Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br.CCCCCC.C(OC(=O)C)C>CN(C)C=O>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: OCCCO
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCCCOCc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.8 %

Procedure:
3.7 g(49 mmol) of 1,3-propandiol was dissolved in 50 ml of dimethylformamide and cooled to 0° C. 2 g(50 mmol) of 60% sodium hydride dispersed in mineral oil was added slowly. After the mixture was stirred for 10 minutes, 10 g(49 mmol) of 2-chlorobenzyl-bromide dissolved in 10 ml of dimethyformamide was added slowly. After stirring for one hour at room temperature, dimethylformamide was removed under reduced pressure, 100 ml of ethylacetate was added to the residue and the organic layer was washed with saturated sodium chloride solution (100 ml×3). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography(eluent: n-hexane/ethylacetate=4/1, v/v) to give 3.52 g(Yield 35.8%) of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.CCOC(C)=O>C(Cl)Cl>[Br:20][C:13]1[CH:12]=[C:11]([C:8]([CH3:10])([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:18])[CH3:19])[CH:16]=[CH:15][C:14]=1[NH2:17]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 4-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-phenylamine (as prepared in the previous step, 1.41 g, 5.04 mmol) in 25 mL of DCM at 0° C. was slowly added N-bromosuccinimide (NBS) (898 mg, 5.04 mmol) in three portions over five minutes. After stirring at RT for 2 h, the mixture was treated with 50 mL of EtOAc and washed with H2O (2×30 mL) and brine H2O (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (DCM) to give 1.59 g (88%) of the title compound as a light yellow oil. Mass spectrum (ESI, m/z): Calcd. for C16H28BrNOSi, 358.1 (M+H). found 358.4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])(C)([CH3:3])[CH3:2]>Cl.O1CCOCC1>[CH:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reaction time: 3 h
Yield: 5.3 %

Procedure:
2-(tert-Butoxycarbonyl)amino-5-trifluoromethylbenzoic acid (6.0 g) was dissolved in 4M HCl (4 mL) in dioxane. After 3 h, the solution was concentrated to a white solid. A portion of this material (200 mg) was dissolved in THF (2.5 mL) and 2M K2CO3 (1.46 mL) was added followed by cyclohexanecarbonyl chloride (0.2 mL). The reaction was stirred for 10 min before EtOAc was added. The EtOAc layer was washed with 1N HCl and brine before it was dried, filtered, and concentrated to a crude material. This material was crystallized with CH3CN to give the title compound (302 mg). MS found: (2M−1)−=629.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I:10]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: ClI
Solvent: CC(=O)O
Product: N#Cc1cc(I)ccc1N
Yield: 65 %

Procedure:
One general synthetic procedure for the methods of the present invention is depicted in Scheme 2 below. lodination of 2-aminobenzonitrile with iodine monochloride in glacial acetic acid (AcOH) at room temperature occurred regioselectively at the position para to the amino group to give 2-amino-5-iodobenzonitrile (9) in 65% yield as reported by others (Harris, N. V.; Smith, C.; Bowden, K. Eur. J. Med Chem. 1992; 27, 7-18). A catalytic amount (0.1 mmol) of commercially available [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)′CH2Cl2 [(dppf)PdCl2—CH2Cl2] (Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J. Am Chem. Soc. 1984, 106, 158-163) was added to a THF solution of the organozinc halide (5 mmol) resulting in the formation of a solution having a deep yellow color after a few minutes. After complete addition of (dppf)PdCl2 to the reaction mixture, a solution of aryl halide 9 (2 mmol) in THF was added to the reaction mixture and the mixture was then heated at reflux for 30 min. The cross-coupling reaction was complete by thin layer chromatography (TLC). The intermediate amino nitrile 10 formed by the cross-coupling reaction were purified by column chromatography on silica gel, and their identity and purity were established from their 1H NMR spectra, which contained the expected singlet at approximately δ 3.8, along with OMe, NH2, and aromatic proton peaks consistent with assigned structures (data provided below).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:23]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.O.NN>O1CCCC1.C(OCC)(=O)C>[NH2:23][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([OH:8])=[C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Temperature: 25 °C
Yield: 75.4 %

