Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:32](I)[CH3:33]>O>[CH2:32]([O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2)[CH3:33]
Reactant: CCI
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 21.8 %

Procedure:
To a mixture of 0.25 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.14 g of potassium carbonate and 3 ml of DMF, a mixture of 0.15 g of ethyl iodide and 1 ml of DMF was added at room temperature and stirred while heating at 60° C. for 1.5 hours. To the reaction mixture, 70 mg of potassium carbonate and 53 mg of iodoethane were added, and the reaction solution was stirred while heating at 60° C. for 3.5 hours. The reaction solution was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 60 mg of 2-(3-ethoxypyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 161”).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([CH2:33][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([N:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(ccn3CC3CCN(C(=O)OC(C)(C)C)C3)c2)CC1
Temperature: 110 °C
Yield: 39.3 %

Procedure:
A mixture of 21.7 mg (0.08 mmol) (1H-indol-5-yl)-(4-isopropyl-piperazin-1-yl)-methanone (intermediate 1), 24.1 mg (0.12 mmol) 3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (commercially available), 38.6 mg (0.16 mmol) cyanomethylenetri-n-butylphosphorane in 1.5 mL toluene was heated to 110° C. for an extended period of time. After evaporation the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. The combined product fractions were evaporated to yield 14.3 mg of the title compound. MS(m/e): 455.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]3[N:16]=[C:15]([CH3:17])[C:14]([N:18]4[C:22]([CH3:23])=[N:21][C:20]([CH3:24])=[N:19]4)=[C:10]3[O:11][C:12]=2[CH3:13])=[C:4]([CH3:25])[CH:3]=1.COC1C2[C:32](=[C:33]3C(=CC=2)C(OC)=C[CH:35]=[N:34]3)[N:31]=CC=1.N1C=CN=C1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[N:31]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]4[N:16]=[C:15]([CH3:17])[C:14]([N:18]5[C:22]([CH3:23])=[N:21][C:20]([CH3:24])=[N:19]5)=[C:10]4[O:11][C:12]=3[CH3:13])=[C:4]([CH3:25])[CH:3]=2)[CH:32]=[CH:33][N:34]=[CH:35]1
Reactant: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(Br)cc4C)c(C)oc23)n1
Reactant: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1c[nH]cn1
Solvent: CN1CCCC1=O
Product: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(-n5ccnc5)cc4C)c(C)oc23)n1
Temperature: 110 °C
Reaction time: 120 h

Procedure:
3-(4-Bromo-2-methylphenyl)-7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2,6-dimethyl pyrazolo[5,1-b]oxazole (Ex. 6.41) (40 mg, 0.100 mmol), 4,7-dimethoxy-1,10-phenanthroline (24.01 mg, 0.100 mmol), 1H-imidazole (8.16 mg, 0.120 mmol), Cu2O (0.715 mg, 5.00 μmol) and Cs2CO3 (45.6 mg, 0.140 mmol) are added to NMP (2 ml) and stirred at 110° C. for 5 days.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH2:13]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([N:20]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: c1ccc(CNCCCN2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN(CCCN2CCOCC2)Cc2ccccc2)cc1
Temperature: 65 °C

