Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Pd].C1COCC1.CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(F)c(NC(=O)c2ccccc2)c1
Yield: 91 %

Procedure:
A mixture of N-(2-fluoro-5-nitro-phenyl)-benzamide (4.86 g, 18.7 mmol) and 10% Pd/C, (486 mg) in a 1:1 mixture of THF-MeOH (80 ml) was hydrogenated at 23° C. After 25 h the reaction mixture was filtered through celite and concentrated to give N-(5-Amino-2-fluorophenyl)benzamide (3.92 g, 91%). MS (ESI+) [M+H]/z Calc'd 231, found 231.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C([O-])([O-])=O.[K+].[K+].[CH2:18]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:19]([CH3:21])[CH3:20]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CNCC(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CN(CC(C)C)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 29.8 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (1.59 g, 10 mmol) in DMSO (15 mL) were added K2CO3 (3.04 g, 22 mmol) and diisobutylamine (1.42 g, 11 mmol). The mixture was heated at 90° C. overnight, then cooled to rt, diluted with water (50 mL) and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as pale yellow oil (0.80 g, 30%).
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>CN(C=O)C>[Cl:17][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Temperature: 105 °C

Procedure:
To a mixture of 3-nitro-5-trifluoromethylpyridin-2-ol (3.2 g) and DMF (1 drop), phosphorous oxychloride (8.2 ml) was added at room temperature. The mixture was heated to 105° C., and stirred with heating for 2 days. The reaction mixture was cooled to room temperature, and then the reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 2.5 g of 2-chloro-3-nitro-5-trifluoromethylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)=[O:5])[CH3:2].Cl[CH2:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=1.[I-:26].[Na+]>C(#N)C>[I-:26].[CH2:1]([O:3][C:4]([N+:6]1[CH:10]=[CH:9][N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1ccc(CCl)cc1
Reactant: CCOC(=O)n1ccnc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(Cn2cc[n+](C(=O)OCC)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
1.4 g of 1-ethoxycarbonylimidazole, 2.5 g of ethyl 4-chloromethylphenoxyacetate and 1.7 g of sodium iodide were added to 5 ml of dry acetonitrile, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was triturated with an adequate amount of dry diethyl ether, the resulting powder was collected by filtration and dried to obtain 4.6 g of 1-ethoxycarbonyl-3-(4-ethoxycarbonylmethoxybenzyl)imidazolium iodide (quantitative yield). Colorless hygroscopic amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10](=[O:18])[N:11]([CH:13]3[CH2:17][CH2:16][NH:15][CH2:14]3)[N:12]=2)[C:5]([O:19][CH3:20])=[CH:4][C:3]=1[NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.Br[CH2:40][CH2:41][CH2:42][CH3:43]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10](=[O:18])[N:11]([CH:13]3[CH2:17][CH2:16][N:15]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:14]3)[N:12]=2)[C:5]([O:19][CH3:20])=[CH:4][C:3]=1[NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc(NC(=O)OCc2ccccc2)c(Cl)cc1-c1nn(C2CCNC2)c(=O)o1
Reactant: CCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCN1CCC(n2nc(-c3cc(Cl)c(NC(=O)OCc4ccccc4)cc3OC)oc2=O)C1
Temperature: 60 °C

Procedure:
1.5 g (3.37 mmol) of phenylmethyl [2-chloro-4-(5-oxo-4-(pyrrolidin-3-yl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-methoxyphenyl]carbamate dissolved in 26 ml of acetonitrile, and 1.41 ml (10.1 mmol) of triethylamine are placed in a 100 ml three-necked round-bottomed flask. A solution of 0.6 g (4.38 mmol) of 1-bromobutane in 4 ml of acetonitrile is added and the mixture is heated at 60° C. for 15 h.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:52])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:51])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:50])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:49])[CH2:22][CH2:23][C:24](=[O:48])[CH:25]([CH3:47])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:46])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:45])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:44])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:43])[CH3:42])=[CH:3][CH2:4][OH:5].[C:53](OC(=O)C)(=[O:55])[CH3:54]>N1C=CC=CC=1>[C:53]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:52])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:51])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:50])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:49])[CH2:22][CH2:23][C:24](=[O:48])[CH:25]([CH3:47])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:46])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:45])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:44])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:43])[CH3:42])(=[O:55])[CH3:54]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: c1ccncc1
Product: CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC(=O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 6 h
Yield: 86.1 %