Procedure:
5-Chloro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenol (0.49 g) was dissolved in tetrahydrofuran (10 mL). To the solution was added hydrazine monohydrate (0.25 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.27 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.BrBr.[CH2:14]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>CO.O1CCOCC1>[CH3:10][CH:9]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)[CH:8]([OH:11])[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: CCC(=O)c1ccc(O)cc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.8 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 5 minutes. To the reaction liquid were then added 8.1 g of 4-benzylpyridine, 100 ml of methanol and 3.3 g of anhydrous sodium acetate, and the mixture was refluxed under heating for 5 hours. After refluxing the mixture, the reaction mixture was worked up in the same manner as described in Example 46, whereby 12.3 g (79.9%) of ifenprodil were obtained as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=3)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH:26]([C@H:28]([C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1)[CH3:29])[NH2:27].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[CH:17]=4)[N:26]([C@H:28]([C:30]3[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=3)[CH3:29])[N:27]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)NN)cc1
Reactant: COc1ccc2cc(C(=O)C#Cc3cc(Cl)cc(Cl)c3)cnc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2cnc3cc(OC)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step F (118 mg, 0.33 mmol) in DMF was added the ethyl 4-[(1S)-1-hydrazinoethyl]benzoate hydrochloride (89 mg, 0.36 mmol) and triethyl amine (55 μL, 0.39 mmol). After stirring the reaction mixture at room temperature for 18 hours it was concentrated in vacuo. The residue was diluted with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 25% ethyl acetate-hexanes. This material was then re-purified with 3% acetonitrile-dichloromethane to give the desired compound. 1H NMR (500 MHz, CDCl3): 8.76 (d, J=2.0 Hz, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.92 (1.8 Hz, 1H), 7.85 (d, J=1.8 Hz, 2H), 7.68 (d, J=8.9 Hz, 1H), 7.5 (d, J=2.1 Hz, 1H), 7.36 (t, J=1.8 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 6.76 (s, 1H), 4.42 (q, J=7.0 Hz, 1H), 4.03 (s, 3H), 2.04 (s, 3H), 2.01 (t, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). LC-MS: 4.28 min; (M+H)=546.0.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:27]=[CH:26][C:10]([CH2:11][C:12]2[O:13][C:14]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[C:18]([OH:25])[C:15]=3[C:16]=2[CH3:17])=[CH:9][CH:8]=1.Cl[CH:29]([O:31]C)Cl.O>ClCCl>[CH:29]([C:27]1[CH:26]=[C:10]([CH:9]=[CH:8][C:7]=1[O:6][CH3:5])[CH2:11][C:12]1[O:13][C:14]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[C:18]([OH:25])[C:15]=2[C:16]=1[CH3:17])=[O:31]
Reactant: COC(Cl)Cl
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc2oc(Cc3ccc(OC)c(C=O)c3)c(C)c2c1O
Temperature: 0 °C
Yield: 36.9 %

Procedure:
To a suspension of aluminium chloride (214 mg; 1.6 mmole) in dichloromethane (5 mL) cooled at 0° C. was added 2-(p-methoxy-benzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran (100 mg; 0.32 mmoles). A red solution resulted. To this solution was added dropwise dichloromethylmethylether (87 Σl; 0.96 mmole). There was a vigorous reaction and a color change from red to green was observed. Ice and water was then added and the mixture was extracted with ethylacetate. The organic phase was dried (Na2SO4), and concentrated in vacuo and the residue was chromatographed on silica gel. Elution with 10% ethylacetate in hexane yielded 40 mg (37%) of 2-(3-formyl-4-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:9]([OH:11])[OH:10].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:9]([OH:10])[OH:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C)c1B(O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CBr)c1B(O)O

Procedure:
2,6-dimethylphenylboronic acid (2.22 g, 14.8 mmol), NBS (1.31 g, 7.36 mmol, 0.5 eq) and AIBN (0.17 g, 1.0 mmol. 0.07 eq) were heated in refluxing CCl4 for 2 hours. The solution was allowed to cool then filtered. The solution was then washed with water (50 mL), dried over Na2SO4 and the solvent evaporated in vacuo. The resulting white powder (1.66 g) was ˜84% pure by HPLC and contained starting material and some di-brominated product. Column chromatography on silica gel 60 (elution conditions 0%-2% methanol in dichloromethane) failed to improve the purity and the crude material was used for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH2:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=[C:6]([C:15]([O:17]CC)=[O:16])[C:5]=1[C:20]1[C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][C:23]([O:31][CH3:32])=[C:22]2[O:33][CH2:34][O:35][C:21]=12)[CH3:2].[OH-].[K+].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH2:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]=1[C:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]([O:31][CH3:32])=[C:22]2[O:33][CH2:34][O:35][C:21]=12)[CH3:2]
Reactant: CCOC(=O)c1cc(OC)c(OCC)c(OCC)c1-c1c(C(=O)OCC)cc(OC)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1c(OC)cc(C(=O)O)c(-c2c(C(=O)O)cc(OC)c3c2OCO3)c1OCC
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
In 4 ml of dioxane was dissolved 49 mg of diethyl 2,3-diethoxy-4,4'-dimethoxy-2',3'-methylenedioxy-1,1'-biphenyl-6,6'-dicarboxylate obtained in Example 6, and 1 ml of a 5% aqueous solution of potassium hydroxide was added to the solution. The mixture was heated at 70° C. and stirred overnight. The pH value was adjused to 1 to 2 by 3N hydrochloric acid, the reaction mixture was extracted with chloroform, and the solvent was removed from the extract to obtain 38 mg of 2,3-diethoxy-4,4'-dimethoxy-2',3'-methylenedioxy-1,1'-biphenyl-6,6'-dicarboxylic acid having the following physical properties (the yield was 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]=[O:13].C1(C)C=CC=CC=1>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][OH:13])[C:6](=[O:11])[CH2:5]2
Reactant: C=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C1Cc2cc(Cl)ccc2N1CO
Temperature: 25 °C

