Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]#[N:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2([C:14]#[N:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C2(C#N)CCCCC2)cc1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A suspension of sodium hydride (0.3 g, 7.5 mmol, 60% dispersion in oil) in THF (9 mL) was cooled to 0° C. and treated slowly with 2-(3,4-dimethoxyphenyl)acetonitrile (0.532 g, 3 mmol) in THF (3 mL). After stirring for 15 min at this temperature 1,5-dibromopentane (0.49 mL, 3.6 mmol) in THF (3 mL) was added, the bath was removed, and the reaction was left stirring at room temperature for 18 h. The reaction was quenched with saturated aqueous ammonium chloride, extracted with EtOAc and washed with brine. The organic layer was dried (MgSO4), filtered and concentrated to provide 1-(3,4-dimethoxyphenyl)cyclohexanecarbonitrile, which was used without further purification in the next step. MS (ESI) m/z 246 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]#[N:25])[CH:21]=2)[NH:16][CH:15]=1.C[OH:27].C(Cl)Cl>>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([NH2:25])=[O:27])[CH:21]=2)[NH:16][CH:15]=1
Reactant: CO
Reactant: N#CCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Solvent: ClCCl
Product: NC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
TLC Polygram silica, 5% methanol/methylene chloride showed a single new product with Rf 0.13 identical with that of a sample prepared by the method of Example 2 (ii).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[C:6]([F:8])[CH:7]=1.[Li+].[OH-]>>[NH2:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1nc(-c2c(F)cccc2F)c(F)cc1N
Agent: [Li+]
Agent: [OH-]
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Yield: 79 %

Procedure:
Method 2 was followed using methyl 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinate (1.0 equiv.) and LiOH (1.0 equiv.) to give 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid in 79% yield. LCMS (m/z): 269.0 (MH+), Rt=0.79 min.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:32])[C:18]([OH:31])([C:23]3[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:33])[CH:12]=2)=[CH:6][CH:5]=1.Cl>O1CCOCC1>[Cl:33][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[CH:17]([CH3:32])[C:18]([OH:31])([C:23]1[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=1)[C:19]([F:20])([F:22])[F:21])[O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:34])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(c1ccc(Oc2ccc(C(=O)O)cc2)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of 4-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-phenoxy}-benzoic acid methyl ester (22 mg) in dioxane (0.65 ml) was added conc. aqueous HCl (88 mg). The mixture was stirred at 100° C. for 1 h. The mixture was concentrated to dryness. The residue was dissolved in tetrahydrofuran (0.1 ml) and methanol (0.1 ml). 2 M aqueous NaOH solution (0.22 ml) was added and the mixture was stirred at room temperature for 2 h. The mixture was acidified with 2 M aqueous HCl. The organic solvents were evaporated. The precipitate was filtered, washed with water and dried to give the title compound as a colorless solid (15 mg). MS (m/e, ISP neg. ion)=466.0 [M−H+].