Procedure:
To a solution of 3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaen-22-on-1-ol (6.8 g) in pyridine (1 g), acetic anhydride (3.5 g) is added, and the resultant mixture is allowed to stand at room temperature for 6 hours. The reaction mixture is treated as in Example 7 (5) (a) to give 1-acetoxy-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaen-22-one (6.2 g), which is then similarly reduced. The resultant product (4.7 g) is treated as in Example 1 (5) (a) to give 1-acetoxy-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaen-22ol (1.9 g) as a fraction (1) and 3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaene-1,22-diol (0.8 g) as a fraction (2). The latter is treated with acetic anhydride as above to give 1-acetoxy-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,26,30,34,38-tetracontanonaen-22-ol (0.73 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:13]([CH3:12])(=[O:15])=[O:14])[CH2:6][CH2:5]2
Reactant: Fc1cc(Br)cc2c1NCC2
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCc2cc(Br)cc(F)c21
Yield: 66.6 %

Procedure:
This compound was prepared according to the general procedure for sulfonylation of indolines and tetrahydroquinolines described in Example 4 using 5-bromo-7-fluoroindoline (0.21 g, 0.97 mmol) and methanesulfonyl chloride (0.15 mL, 1.94 mmol) to provide 5-bromo-7-fluoro-1-(methylsulfonyl)indoline (0.19 g). MS (ES) m/z 293.6; HPLC purity 98.4% at 210-370 nm, 8.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][S:6][CH2:7][C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH3:46][NH:47][CH:48]1[CH:55]2[CH2:56][C:51]3([OH:58])[CH2:52][CH:53]([CH2:57][CH:49]1[CH2:50]3)[CH2:54]2>C1COCC1>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][S:6][CH2:7][C:8]([N:47]([CH:48]1[CH:55]2[CH2:54][CH:53]3[CH2:52][C:51]([OH:58])([CH2:50][CH:49]1[CH2:57]3)[CH2:56]2)[CH3:46])=[O:10]
Reactant: O=C(O)CSCOc1ccc(Cl)cc1Cl
Reactant: CNC1C2CC3CC1CC(O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)CSCOc1ccc(Cl)cc1Cl)C1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2,4-dichloro-phenoxymethylsulfanyl)-acetic acid (125 mg, 0.47 mmol) in dry THF (20 mL) was added HOBt (76 mg, 0.56 mmol) and EDAC (108 mg, 0.56 mmol). After stirring for 1 hr at room temperature, DIPEA (180 μL) and 4-methylaminoadamantan-1-ol (93 mg, 0.52 mmol) were added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were removed in vacuo and the residue was purified using prep. HPLC/MS affording crude 2-(2,4-dichloro-phenoxymethylsulfanyl)-N-(5-hydroxy-adamantan-2-yl)-N-methyl-acetamide which was used without further purification in the next step.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([SH:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1.[O:23]1[CH:27]=[CH:26][CH2:25][CH2:24]1>CCOCC.C1(C)C(S(O)(=O)=O)=CC=CC=1>[F:22][CH:2]([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([S:17][CH:24]2[CH2:25][CH2:26][CH2:27][O:23]2)=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(S)c1CC(C)C
Reactant: C1=COCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOCC
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(SC2CCCO2)c1CC(C)C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 7.07 g (0.021 mol) of compound 7, 2.92 g (0.042 mol) of dihydrofuran, and catalytic toluenesulfonic acid (9 mg) in 80 ml of ether was stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by HPLC (20% EtOAc in hexane) to give 5.82 g (68%) of the desired product as a yellow oil, n25D 1.5803.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][C@@H:33]([CH3:35])[N:32](C(=O)C(F)(F)F)[CH2:31][C:30]2=[O:42])[CH:26]=[CH:27][CH:28]=1>Cl>[F:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[N:7][C:2]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][C@@H:33]([CH3:35])[NH:32][CH2:31][C:30]3=[O:42])[CH:24]=2)=[N:3][CH:4]=1
Reactant: C[C@@H]1CN(c2cccc(N)c2)C(=O)CN1C(=O)C(F)(F)F
Reactant: CC(C)NC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Agent: Cl
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2cccc(N3C[C@@H](C)NCC3=O)c2)ncc1F
Temperature: 95 °C
Yield: 55 %