Procedure:
A suspension of 1-(2-bromoethyl)-4-nitrobenzene (0.314 g, 1.366 mmol), N-benzyl-3-morpholinopropan-1-amine (0.128 g, 0.546 mmol), and potassium carbonate (0.189 g, 1.366 mmol) in dimethylformamide (1.821 ml) was heated at 65° C. for 20 hours. The reaction was partitioned in ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by flash chromatography to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1[C@H](OCCO)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1[C@H](OCCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (7 g, 18.3 mmol) in dry CH2Cl2 (100 mL) was added Et3N (54 g, 10 mL, 0.73 mmol) at −5-0° C. Then a solution of MsCl (4.2 g, 36.5 mmol) in dry CH2Cl2 (50 mL) was added dropwise at the same temperature. After addition, it was allowed to warm to rt gradually. The reaction mixture was washed with 10% citric acid solution (30 mL), NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (8.4 g), which was used in the next step without purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[CH:12]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:5]=1[F:31])(=[O:3])[NH2:2].C(Cl)CCl.[CH3:36][C:37]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:38]=1[C:39](O)=[O:40]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:36][C:37]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:38]=1[C:39]([O:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH:12]([CH2:13][NH:14][C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[NH2:2])=[C:5]([F:31])[CH:6]=2)=[O:30])=[CH:27][CH:26]=1)=[O:40]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc(C(N)=O)c(F)c1)c1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccc(C(=O)OCc2ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc3ccc(C(N)=O)c(F)c3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-2-(4-(hydroxymethyl)phenyl)-3-oxopropylcarbamate (E337-1) in pyridine was added was added EDC, DMAP, and 2,4-dimethylbenzoic acid, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2 gradient) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(4-carbamoyl-3-fluorophenylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E337-2).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[CH:7][CH:8]=2)[N:3]=1.[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][CH2:25][CH2:26][NH2:27])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:17]([O:21][C:22]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[CH:7][CH:8]=2)[N:3]=1)=[O:28])([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1ccc2cc(C(=O)O)c(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2cc(C(=O)O)c(NCCCNC(=O)OC(C)(C)C)nc2c1
Temperature: 100 °C

Procedure:
A suspension of 2-Chloro-7-methoxy-quinoline-3-carboxylic acid (60 mg, 0.22 mmol), (3-Amino-propyl)-carbamic acid tert-butyl ester (77 mg, 0.44 mmol), Potassium carbonate (73 mg, 0.46 mmol), and Molecular sieve-4A (300 mg) in dry DMSO (4 ml) was heated at 100° C. for over night. The reaction mixture was purified by chromatography on SCX column using MeOH as eluent and 2-(3-tert-Butoxycarbonylamino-propylamino)-7-methoxy-quinoline-3-carboxylic acid was obtained as white solid after recrystallization from CH2Cl2 and Hexane; 70 mg (85%).
Reaction SMILES: Br[CH2:2][C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([CH3:14])([CH3:13])[C:3](=[O:15])[CH2:2][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:7][CH:8]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C(=O)CBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(Cc1ccc(Cl)cc1)C(=O)Cn1cncn1
Yield: 52 %

Procedure:
37 (0.13 mol) of 4-bromo-1-(4-chlorophenyl)-2,2-dimethyl-3-butanone, 13.3 g (0.019 mol) of 1,2,4-triazole and 53.8 g (0.39 mol) of potassium carbonate are heated under reflux in 300 ml of acetone for 8 hours. The mixture is allowed to cool, the inorganic residue is filtered off with suction and the filtrate is concentrated. The residue is taken up in chloroform and the mixture is washed with water, dried over sodium sulphate and concentrated. The residue is stirred with diethyl ether, filtered off with suction and dried at 50° C. in vacuo. 18.8 g (52% of theory) of 1-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-3-butanone of melting point 127° C. are obtained. ##STR18##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:20][C:21]2[C:22]([CH3:37])=[N:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c2ccccc12
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Product: CCOC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc12

Procedure:
In analogy to the procedures described in example 5C] and 5D], 3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester [Helvetica Chimica Acta (2001), 84(8), 2198-2211] was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 4G]) to give 3-{4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-naphthalen-1-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light pink solid.
Reaction SMILES: [F:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a stirred solution of 6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.55 g, 1.58 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.32 g, 1.58 mmol) in DCM (3 mL). After stirring for 2 h at 0° C., the mixture was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.50 g, 88%) as a white solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 8.02-8.06 (m, 2H), 7.77 (s, 1H), 7.61 (m, 1H), 7.37 (dd, J=8.4, 1.5 Hz, 1H), 7.01 (m, 1H), 5.48 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]1[CH2:11][C:10](=[O:12])[O:9][C:7]1=[O:8])=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C.C(OCC)(=O)C>[C:7]([CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:11][C:10]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:12])([OH:9])=[O:8]
Reactant: COC(=O)NC1CC(=O)OC1=O
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)NC(CC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To 17.58 g of 2-methoxycarbonylaminosuccinic anhydride and 33.77 g of 4-chlorobenzene suspended in 150 ml of dichloroethane was added 33.40 g of anhydrous aluminum chloride under ice cooling, and the mixture was stirred at room temperature for 1 hour. Under ice cooling, to the mixture were added 100 ml of 10% hydrochloric acid and then 500 ml of ethyl acetate. After the organic layer was collected by separation, washed with water and dried, the solvent was removed. The resulting crude crystals were recrystallized from ethyl acetate to obtain 24.2 g of 3-carboxy-3-methoxycarbonylamino-4'-chloropropiophenone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:7]([CH:15]2[CH2:17][CH2:16]2)=[O:8])[CH:13]=1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1cc(Br)ccc1F
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)C1CC1