Procedure:
In an high pressure autoclave, 5-chloro-1,3-dihydro-indol-2-one (5 g, 0.029 mol), paraformaldehyde (1.07 g) and toluene (60 ml) are heated up to 120° C. for 4 h. The mixture is cooled down to room temperature, diluted with ether and filtrated to give 5-chloro-1-hydroxymethyl-1,3-dihydro-indol-2-one a22 as white crystals (4.03 g, 70%).
Reaction SMILES: [F:1][CH:2]([F:10])[N:3]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[N:4]1.[Br:11][C:12]1[CH:17]=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:15](I)=[CH:14][N:13]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:12]1[N:13]=[CH:14][C:15]2[CH:9]=[C:8]([C:6]3[CH:5]=[N:4][N:3]([CH:2]([F:10])[F:1])[CH:7]=3)[N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[C:16]=2[CH:17]=1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Reactant: C#Cc1cnn(C(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)n1c(-c2cnn(C(F)F)c2)cc2cnc(Br)cc21
Temperature: 60 °C
Yield: 34.3 %

Procedure:
1-(Difluoromethyl)-4-ethynyl-1H-pyrazole (Preparation 152, 187 mg 1.31 mmole) was dissolved in DMF (4.2 mL) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (Preparation 8, 444 mg 1.17 mmole) was added. To the solution was added triethylamine (0.80 mL, 576 mg 5.7 mmole) and copper(I) iodide (9 mg 0.047 mmole). The reaction was sealed and flushed with nitrogen. Bis(triphenylphosphine)palladium dichloride (37.6 mg 0.046 mmole) was added and the reaction was again flushed with nitrogen, then heated at 60° C. for 140 minutes. The reaction was added to ethyl acetate (45 mL) and washed with water (3×15 mL) and with brine, then dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with 5% ethyl acetate in chloroform to afford the title compound 157 mg. 1H-NMR (d6-acetone, 500 MHz): δ 3.37 (s, 3H), 7.06 (d, J=0.63 Hz, 1H), 7.70 (t, J=59.6 Hz, 1H), 8.04 (s, 1H), 8.16 (m, 1H), 8.51 (s, 1H), 8.73 (d, J=0.95 Hz, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38]([NH:41][C:42]1[CH:47]=[CH:46][C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=1)(=[O:40])=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:45]2[CH:44]=[CH:43][C:42]([NH:41][S:38]([CH3:37])(=[O:39])=[O:40])=[CH:47][CH:46]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 89 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 4-(methanesulfonylamino)phenyl boronic acid pinacol ester (0.21 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded N-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-methanesulfonamide (130 mg, 96%) as a white solid: LC/MS m/e calcd for C27H27N3O4S2 [M+H]+ 522.66, observed 522.3.
Reaction SMILES: S(=O)(=O)(O)O.COCCOC[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([CH2:25][NH:26][CH2:27][C:28]1[CH:29]=[C:30]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41]4[CH:42]=[C:43]([CH:49]=[CH:50][CH:51]=4)[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:36][CH:35]=3)[CH:31]=[CH:32][CH:33]=1)=[O:24])[CH:17]=[CH:16]2>CO.O1CCCC1.C(OCC)(=O)C>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([CH2:25][NH:26][CH2:27][C:28]1[CH:29]=[C:30]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41]4[CH:42]=[C:43]([CH:49]=[CH:50][CH:51]=4)[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:36][CH:35]=3)[CH:31]=[CH:32][CH:33]=1)=[O:24])[CH:17]=[CH:16]2
Reactant: CCOC(=O)c1cccc(Nc2ccc(-c3cccc(CNCC(=O)c4ccc5cc(OCOCCOC)ccc5c4)c3)cc2)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(Nc2ccc(-c3cccc(CNCC(=O)c4ccc5cc(O)ccc5c4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.2 %

