Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:27])[CH:21]=1.[C:28]([O-])([O-])=O.[K+].[K+].C(I)I>CN(C=O)C>[O:26]1[C:23]2[CH:24]=[CH:25][C:20]([CH2:19][C:3]3[CH:4]=[C:5]([C@H:8]4[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]4)[CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:21][C:22]=2[O:27][CH2:28]1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)c(O)c3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ICI
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 100 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(3,4-dihydroxybenzyl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol (E055) (30 mg, 0.0756 mmole) in DMF (4 mL) were added K2CO3 and CH2I2 (7.3 μL). The reaction mixture was stirred at 100° C. overnight and filtered. The resulting crude solution was purified by reverse phase preparative HPLC to yield the title compound (16 mg, 0.0401 mmole, 53%) as a brown gum.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12]C(=O)[S:10][C:9]=2[CH:14]=1.Cl>C(O)C>[SH:10][C:9]1[CH:14]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=1[OH:12]
Reactant: COc1ccc2oc(=O)sc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(O)c(S)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Aqueous 2 N sodium hydroxide solution (44.7 mL) was added to an ethanol solution of the compound (7.76 g, 42.6 mmol) synthesized in the above (1), and stirred in a nitrogen atmosphere at 65° C. for 1.5 hours. The reaction liquid was neutralized with aqueous 5 N hydrochloric acid solution, and extracted twice with chloroform. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure to obtain the entitled compound (7.4 g, 100%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=O.[CH:21]1([C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27])[CH2:23][CH2:22]1.C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:26]([CH3:27])[C:25]([C:24]([CH:21]1[CH2:23][CH2:22]1)=[O:29])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cc(Br)ccc2N)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Reaction time: 16 h
Yield: 47 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-(4-methanesulfonyl-phenyl)-methanone [example A15] and 1-cyclopropyl-1,3-butanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 47%; MS: m/z=443 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[CH3:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[C:18]([CH3:20])[CH:19]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:21]([C:16]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH3:13])[CH:15]=2)(=[O:23])=[O:22])[N:3]=1
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Reactant: Brc1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(S(=O)(=O)n2nc(Br)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.3 %

Procedure:
3-bromo-1H-indazole (3 gram; 15 mmol) was dissolved in 30 ml DMF, followed by the addition of sodiumhydride (850 mg, 21 mmol). After stirring for 20 min at room temperature, 3,5-dimethylbenzene-1-sulfonyl chloride (4.4 gram, 21 mmol) was added and the reaction mixture was stirred for another 2 h at room temperature. The reaction was quenched by the addition of water and the formed solids were filtered off and washed with little methanol. The solids were dried to obtain 3-bromo-1-(3,5-dimethylphenylsulfonyl)-1H-indazole (2.1 gram) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](=[N:11]/[S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/C.[F:18][C:19]([Si](C)(C)C)([F:21])[F:20]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:11][S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[C:19]([F:21])([F:20])[F:18]
Reactant: C/C(=N\[S@@](=O)C(C)(C)C)c1ccc(F)cc1Br
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@H](c1ccc(F)cc1Br)C(F)(F)F
Temperature: -60 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Add tetrabutylammonium triphenyldifluorosilicate (29.8 g, 55.19 mmol) to a stirring mixture of (S,E)-N-(1-(2-bromo-4-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (13 g, 42.46 mmol) in THF. Cool the mixture to about −60° C. and add the (trifluoromethyl)trimethylsilane over about 10 min. Warm up to −55° C. and stir for 2 h. Continue to warm up to 0° C. Cool the mixture back to −30° C., and quench with saturated NH4Cl (150 mL). Extract product into ethyl acetate (2×200 mL). Combine extracts, wash with aqueous saturated sodium chloride, dry over Na2SO4, filter, and concentrate. Purify the material on 700 g silica eluting with 8:2 to 1:1 hexanes:ethyl acetate to a crude material. Crystallize the material to give long needles (9.7 g, 91%). MS (ES) m/z 377 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]([OH:20])[CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21]
Reactant: CC[C@@H](Nc1cccc(C(C)O)c1)c1ccc(Cl)c(C)c1
Solvent: ClCCl
Product: CC[C@@H](Nc1cccc(C(C)=O)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of INT 10 (446 mg, 1.47 mmol) in CH2Cl2 was added DMP (747 mg, 1.76 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous NaHCO3/saturated aqueous Na2S2O3 5/1 and diluted with CH2Cl2. The mixture was stirred vigorously until the organic layer was clear. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/CH2Cl2) to afford INT 11.