Procedure:
In an analogous manner to that described for the preparation of Building block C [a)], the reaction of 5-bromo-2-fluoro-N-methoxy-N-methyl-benzamide with cyclopropylmagnesium bromide in tetrahydrofuran yielded the title compound as a light yellow liquid; (HPLC 2.783 min 100%). Mass (calculated) C10H8BrFO [243.074]; (found) [M+H]+=243, [M+2-H]+=245.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:9][CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])(=[O:5])[CH3:4].Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1C=CC=CC=1.CN(C)C=O>[C:3]([O:6][CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:9][CH2:10][N:11]([CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:12]([CH3:15])(=[O:13])=[O:14])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C=Cc1cccc(CBr)c1
Reactant: CCCCCC(CCCNS(C)(=O)=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCCC(CCCN(Cc1cccc(C=CC(=O)OCC)c1)S(C)(=O)=O)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Sodium hydride (0.59 g., 0.025 mole) is suspended in benzene (20 ml.) and dimethylformamide (35 ml.). N-(4-acetoxynonyl)methanesulfonamide [Example 1, Step B] (6.1 g., 0.022 mole) is added and stirred 1 hour at room temperature. Ethyl m-bromomethylcinnamate (6.68 g., 0.025 mole) is added dropwise with stirring over 1 hour. The suspension is stirred at room temperature for 20 hours and then separated between ethyl acetate and water. After being washed with water, the organic layer is dried over anhydrous magnesium sulfate. Removal of the ethyl acetate by evaporation in vacuo gives an oil which, after chromatograpy on silica gel, gives ethyl m-[N-(4-acetoxynonyl)-methanesulfonamidomethyl]cinnamate, 4.1 g. (40% yield). Anal. Calcd. for C24H37NO6S: C, 61.64; H, 7.98; N, 3.00 Found: C, 61.36; H, 8.40; N, 3.07
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:19]1([C:25]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:26]2[CH:30]=[C:29]([CH2:31]Cl)[N:28]=[CH:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:31][C:29]1[N:28]=[CH:27][N:26]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:30]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
To a solution of diethylphosphite (4.30 g, 31.2 mmol) in dry tetrahydrofuran (hereinafter abbreviated to THF) (10 ml) was added 1M THF solution of lithium bis-(trimethylsilyl)amide (31.2 ml, 31.2 mmol) dropwise over 1 hour at −72° C. under argon flow, followed by adding dropwise (1-triphenylmethylimidazol-4-yl)methyl chloride (9.30 g, 26.0 mmol) in THF (80 ml) over 30 minutes. The reaction mixture was stirred for 15 minutes at the same temperature, and then was heated to room temperature and stirred for additional 3 hours at room temperature. After the reaction was quenched by addition of saturated aqueous ammonium chloride (150 ml), the THF was removed and the residue was extracted four times with ethyl acetate (100 ml). The organic layers were dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude pale yellow solid product was purified by chromatography on silica gel column using methanol-ethyl acetate (1:20) to give diethyl(1-triphenylmethylimidazol-4-yl)methylphosphonate (10.30 g, 86%) as a white powder. This powder was recrystallized from a mixture of ethyl acetate and hexane to provide the titled compound as white small needles (m.p. 141-144° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8](C(N)=O)[CH:7]=1.C(#[N:27])C>>[NH2:27][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CC#N
Reactant: CC(C)(C)C(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2)cc1F
Product: CC(C)(C)C(=O)Nc1ccc(Oc2ccnc(N)c2)cc1F
Yield: 70 %

