Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:40]=[CH:39][C:20]([CH2:21][N:22]([C:34](=[O:38])[C:35]([OH:37])=[O:36])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]2[CH:40]=[CH:39][C:20]([CH2:21][N:22]([C:34](=[O:38])[C:35]([OH:37])=[O:36])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C#Cc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)O)cc2)cc1
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(CCc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)O)cc2)cc1
Yield: 54 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step c) but using {(4-{[4-(heptyloxy)phenyl]ethynyl}benzyl)[4-(trifluoromethyl)benzyl]amino}(oxo)acetic acid in EtOAc gave the title compound as a colorless oil (54%). M−(LC/MS(ESI)): 554. HPLC (Condition A), Rt: 5.95 min (HPLC purity: 95.1%).
Reaction SMILES: C([C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)(O)=O.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)C=O)([O-:16])=[O:15].CC1C=CC(C(C)C)=CC=1>>[N+:14]([C:17]1[CH:24]=[C:23]([CH:13]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[C:10](=[O:11])[O:12]2)[CH:22]=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: COC(=O)c1cccnc1C(=O)O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C1OC(c2cccc([N+](=O)[O-])c2)c2ncccc21
Temperature: 180 °C
Yield: 37.2 %

Procedure:
A solution of 2,3-pyridinyldicarboxylic anhydride (20 g, 134 mmoles) in 25 ml of anhydrous methanol was refluxed for 30 minutes. The methanol was removed and the two positional isomers (2-carboxy-3-methoxycarbonylpyridine and 2-methoxycarbonyl-3-carboxypyridine) are isolated and separated. The 2-carboxy-3-methoxycarbonyl pyridine was added to a solution of 3-nitrobenzaldehyde (101.35 g, 670 mmoles) in p-cymene (105 ml, 670 mmoles) and heated at 180° C. for 13.5 hours. The solution was cooled, filtered and the excess 3-nitrobenzaldehyde and p-cymene removed by bulb to bulb distillation using a Kugelrohr apparatus. The residue was triturated with methylene chloride and the solid residue was discarded. The product was isolated from the filtrate yielding 12.7 g of 7-(3-nitrophenyl)-furo[3,4-b]pyridin-5-one (37.2%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[CH3:19])=[C:9]([C:20](O)=[O:21])[CH:8]=[N:7][C:6]=12.Cl.[F:24][C:25]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[CH3:19])=[C:9]([C:20]([N:28]3[CH2:27][CH2:26][C:25]([F:24])([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:30][CH2:29]3)=[O:21])[CH:8]=[N:7][C:6]=12
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)O)cnc2c(Br)cnn12
Reactant: Fc1ccc(C2(F)CCNCC2)cc1
Agent: Cl
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(F)(c3ccc(F)cc3)CC2)cnc2c(Br)cnn12
Yield: 48.3 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-bromo-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (100 mg, 0.27 mmol) obtained in step 2 and 4-fluoro-4-(4-fluorophenyl)piperidine hydrochloride (WO2008/012622, 71 mg, 0.33 mmol), the title compound (71 mg, 48%) was obtained.
Reaction SMILES: ClC([O:4][CH2:5][CH3:6])=O.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CNCC1[C:22]([S:32][CH2:33][CH2:34][CH3:35])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31]>C1COCC1.C(Cl)Cl>[CH3:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:24]=1[N:23]=[C:22]([S:32][CH2:33][CH2:34][CH3:35])[C:6]([CH:5]=[O:4])=[CH:31]2
Reactant: CCCSc1nc2c(C)cccc2cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCSc1nc2c(C)cccc2cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 229 %

Procedure:
To ethyl chloroformate (0.4 ml, 4.2 mmol) and potassium carbonate (0.875 g, 6.3 mmol) were added to (3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-amine (1.058 g, 2.1 mmol) which was dissolved in anhydrous THF (10 mL). The resulting mixture was stirred at room temperature for overnight. The mixture was diluted with methylene chloride, and was washed one time with water. The organic phase was dried over potassium carbonate and concentrated by rotary evaporation. The resulting sample was dried under vacuum gave a light yellow solid (1.18 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][O:12]C(Cl)Cl.C(OCC)(=O)C.CCCCCC>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([CH:7]=1)[CH:11]=[O:12]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(F)c(C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C)c(F)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 g of 4-fluoro-3-methylanisol was dissolved in 80 ml of dichloromethane, and 10 ml of titanium tetrachloride and 7.5 ml of dichloromethyl methyl ether were added to the solution successively at 0° C. The resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice-water, followed by the addition of 300 ml of ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the resulting mixture was evaporated to give a solid. n-Hexane was added to this solid, and the resulting mixture was filtered. The filter cake was washed with n-hexane to give 5.8 g of the title compound as white crystals.
Reaction SMILES: [BH4-].[Na+].[Br-].[CH2:4]([N+:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.CCOC(C)=O>[CH2:4]([N:11]1[CH:16]=[C:15]([F:17])[CH2:14][CH2:13][CH:12]1[CH2:18][NH:19][C:20](=[O:21])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c[n+]1Cc1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCC(F)=CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 62 %