Procedure:
To the suspension solution of 2-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (100 mg, 0.32 mmol) and (5R)-1-(3-aminophenyl)-5-methyl-4-(trifluoroacetyl)-2-piperazinone (147 mg, 0.48 mmol) was added 2 drops of 12N HCl. The reaction mixture was then sealed and heated in a 95° C. oil bath for 16 h. The reaction was followed by LC/MS. The reaction was evaporated to dryness. The residue was then dissolved in THF (10 mL) with LiOH (1.0 M solution 0.64 mL). The reaction mixture was heated at 50° C. for 3 h. Then the solvent was evaporated to dryness on high vacuum and the residue was loaded on silica gel column and eluted with 2.0 to 9.0% MeOH (with 0.1% NH4OH) in CH2Cl2. Oil was then recrystalized from hot EtOH to yield the pure title compound (84 mg, 55%). MS: M(C25H28FN7O2)=477.54 (M+H)+=478.
Reaction SMILES: [C:1]([N:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C.[H][H]>C(O)C.[Pd].[C]>[C:1]([N:8]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: [H][H]
Reactant: C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc(N)cc1
Yield: 96.9 %

Procedure:
Nα -Boc-4-Nitrophenyl-D-alanine (209 grams, 0.68 mole) was dissolved in 500 mL of ethyl alcohol and acidified with acetic acid (10 mL). To this was added 0.65 g of 10% Pd/carbon, and the mixture was hydrogenated at about room temperature using H2 at about 40 psi until the uptake of hydrogen had ceased (6 hours). The catalyst was removed by filtration, and the reaction products were concentrated under vacuum to yield a viscous oil that solidified upon trituration with petroleum ether. The amino acid was collected by filtration, washed with petroleum ether and dried to give 184 g of Nα -Boc-4-aminophenyl-D-alanine (0.659 mole, 97%) having [α]D =-40.2° (c=1.0 in EtOAc) and -23.4° (c=1.0 in MeOH); mp=128°-133° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[CH:17]=[O:18])[CH:20]=1
Reactant: OB(O)c1cccnc1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 95 °C
Yield: 47 %

Procedure:
5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) (1.53 g, 4.30 mmol), pyridine-3-boronic acid (CXXXI) (0.58 g, 4.73 mmol), and potassium phosphate tribasic (1.37 g, 6.45 mmol) was dissolved in 1,4-dioxane (43.0 mL) and water (9.0 mL) Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.4301 mmol) was added, and the reaction was heated to 95° C. for 2.5 h. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic phase was separated and washed sequentially with water and brine. The material was dried (MgSO4), concentrated, and purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge (100% hexanes→1:1 EtOAc:hexanes) to afford 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXXXII) (0.62 g, 2.02 mmol, 47% yield) as a tan amorphous solid. 1H NMR (DMSO-d6) δ ppm 10.23 (s, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.61 (dd, J=4.8, 1.5 Hz, 1H), 8.39 (d, J=0.98 Hz, 1H), 8.17-8.14 (m, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.95-7.93 (m, 1H), 7.64-7.60 (m, 1H), 6.13 (dd, J=9.4, 2.4 Hz, 1H), 3.93-3.90 (m, 1H), 3.86-3.81 (m, 1H), 2.45-2.41 (m, 1H), 2.11-2.07 (m, 2H), 1.82-1.78 (m, 1H), 1.66-1.62 (m, 2H); ESIMS found for C18H17N3O2 m/z 308 (M+H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added phenylacetyl chloride (285 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (578 mg, 93%).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[CH3:6][C:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[OH:16])=[O:8].[OH-].[Na+]>O>[C:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:2][C:3]([OH:5])=[O:4])(=[O:8])[CH3:6]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1cc(F)ccc1OCC(=O)O
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Chloroacetic acid (99.3 mmol, 9.4 g) was added to a suspension of 5-fluoro-2-hydroxy acetophenone (33.1 mmol, 5.1 g) in water (60 mL) containing sodium hydroxide (165.4 mmol, 6.6 g) and the reaction mixture was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature, poured into a separatory funnel and the oily liquid at the bottom of the funnel was discarded. The aqueous top layer was collected, cooled to 0° C. and acidified with conc. HCl. The white precipitate was collected, and air died. The dry solid was crystallized from toluene to obtain (2-acetyl-4-fluoro-phenoxy)-acetic acid, (57%, 4.3 g).
Reaction SMILES: [OH:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CN(O)C(=O)c1ccc(CCCCc2ccncc2)cc1
Solvent: c1ccncc1
Product: CC(=O)ON(C)C(=O)c1ccc(CCCCc2ccncc2)cc1
Reaction time: 20 h

