26]C(=O)OCC1C=CC=CC=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[NH2:26][C@@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[C@@H:11]([OH:37])[CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.8 %

Procedure:
Method 1 A solution containing the product from Example 23J (0.568 g, 0.95 mmol) in a mixture of ethyl acetate (5 mL) and methanol (5 mL) was treated with Pd(OH)2 on carbon (0.2 g, 20% Pd by wt.) and HCl solution (0.25 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) for 16 hours at 25° C., filtered through a bed of celite®, rinsed with a mixture of 50% ethyl acetate in methanol, and concentrated. The residue was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.442 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[C:12]([NH:16][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[F:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1F
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a suspension of 4-chloro-2-fluorobenzoic acid (0.3494 g, 2.00 mmol) in methylene chloride (10 ml) were added t-butylamine (0.32 ml, 3.05 mmol) and HOBt (0.3248 g, 2.40 mmol), and then WSC HCl (0.4596 g, 2.40 mmol) was added and stirred for 3 hours. The reaction mixture was added into water and extracted three times with ethyl acetate. The combined extracts were dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (0.4403 g; 96%).