Procedure:
NaBH4 (5.56 mmol, 0.21 g) was added to a solution of 1-benzyl-2-((tert-butoxycarbonylamino)methyl)-5-fluoropyridinium bromide (1.40 mmol, 0.60 g) in MeOH at 0° C. The resulting mixture was stirred at 0° C. for 40 min. An aliquot was checked by analytical HPLC and some of the starting material remained. Additional NaBH4 (5.56 mmol, 0.21 g) was added at 0° C. and the resulting mixture was stirred for extra 40 min. The reaction mixture was diluted with EtOAc and washed with brine. EtOAc layer was separated, dried with MgSO4 and concentrated in vacuo to give desired tert-butyl (1-benzyl-5-fluoro-1,2,3,4-tetrahydropyridin-2-yl)methylcarbamate in 62% yield which was used for next step without further purification. MS (ESI) 321 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16](CP(=O)(OCC)OCC)=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.ClC1N=C(Cl)C(C(F)(F)F)=CN=1.COC1C=CC=CC=1N>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][CH:16]=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: COc1ccccc1N
Product: COc1ccccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Yield: 46 %

Procedure:
This material was prepared in a manner analogous to diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate using commercially available starting materials (2,4-dichloro-5-(trifluoromethyl)pyrimidine and 2-Methoxyaniline). The crude product from this reaction was recrystallized using MeCN to afford a white solid, 610 mg, 46% yield. 1H NMR (CDCl3): 3.93 (s, 3H), 6.94 (dd, J=8.1 Hz, 1.5 Hz, 1H), 7.03 (td, J=7.8 Hz, 1.5 Hz, 1H), 7.10 (td, J=7.6 Hz, 1.8 Hz, 1H), 8.14 (br s, 1H), 8.41 (dd, J=8.1 Hz, 1.8 Hz, 1H), 8.56 (s, 1H). MS (ES+): m/z=304.00 [MH+]. HPLC: tR=3.89 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:27][CH:26]=3)[O+:19]=2)=[CH:14][CH:13]=1)[CH2:7][CH2:8][CH2:9][CH3:10].[CH2:37]([O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][C:53](=O)[CH:54]=2)=[CH:45][CH:44]=1)[CH2:38][CH2:39][CH2:40][CH3:41].C(OC(=O)C)(=O)C.O>C(O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[C:22]([CH:24]=[C:53]3[CH:52]=[C:51]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[O:50][C:49]([C:46]4[CH:45]=[CH:44][C:43]([O:42][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:48][CH:47]=4)=[CH:54]3)[CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:27][CH:26]=3)[O+:19]=2)=[CH:16][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCOc1ccc(-c2cc(C)cc(-c3ccc(OCCCCC)cc3)[o+]2)cc1
Reactant: CCCCCOc1ccc(-c2cc(=O)cc(-c3ccccc3)o2)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CCCCCOc1ccc(C2=CC(=Cc3cc(-c4ccc(OCCCCC)cc4)[o+]c(-c4ccc(OCCCCC)cc4)c3)C=C(c3ccccc3)O2)cc1