Procedure:
1 ml of concentrated sulfuric acid is added to a solution of 1.2 g (1.9 mmol) of ethyl 3-[3′-({[6-(2-methoxyethoxymethoxy)naphthalene-2-carbonyl]methylamino}methyl)biphenyl-4-ylamino]benzoate in 10 ml of methanol and 10 ml of tetrahydrofuran. The reaction medium is stirred at room temperature for 6 hours, diluted with ethyl acetate and washed with water. After extraction, the organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture. 1 g of ethyl 3-(3′-{[(6-hydroxynaphthalene-2-carbonyl)methylamino]methyl}biphenyl-4-ylamino)benzoate is obtained in the form of a beige-colored foam, in a yield of 80%.
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[N:12]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.C1(N2C3N=C(S(C)=[O:36])N=CC=3C(C)=C(I)C2=O)CCCC1>>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:5]2[N:6]=[C:7]([S:10]([CH3:11])=[O:36])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: Cc1c(I)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: CSc1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Product: CS(=O)c1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1

Procedure:
Prepared from 6-bromo-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one following the procedure described for 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one. MS (APCI) Calc'd for C13H14BrN3O2S: 357, 355.0. Found: 358 (M+1), 356. 1H NMR δ (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.63 (s, 1H), 5.91 (m, 1H), 2.89 (s, 3H), 2.15 (br s, 2H), 2.04 (br s, 2H), 1.87–1.79 (m, 2H), 1.61–1.58 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][C@@H:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20]>>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([NH:17][C@@H:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[O:15])[CH3:12])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: CCC[C@H](N)C(=O)OC
Agent: Cl
Product: CCC[C@H](NC(=O)[C@H](C)NC(=O)Cc1ccccc1)C(=O)OC

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and methyl 2-(S)-aminopentanoate hydrochloride (prepared from L-2-aminovaleric acid (Bachem) using General Procedure H (without extractions)), the title compound was prepared as a solid (mp=135-137° C.). The reaction was monitored by tlc (Rf=0.30 in 50% EtOAc/hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:31])([F:30])[C:12]3[N:17]=[N:16][C:15]([NH:18]CC4C=CC(OC)=CC=4OC)=[CH:14][CH:13]=3)=[N:9][N:10]=2)[CH:7]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:31])([F:30])[C:12]3[N:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: COc1ccc(CNc2ccc(C(F)(F)c3nnc4ccc(Br)cn34)nn2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(F)(F)c2nnc3ccc(Br)cn23)nn1
Yield: 95.8 %

Procedure:
A solution of 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-N-(2,4-dimethoxybenzyl)pyridazin-3-amine (16.5 g, 33.6 mmol) and anisole (5.45 g, 50.4 mmol) in TFA (150 mL) was stirred at 70° C. for 30 min. The reaction was concentrated to dryness via rotary evaporation and the resulting residue was sonicated in a solution of Et2O/NaHCO3 (pH=7). The resulting solid was collected by filtration, rinsed with water and then Et2O, and dried in vacuum over P2O5 to provide the title compound, 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)pyridazin-3-amine 45H (11.0 g, 32.2 mmol, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.14 (d, J=9.35 Hz, 1 H) 7.71 (dd, J=9.85, 1.77 Hz, 1 H) 7.92 (d, J=9.35 Hz, 1 H) 7.92 (d, J=10.20 Hz, 1 H) 8.02 (d, J=10.20, 1 H) 8.74 (s, 1 H). ESI-MS:m/z 340.9 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:36])([F:35])[C:11]1[CH:12]=[C:13]([CH2:21][O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][C@H:24]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([O:22][CH2:21][C:13]2[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=[C:11]([C:10]([F:9])([F:35])[F:36])[CH:12]=2)[C@@H:24]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3ccccc3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
Benzyl bromide (0.134 ml) was added to a mixture of (+)-cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl piperidine (prepared from the hydrochloride salt, Example 5) (0.5 g) and potassium carbonate (0.468 g) in N,N-dimethylformamide (2 ml) and the mixture stirred at 23° C. for 2.5 h. Water (20 ml) was added and the mixture extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (1×10 ml) and brine (1×10 ml) then dried (K2CO3) and concentrated to leave an oil. Purification on silica gel eluting with hexanes-ethyl acetate (19:1 then 9:1 then 4:1 then 1:1) provided the title compound as a solid, m.p.=89°-93° C. Found: C, 66.11; H, 5.25; N, 2.81. Calcd. for C27H25NOF6 ; C, 65.71; H, 5.11; N, 2.84%.