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[ClH:3].[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:25][C:17]2[CH:18]=[CH:19][C:20]3[NH:21][C:22]4[N:23]=[C:7]([NH:8][C:9]5[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=5)[CH2:14][CH2:15][C:16]=2[CH:24]=3)[N:6]=[CH:5][C:4]=4[Cl:3])=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)c1ccc(Cl)cc1
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and 4-chlorobenzoyl chloride as the starting materials in 66% yield. LCMS for C25H20Cl2N5O (M+H)+: m/z=476.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.Cl[C:13]1[C:18]2[N:19]=[CH:20][S:21][C:17]=2[CH:16]=[CH:15][CH:14]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd].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>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:13]2[C:18]3[N:19]=[CH:20][S:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Clc1cccc2scnc12
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(-c2cccc3scnc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
a 500 mL 2-neck round-bottomed flask was equipped with a reflux condenser and replaced by nitrogen. 70 mL of THF that was dried with 0.11 mol of Mg metal was added to the above flask and then, 0.10 mol of 1-bromo-4-(trifluoromethyl)benzene was added in a dropwise fashion. The reaction was significantly exodermic and thus a cooling bath was equipped to reduce the temperature inside the reactor less than 50° C. It was agitated for 2 hours at room temperature, 0.11 mol of zinc chloride was added with 100 mL of THF, and further agitated for 2 hours to obtain a slurry-phase reaction mixture. Another flask was replaced by nitrogen and then 4-chlorobenzothiazole derivative (0.10 mol), Pd (0.10 mol), and Pd(PPh3)4 (3 mol %) were dissolved in 100 mL of THF. The prepared solution was added to the reaction mixture and then agitated at 60° C. for 24 hours. After the reaction is complete, the resulting product was placed on a silica gel column to remove an inorganic slurry, and then a THF solution was concentrated under vacuum to obtain 4-(4-(trifluoromethyl)phenyl)benzo[d]thiazole at a yield of 91% using column chromatography.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)O1>>[F:11][C:4]1[CH:3]=[C:2]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]#[N:10]
Reactant: N#CCc1ccc(Br)cc1F
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: N#CCc1ccc(-c2ccc(O)cc2)cc1F

Procedure:
According to a method similar to Example (8-1), from (4-bromo-2-fluorophenyl)acetonitrile (3.0 g, 14 mmol) obtained in Example (11-1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.45 g, 14 mmol), (3-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl)acetonitrile was obtained as a colorless solid (2.9 g, yield: 91%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[N:8]1[N:12]2[CH2:13][CH2:14][CH2:15][NH:16][C:11]2=[C:10]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:9]=1>C(O)=O>[CH:1]([N:16]1[CH2:15][CH2:14][CH2:13][N:12]2[N:8]=[CH:9][C:10]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:11]12)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCc1cnn2c1NCCC2
Solvent: O=CO
Product: O=CN1CCCn2ncc(CCC(=O)O)c21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To formic acid (50 ml) was added acetic anhydride (60 ml), and the mixture was stirred at 40° C. for 2 hours. The resulting mixture was added to the above oily product [3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionic acid] and the mixture was stirred at room temperature for 15 hours. After evaporation of the solvent in vacuo, to the residue was added water. The mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and concentrated in vacuo. The residue was dissolved in methanol, and the insoluble materials were removed by filtration. The filtrate was concentrated in vacuo to give 3-(4-formyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionic acid (23 g) as an oil.
Reaction SMILES: C([Sn](=O)CCCC)CCC.C[Si]([N:15]=[N+:16]=[N-:17])(C)C.C[C:19]1[C:20]([CH:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=2)[CH:34]=[CH2:35])=[CH:21][C:22]2[C:23]([CH3:32])([CH3:31])[CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[C:27]=2[CH:28]=1.CC1(C)CCC(C)(C)C2C=C(C(C3C=CC(C#N)=CC=3)C=C)C=CC1=2>C1(C)C=CC=CC=1>[CH3:29][C:26]1([CH3:30])[CH2:25][CH2:24][C:23]([CH3:31])([CH3:32])[C:22]2[CH:21]=[C:20]([CH:33]([C:36]3[CH:43]=[CH:42][C:39]([C:40]4[NH:41][N:17]=[N:16][N:15]=4)=[CH:38][CH:37]=3)[CH:34]=[CH2:35])[CH:19]=[CH:28][C:27]1=2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C=CC(c1ccc(C#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: C=CC(c1ccc(C#N)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: C=CC(c1ccc(-c2nnn[nH]2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 110 °C
Yield: 48 %

Procedure:
Dibutyl tin oxide (15.1 mg, 10% mol) and 2 equivalents of trimethylsilyl azide (0.19 ml, 1.46 mmol), are added successively to a solution of the (E) compound 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]benzonitrile (0.24 g, 0.73 mmol) in anhydrous toluene (1.25 ml). The reaction medium is heated for 16 hours at reflux (110° C.) under an atmosphere of argon and with magnetic stirring. The mixture is purified by flash chromatography on silica (eluent CH2Cl2 then MeOH:CH2Cl2=5:95) to obtain, after evaporation, 0.13 g of a white powder (E) 5-[4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]phenyl]-1H-tetrazole (compound CB62458) (yield=48%).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([O:15][C:16]([F:19])([F:18])[F:17])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.ClCCCl.[Na]>O>[N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:23]3[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]3)=[C:9]([O:15][C:16]([F:19])([F:18])[F:17])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(N2CCOCC2)cc1OC(F)(F)F
Agent: [Na]
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A 40 mL vial was charged with 4-(morpholin-4-yl)-2-(trifluoromethoxy)benzaldehyde (400 mg, 1.45 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (270 mg, 1.45 mmol, 1.00 equiv), 1,2-dichloroethane (15 mL). The resulting solution was stirred for 1 h at room temperature. Sodium triacetoxyhydroborate (925 mg, 4.36 mmol, 3.00 equiv) was added. The resulting solution was stirred for 15 hours at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 15 mL of water. The resulting solution was extracted with dichloromethane (3×15 mL) and the organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 590 mg (91% yield) of tert-butyl 4-[[4-(morpholin-4-yl)-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 446 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10](C(OC)=O)[C:11]([O:13]C)=[O:12].[OH-].[Na+].C(O)C>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(CCc1ccccc1F)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCc1ccccc1F

Procedure:
Dimethyl 2-[2-(2-fluorophenyl)ethyl]malonate, sodium hydroxide (22.7 g), ethanol (150 ml) and water (100 ml) were heated under reflux for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was acidified with hydrochloric acid, and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-fluorophenyl)butanoic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:24])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][CH:10]=2)=[O:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28]
Reactant: CC(C)S(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To propane-2-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-amide (50, 40.0 mg, 0.087 mmol) in tetrahydrofuran (10 mL) was added Dess-Martin periodane (48.0 mg, 0.11 mmol). The reaction was stirred at room temperature for 5 minutes. The reaction was poured into sodium thiosulfate and potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% methanol in methylene chloride to give the compound (51, 13.4 mg, 33.5%). MS (ESI) [M+H+]+=458.1.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([C:10]#[N:11])=[N:8][CH:9]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:3][C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([C:10]#[N:11])=[N:8][C:9]=1[Br:1]
Reactant: N#Cc1ncc(N)cc1Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1nc(Br)c(N)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
Bromine (7.22 g) was added to a stirring mixture of 5-amino-3-chloro-2-cyanopyridine (4.61 g) and sodium acetate (4.81 g) in anhydrous acetic acid (150 mL) at room temperature. The mixture was stirred at 60° C. for 2 hours. The solvents and excess bromine were evaporated and the residue was recrystalliezed from ethyl acetate to give 5-amino-6-bromo-3-chloro-2-cyano-pyridine (6.23 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74]([C:77]#[C:78][C:79]2([O:85][Si:86]([CH3:89])([CH3:88])[CH3:87])[CH2:84][CH2:83][O:82][CH2:81][CH2:80]2)=[C:73]([CH3:90])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74]([C:77]#[C:78][C:79]4([O:85][Si:86]([CH3:87])([CH3:89])[CH3:88])[CH2:84][CH2:83][O:82][CH2:81][CH2:80]4)=[C:73]([CH3:90])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])=[CH:7][CH:6]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 34 mg, 0.146 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (62 mg, 0.294 mmol) and water (0.2 mL) were added to a solution of 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-4-trimethylsilanyloxy-tetrahydro-pyran (Example 130-(4); 56.1 mg, 0.098 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (43.5 mg, 74%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[C:5]2=[CH:4][CH:3]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:62][O:63][C:64]1[CH:71]=[CH:70][C:67]([CH2:68][NH2:69])=[CH:66][CH:65]=1>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:62][O:63][C:64]1[CH:71]=[CH:70][C:67]([CH2:68][NH:69][C:2]2[N:7]=[C:6]3[NH:8][CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[C:5]3=[CH:4][CH:3]=2)=[CH:66][CH:65]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(=O)c1c[nH]c2nc(Cl)ccc12