Procedure:
A mixture of 3.1 g. of 2,6-bis(4-amyloxyphenyl)-4-methylpyrylium perchlorate, 2.0 g. of 2-(4-amyloxyphenyl)-6-phenyl-4-pyrone, and 20 ml. of acetic anhydride are stirred and heated at its boiling temperature for 5 to 10 minutes, cooled, diluted with ethanol with stirring, and chilled in a freezer. A solid separates from the mixture and is collected and washed with water. Another crop is obtained by adding water to the reaction mixture, extracting with dichloromethane, removing the solvent by evaporation, and recrystallizing the residue from acetic acid. The two crops are combined and recrystallized again from acetic acid. mp = 68°C. The theoretical values calculated for C50H55ClO, and the actual values found are as follows:
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].[N:21]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:21])=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c(N)c(N)n(C)c1=O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To the stirring solution of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (1.13 g, 4.0 mmol) in glacial acetic acid (22.5 ml) and water (7.5 ml) at 65° C. was added sodium nitrite (345 mg, 5.0 mmol) in portions. The pink mixture was stirred at 65° C. for 1 hour and then cooled to 0-5° C. After filtration, the violet solid was washed with water (2x 10 ml) and then suspended in water (20 ml) and heated at 65° C. while sodium hydrosulfite (2.78 g, 16.0 mmol) was added in portions. The pale yellow solution was stirred at 65° C. for an additional 1 hour, cooled to room temperature and extracted with chloroform (3x 25 ml). The combined extracts were dried over magnesium sulfate and filtered to provide crude (R)-3-(5-acetoxyhexyl)-5,6-diamino-1-methyluracil in chloroform. To this clear solution was added 1,1′-carbonyldiimidazole (650 mg, 4.0 mmol). After stirring overnight at room temperature, the mixture was washed with water (2x 25 ml), with 1 N aqueous hydrochloric add (2x 25 ml), with water (2x 25 ml), with saturated aqueous sodium chloride solution (25 ml) and then dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided the crude product which was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-3-methyluric acid (280 mg) as a beige solid which was dissolved in 20 ml of ethanol. To this solution was added hydrogen chloride in ethyl ether (1 M, 2.0 ml, 2.0 mmol). After refluxing overnight, the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-hydroxyhexyl)-3-methyluric acid (210 mg, 19% yield) as a beige solid.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:40]#[N:41])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:42][O:43]C(=O)C)(=O)C>N.C(O)C.[Pd]>[NH2:41][CH2:40][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@H:8]2[C@H:9]([OH:10])[C@H:5]([OH:4])[C@@H:6]([CH2:42][OH:43])[O:7]2)=[C:19]([NH:23][CH2:24][CH:25]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[N:18]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(C)cc4)c4ccc(C)cc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: N
Solvent: CCO
Product: Cc1ccc(C(CNc2nc(CN)nc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ccc(C)cc2)cc1
Reaction time: 16 h
Yield: 50.7 %

Procedure:
(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(4-methylphenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (Preparation 59) (837 mg, 1.33 mmol) was dissolved in a saturated solution of ammonia in ethanol (25 ml). 10% Palladium on carbon (168 mg) was added and the suspension was stirred under an atmosphere of hydrogen (414 kPa, 60 psi) for 16 hours. The reaction mixture was filtered through Arbocel (Trade Mark) and the filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (100 ml) and sodium carbonate (100 mg) was added. The suspension was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of dichloromethane (15 ml) and water (15 ml). The dichloromethane layer was washed with water (15 ml) and saturated aqueous sodium chloride solution. The solvent was removed under reduced pressure. The residue was triturated with diethyl ether to give the title compound as a solid (340 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][C:26]#[N:27])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:30].[K+].[K+].OO>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][C:26](=[O:30])[NH2:27])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OCC#N)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(OCC(N)=O)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 24 h
Yield: 504.2 %

Procedure:
2.10 g (5.4 mmol) of 4-(3-cyanomethoxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (example 245) and 0.15 g (1.1 mmol) of potassium carbonate were suspended under argon in 10 mL of DMSO at rt; while stirring, 0.93 mL (1.05 g=2.0 eq.) of hydrogen peroxide solution (35% in water) was added below 25° C. and stirring continued at ambient temperature for 24 hours. Then, the reaction mixture was poured into crashed ice and extracted three times with MeCl2 /2-propanol (4:1); the organic phases were evaporated i.V. to yield 2.26 g of the crude title compound as colorless solid. MS: 408.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)([OH:31])=[O:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([C:29]([OH:31])=[O:30])[CH:37]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: CC(c1ccc(-c2cccc(C(=O)O)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 3-carboxyphenylboronic acid to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=518.2 [M−H+].
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[CH2:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B1C2CCCC1CCC2.Br[C:25]1[CH:35]=[CH:34][C:28]2[O:29][C:30]([F:33])([F:32])[O:31][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O.C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][C:35]2[CH:25]=[CH:26][C:27]3[O:31][C:30]([F:32])([F:33])[O:29][C:28]=3[CH:34]=2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: C=C1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(Cc2ccc3c(c2)OC(F)(F)O3)C1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
1-Boc-3-methylene piperidine (842 mg, 4.27 mmol) was degassed (neat) for 15 minutes and then treated with a THF solution of 9-BBN (0.5 M in THF, 8.6 mL, 4.3 mmol). The reaction mixture was refluxed for 2 h, then cooled to rt. The reaction mixture was then added, via cannula, to a preformed solution of 5-bromo-2,2-difluoro-1,3-benzodioxole (1.00 g, 4.22 mmol), Pd(dppf)Cl2—CH2Cl2 (94 mg, 0.128 mmol), and potassium carbonate (746 mg, 5.40 mmol) in DMF/H2O (10 mL/1 mL). The resultant mixture was heated at 60° C. for 18 h, cooled to rt, poured into water, basified to pH 11 with 1 N NaOH, and extracted with EtOAc (3×). The organic layers were combined, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([Cl:9])[CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C)C(=O)C>[Cl:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: Fc1ccc(Cl)cc1Cl
Solvent: CC(=O)N(C)C
Product: Clc1ccc(N2CCNCC2)c(Cl)c1