Reaction SMILES: [F:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[CH2:17][CH3:18]>>[CH2:16]([C:10]1[CH:9]=[CH:8][C:7]2[C:6]3[C:14](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[CH2:13][C:12]=2[C:11]=1[F:15])[CH2:17][CH3:18]
Reactant: Fc1cccc2c1Cc1c(F)cccc1-2
Reactant: CCC=O
Product: CCCc1ccc2c(c1F)Cc1c(F)cccc1-2

Procedure:
The reaction of 1,8-difluorofluorene with propionaldehyde is effected in a similar manner to the procedure described in Example 2. 2-Propyl-1,8-difluorofluorene is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][NH2:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)S[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:20].O[O:22][S:23]([O-:25])=O.[K+]>CO.O>[CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][NH2:19])[C:13]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:23](=[O:25])(=[O:22])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1ccc2c(c1C)N(CCCN)c1ccccc1S2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1C)N(CCCN)c1ccccc1S2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To 20 ml of a solution of 870 mg of 1,2-dimethyl-10-(3-aminopropyl)phenothiazine obtained in Example 1 in methanol was added an aqueous solution of 3.7 g of oxone in 20 ml of water and the resulting mixture was stirred at room temperature for 30 min. After evaporating the solvent, the residue was purified by silica gel column chromatography to give 200 mg of the title compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:15][CH2:14][C:11]3([O:13][CH2:12]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)CC(=O)C>O>[OH:13][C:11]1([CH2:12][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)[CH2:14][CH2:15][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A mixture of 37.5 parts of 6-(phenylmethyl)-1-oxa-6-azaspiro[2.5]octane, 24.9 parts of ethyl 4-hydroxybenzoate, 20.7 parts of potassium carbonate and 200 parts of 4-methyl-2-pentanone was stirred overnight at reflux temperature. After cooling, water was added. The precipitated product was filtered off, washed with water and crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 23 parts (41.5%) of ethyl 4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methoxy]benzoate; mp. 100.2° C. (int. 78).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cccnc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1cc(F)c(O[C@H]2CCCC[C@@H]2c2cccnc2)cc1F
Yield: 90.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-pyridin-3-ylcyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.11 g, 0.19 mmol) prepared in Example 39c, triethylsilane (0.15 mL), trifluoroacetic acid (0.19 g) and dichloromethane (1.9 mL), to yield the title compound (77 mg, 92%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>C1COCC1>[N+:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[O:3][C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccncc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Sodium hydride (492.0 mg, 12.30 mmol) was added to a solution of tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (2.095 g, 10.41 mmol) in THF (20 mL) and the reaction stirred at 0° C. for 15 minutes. A suspension of 4-chloro-3-nitro-pyridine (1.5 g, 9.461 mmol) in THF (10 mL) was added and the reaction allowed to warm slowly to ambient temperature over 2 hours. The reaction was quenched with water and the mixture was partitioned between EtOAc and brine. The combined organic extract was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 100% EtOAc/Petroleum Ether) to give tert-butyl (3S)-3-[(3-nitro-4-pyridyl)oxy]piperidine-1-carboxylate as a pale yellow solid (2.65 g, 87% Yield, 93% ee). MS (ES+) 324.1.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:24]([OH:26])=[O:25])=[CH:16][CH:17]=[C:18](SC)[C:19]=2C#N)=[CH:10][CH:9]=1.C1CCN2C(=NCCC2)CC1.ClS(C(C)C)(=O)=O.[OH-].[Na+]>CO.ClCCl.CO.C(Cl)Cl>[C:14]1([C:11]2[CH:12]=[CH:13][C:8]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:9][CH:10]=2)[C:15]([C:24]([OH:26])=[O:25])=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CSc1ccc(C(=O)O)c(-c2ccc(-c3ccccc3N)cc2)c1C#N