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Product: COc1ccc(CNc2ccc3c(C(C)=O)c[nH]c3n2)cc1
Temperature: 65 °C

Procedure:
The reaction was performed according to the protocol described in Org. Lett., 2010, 12(20), 4438-4441. A vial containing 1-(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (100 mg, 0.49 mmol), BrettPhos (2.62 mg, 4.88 μmol) and BrettPhos precatalyst (3.9 mg, 4.88 μmol) and a magnetic stir bar was sealed with a teflon screw-cap, evacuated and backfilled with argon. A balloon of argon was placed on top of the vial, to allow a pressure balance and LiHMDS (1 M in THF, 1172 μL, 1.17 mmol) was added, followed by 4-methoxybenzylamine (76 μL, 0.59 mmol). The reaction mixture was stirred and heated at 65° C. for 22 h, then allowed to cool to RT, quenched by the addition of 1 M HCl (1 mL) diluted with EtOAc and poured into a saturated aqueous solution of NaHCO3. After extracting twice with EtOAc, the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude was purified by flash column chromatography on silica gel (c-hexane to EtOAc). TLC, Rf (EtOAc)=0.75; MS (UPLC/MS): 296.2 [M+H]+, 591.3 [2M+H]+, 613.2 [2M+Na]+; tR (HPLC conditions f): 1.5 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[CH2:7]2>C1COCC1.[Ni]>[Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[CH2:7]2
Reactant: CN1CCc2c(Br)cc([N+](=O)[O-])c(N)c2C1
Agent: [Ni]
Solvent: C1CCOC1
Product: CN1CCc2c(Br)cc(N)c(N)c2C1
Reaction time: 2.5 h

Procedure:
A solution of the product from Example 60 (1.02 g, 3.49 mmol) in 50 mL THF was treated with Raney nickel (prewashed with acetone followed by THF), and the reaction vessel was purged with H2. After stirring for 2.5 hours, the catalyst was removed by filtration and the filtrate evaporated to give a tan oil. The product was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][CH2:19][CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:29][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][F:18])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCCCC(O)CF
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(CF)OC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 38.3 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.3 g) in methylene chloride (25 ml) was slowly added under ice cooling a solution of optically active 1-monofluoro-2-decanol (1.0g, [α]D20 =-7.2) and triethylamine (0.5 g) in methylene chloride (25 ml). The mixture was left to stand until it reached room temperature and stirred for 12 hours. The mixture was poured in ice water and extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in this order, and dehydrated over anhydrous magnesium sulfate. The solution was distilled under reduced pressure to remove the solvent until a crude product was obtained. The product was subjected to silica-gel column chromatography to obtain 1-monofluoro-2-decyl 4-benzyloxybenzoate (0.78 g). The benzoate and 10% palladium carried on carbon (0.13 g) were added to ethanol and then subjected to de-benzylation under a hydrogen atmosphere to obtain 1-monofluoro-2-decyl-4-hydroxybenzoate (0.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][NH:11][CH:12]([CH3:14])[CH3:13])=[O:9])[C:5]([NH:15][C:16]([C:18]2[N:19]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:20]=[C:21]([Br:23])[CH:22]=2)=[O:17])=[C:4]([CH3:31])[CH:3]=1.Cl[C:33]([O:35][CH3:36])=[O:34]>N1C=CC=CC=1>[CH3:36][O:35][C:33]([N:11]([CH:12]([CH3:13])[CH3:14])[NH:10][C:8]([C:6]1[C:5]([NH:15][C:16]([C:18]2[N:19]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:20]=[C:21]([Br:23])[CH:22]=2)=[O:17])=[C:4]([CH3:31])[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])=[O:34]
Reactant: Cc1cc(Cl)nc(C(=O)NNC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)N(NC(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [6-chloro-2-(N′-isopropyl-hydrazinocarbonyl)-4-methyl-pyridin-3-yl]-amide (12-a) (378 mg) was dissolved in pyridine (5 mL), methyl chloroformate (220 μL) was added and the reaction mixture was stirred at room temperature. After 30 min, 1 h and 1.5 h, methyl chloroformate (each 110 μL) was added. After 18 h stirring at room temperature, the reaction mixture was quenched with water and 3× co-evaporated with toluene. The residue was dissolved in water and ethyl acetate, the layers were separated and the aqueous layer was extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate=10:1, Rf=0.13) to afford 382 mg of the title compound (12) of the present invention of the formula