Procedure:
A mixture of 1,3-dichloro-4-fluorobenzene )Aldrich; 4.21 g), piperazine (Aldrich; 11.0 g), and N,N-dimethylacetamide (Aldrich; 15 mL) is heated at 165° C. for 6.5 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated under reduced pressure to give 4.48 g of 1-(2,4-dichlorophenyl)piperazine. 1H NMR (CDCl3) δ 3.00, 3.06, 6.96, 7.19, 7.36.
Reaction SMILES: [N:1]1([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:20]([C:24]1[S:28][C:27]([S:29]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])=[O:30])=[C:26](B(O)O)[CH:25]=1)[CH:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[N:1]1([CH2:10][C:11]([C:13]2[CH:14]=[C:15]([C:26]3[CH:25]=[C:24]([CH2:20][CH:21]([CH3:22])[CH3:23])[S:28][C:27]=3[S:29]([NH:32][C:33]([CH3:35])([CH3:34])[CH3:36])(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: O=C(Cn1cnc2ccccc21)c1cccc(Br)c1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Cc1cc(-c2cccc(C(=O)Cn3cnc4ccccc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 2-benzoimidazol-1-yl-1-(3-bromophenyl)ethanone (42.7 mg, 0.136 mmol; see step (a)) in toluene (7 mL) and ethanol (1 mL) was added 5-isobutyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (73.5 mg, 0.230 mmol; see Example 1(c)), Pd(PPh3)4 (9.4 mg, 8.1 μmol) and Na2CO3 (271 μL, 0.542 mmol, 2.0 M aq), and the reaction mixture was stirred for 3 h at 80° C. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc. The combined organic phase was dried (over anhydrous MgSO4), concentrated in vacuo, and the residue was purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the sub-title compound as a colourless syrup in 90% yield (62 mg, 0.122 mmol).
Reaction SMILES: [I:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:5][NH:6][C:7]2=O.P(Cl)(Cl)([Cl:16])=O>CCOC(C)=O>[Cl:16][C:7]1[C:8]2[C:3](=[C:2]([I:1])[C:11]([CH3:12])=[CH:10][CH:9]=2)[CH:4]=[N:5][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(=O)[nH]ncc2c1I
Solvent: CCOC(C)=O
Product: Cc1ccc2c(Cl)nncc2c1I
Temperature: 108 °C
Yield: 262.9 %

Procedure:
A suspension of 5-iodo-6-methylphthalazin-1(2H)-one (8.51 g, 29 7 mmol) in phosphorous oxychloride (200 ml, 2146 mmol), charged to a 500 mL was stirred at 108° C. (reflux) for 90 min. The POCl3 was then removed under vacuum, and the resulting residue was azeotroped 2× with toluene. The resulting residue was dissolved in a mixture of DCM and MeOH and water. The layers were separated the aqueous layer was washed with DCM 3×. The combined organics were washed with saturated aqueous sodium carbonate and brine. The organic layer was then dried over magnesium sulfate, and loaded on to silica. 1-Chloro-5-iodo-6-methylphthalazine (5.604 g, 61.9% yield) was obtained by column chromatography (ISCO 330 g 15%-60% EtOAc in Hex 60 min) as a yellow solid. MS (M+H)+ 305.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].C([O:10][C:11](=[O:29])[CH:12]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)C.C(OC(=O)C(Br)OC1C=CC(Cl)=CC=1)C.ClC1C=CC(OC(OC2C=CC([N+]([O-])=O)=CC=2)C(O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7])=[CH:16][CH:15]=2)[C:11]([OH:29])=[O:10])=[CH:23][CH:24]=1
Reactant: BrCCCCCBr
Reactant: CCOC(=O)C(Oc1ccc(N)cc1)Oc1ccc(Cl)cc1
Agent: CCOC(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=C(O)C(Oc1ccc(Cl)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Solvent: CCCCO
Product: O=C(O)C(Oc1ccc(Cl)cc1)Oc1ccc(NCCCCCBr)cc1

Procedure:
2.3 g. of 1,5-dibromopentane, 3.2 g. of (4-chlorophenoxy)-(4-aminophenoxy)-acetic acid ethyl ester [obtainable by reacting Na-4-nitrophenolate with α-bromo-α-(4-chlorophenoxy)-acetic acid ethyl ester to obain the ethyl ester of (4-chlorophenoxy)-(4-nitrophenoxy)-acetic acid and subsequent hydrogenation], and 1.4 g. of K2CO3 are refluxed for 12 hours in 40 ml. of n-butanol. As an intermediate compound, the ethyl ester of (4-chlorophenoxy)-[4-(5-bromopentylamino)-phenoxy]-acetic acid is produced. After working up the mixture as usual, (4-chlorohenoxy)-(4-piperidinophenoxy)-acetic acid ethyl ester is obtained.