Procedure:
Prepared in a manner similar to that which is described in Step A of Example 91. 4-(3-Fluoro-4-pivalamidophenoxy)picolinamide (110 mg, 0.33 mmol) in acetonitrile (4 mL) was converted to N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)pivalamide (70 mg, 70% yield). MS(ESI+): m/z 304.21 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:15])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=1.B(Br)(Br)Br>>[F:1][C:2]1([F:15])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COc1ccc(C2C(C)(C)C2(F)F)cc1
Agent: BrB(Br)Br
Product: CC1(C)C(c2ccc(O)cc2)C1(F)F

Procedure:
p-(2,2-Difluoro-3,3-dimethylcyclopropyl)phenol was prepared from 31.8 g. of p-(2,2-difluoro-3,3-dimethylcyclopropyl)anisole and 25 g. of boron tribromide according to the procedure described above in Example 1, part (c). The product was used directly in the following reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=1)[CH3:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>[Pd].C([O-])(=O)C.C(#N)C>[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:19][C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=2)=[CH:16][CH:15]=1)[CH3:12]
Reactant: C=Cc1ccc(OCC)cc1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1ccc(C=Cc2cc(F)c(F)c(F)c2)cc1

Procedure:
A mixture of 10.5 g of 1-bromo-3,4,5-trifluorobenzene, 7.4 g of p-ethoxystyrene, 0.25 g of Pd acetate, 0.6 g of tri-o-tolylphosphine, 7 g of triethylamine and 125 ml of acetonitrile is heated at reflux until completion of the reaction. Customary working-up gives 1-(p-ethoxyphenyl)-2-(3,4,5-trifluorophenyl)ethene (C 76 I), which is hydrogenated on Pd-C (5%) in THF to give 1-(p-ethoxyphenyl)-2-(3,4,5-trifluorophenyl)ethane, C 45 I.
Reaction SMILES: [C:1]([C:3](=[CH:13][C:14]1[CH:19]=[C:18]([O:20]C)[C:17]([OH:22])=[C:16]([Cl:23])[CH:15]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].B(Br)(Br)Br.O>C(Cl)Cl>[C:1]([C:3](=[CH:13][C:14]1[CH:19]=[C:18]([OH:20])[C:17]([OH:22])=[C:16]([Cl:23])[CH:15]=1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:5])#[N:2]
Reactant: COc1cc(C=C(C#N)C(=O)Nc2ccccc2)cc(Cl)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#CC(=Cc1cc(O)c(O)c(Cl)c1)C(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a solution of 2-cyano-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propenanilide (340 mg, 1.03 mmol) in methylene chloride (20 ml) chilled at -70° C. was dropwise added 1M solution of boron tribromide in methylene chloride (2.50 ml, 2.5 mmol). The reaction mixture was gradually allowed to warm to room temperature and poured into water. The product was extracted with ethyl acetate, dried over MgSO4 and concentrated. The resulting solid was suspended in diethyl ether, refluxed for 10 minutes and the resultant solid was filtered to give the objective 2-cyano-3-(3-chloro-4, 5-dihydroxyphenyl) propenanilide (260 mg, 80% in yield).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Cl-].[Li+]>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>[CH2:14]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1)[CH:13]=[CH2:12]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1)COC2=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
5-bromo-2-benzofuran-1(3H)-one (6.68 g, 31.4 mmol) was combined with allyltributylstannane (12.5 g, 37.6 mmol), Pd(PPh3)4 (1.09 g, 0.941 mmol), and lithium chloride (2.66 g, 62.7 mmol) in toluene (100 mL) and the mixture was purged with nitrogen gas. The reaction mixture was then stirred at 100° C. for 4 h. The mixture was cooled to room temperature, filtered, and concentrated. The crude residue was purified by MPLC eluting in stepwise fashion with hexanes, then 10% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes. 1H-NMR (500 MHz, CDCl3): δ ppm 7.87 (d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.35 (s, 1H), 5.96-6.04 (m, 1H), 5.32 (s, 2H), 5.15-5.20 (m, 2H), 3.55 (d, J=6.5 Hz, 2H).