Procedure:
A solution of 200 mg of N-hydroxy-N-methyl-4-[4-(4-pyridinyl)butyl]benzamide in dry pyridine (3.0 ml) was mixed with acetic anhydride (0.5 ml) and was allowed to stand at room temperature for 20 hours. The mixture was then concentrated in vacuo, diluted with dichloromethane, washed with a dilute Na2CO3 solution and water, dried (MgSO4 anhydrous), evaporated and the residue was purified by column chromatography on silica gel to afford the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH2:28][CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:28][CH2:27]2
Reactant: Fc1ccc2c(c1)CCN2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCN3CCc4cc(F)ccc43)cn2)c1
Yield: 11 %

Procedure:
The title compound was prepared in 11% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 5-fluoro-2,3-dihydro-(1H)-indole according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.88 (2H, t, J=8.4 Hz), 3.42 (2H, t, J=6.2 Hz), 4.25 (2H, t, J=6.1 Hz), 6.49 (1H, m), 6.76 (1H, td, J=2.2 and 8.8 Hz), 6.89 (1H, dd, J=6.4 Hz), 7.57 (1H, d, J=5.0 Hz), 7.83 (1H, s), 7.94 (1H, s), 8.27 (1H, s), 8.62 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H17FN4O2, 353. Found, 353.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CO2
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(C)=O)cc3CO1)CO2
Yield: 88.2 %

Procedure:
Prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 6) (100 mg, 0.321 mmol) and acetic anhydride (60.7 ul, 0.642 mmol) according to the procedure described for Example 48. Obtained the title compound as a white solid (100 mg, 88%), MS (ISP) m/e=354.2 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([CH:20]1[CH2:24][C:23](=[O:25])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:32][C:29]1[CH:28]=[CH:27][C:26]([N:22]2[C:23](=[O:25])[CH2:24][CH:20]([C:18]([O:17][CH3:16])=[O:19])[CH2:21]2)=[CH:31][CH:30]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(=O)N(c2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)C1
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinoline (1.0 g, 4.45 mmol), 1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (1.6 g, 6.7 mmol) and DMAP (0.55 g, 4.45 mmol) in 30 mL of toluene (in 5 microwave tubes) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 1 h. The reaction mixture was cooled to RT and diluted with 60 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (100% EtOAc to 15% MeOH in EtOAc) to provide colorless glass. MS (ESI pos. ion) m/z: 423.2 (M+H). Calc'd Exact Mass for C23H22N2O6: 422.43.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[F:11].O1CCCC1.[CH2:17]([CH2:19][NH2:20])[OH:18]>[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:20][CH2:19][CH2:17][OH:18])=[CH:4][C:3]=1[F:11]
Reactant: Fc1cc(C2CO2)ccc1Br
Reactant: NCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCNCC(O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2-(4-Bromo-3-fluoro-phenyl)-oxirane (25.1 g, 109 mmol) was combined with tetrahydrofurane (70 ml) to give a yellow solution. Ethanolamine (66.4 g, 65.1 ml, 1.09 mol) was added. The resulting orange solution was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted twice with ethyl acetate. The organic layers were dried over MgSO4 and concentrated in vacuo to yield a yellow oil (27.9 g, 92%), MS (ISP): 277.9 ([{79Br}M+H]+), 279.9 ([{81Br}M+H]+).