Agent: CC(C)S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1ccccc1-c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
Mix 2″-Amino-6-cyano-5-methylsulfanyl-[1,1′;4′,1″]terphenyl-2-carboxylic acid (0.195 g, 0.521 mmol) and dichloromethane (6 ml) then cool to 0° C. Next add DBU (0.33 ml, 2.162 mmol), and ClSO2CH(CH3)2 (0.13 ml, 1.128 mmol) drop wise to the solution and stir for 16 hours. If TLC shows remaining SM, add DBU (0.3 ml) and ClSO2CH(CH3)2 (0.1 ml) and stir for 16 hours. Dilute the reaction with CH2Cl2 (50 ml) and wash with H2O, satd aq. sodium chloride, dry with Na2SO4, and concentrate under reduced pressure. Analyze by TLC and if reaction has remaining SM add MeOH (2 ml) and 1N NaOH (1 ml, 1 mmol). Heat to reflux for 6 hours. Add 1N HCL (1 ml, 1 mmol) and extract into dichloromethane. Purify the reaction by flash chromatography (Silica gel -dichloromethane then up to 10% MeOH/dichloromethane), to give 6-Cyano-5-methylsulfanyl-3″-propane-2-sulfonylamino)-[1,1′;4′,1″]terphenyl-2-carboxylic acid (0.008 g). MS (m/e): 467(M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:28])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.Cl.CO>[NH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:28])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
1,1-dimethylethyl {1-[2-(7-fluoro-2-oxo-1(2H)-quinolinyl)ethyl]-4-piperidinyl}carbamate (1.32 g; 3.39 mmol) was dissolved in a mixture of chloroform (10 ml) and HCl (12 ml) and stirred at rt under argon for 1 h. The salts were then dissolved in MeOH and all solvents removed. The residues were redissolved in MeOH and stirred with amberlyst ion exchange resin until a neutral pH was reached. This was then filtered and the solvent removed. The crude residue was subjected to chromatography on silica gel using a 0-20% 2M NH3:MeOH/DCM gradient to provide the desired compound (632 mg; 64%)
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([N:16]([CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:40])=[O:5])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)(=[O:30])=[O:31])=[CH:37][CH:36]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(-c3nccs3)cc2)Cc2cccc(OCC(=O)OC(C)(C)C)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(-c3nccs3)cc2)Cc2cccc(OCC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-{[(4-methoxy-benzenesulfonyl)-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester of Step A in CH2Cl2 (2 mL) at 0° C. was added cold TFA (1 mL) and the reaction was stirred at room temperature for 1 h. The reaction was concentrated using a stream of nitrogen. Additional CH2Cl2 (1 mL) was added and the solution was concentrated using a stream of nitrogen. This procedure was repeated and the residue was dried in vacuo to provide the title compound (24.6 mg). MS 524 (M−1).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[C:24](=[O:25])[CH:23]=[C:22](I)[CH:21]=[N:20]1)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.[CH3:27][S:28][C:29]1[N:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[CH:32]=[CH:31][N:30]=1>CN1C(=O)CCC1.C(OCC)(=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>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:31]3[CH:32]=[CH:33][N:34]=[C:29]([S:28][CH3:27])[N:30]=3)[CH:21]=[N:20]2)[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ncc(I)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CSc1nccc(-c2cnn([C@H](CO)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A solution of (S)-2-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-5-iodopyridazin-3(2H)-one (0.402 g, 0.790 mmol), 2-(methylthio)-4-(tributylstannyl)pyrimidine (0.361 g, 0.869 mmol), copper(I) iodide (0.0150 g, 0.0790 mmol) and PdCl2(PPh3)2 (0.0555 g, 0.0790 mmol) in NMP (4 mL) was heated to 120° C. under Ar for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The organics were washed with brine (3×50 mL), dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (1:1) to give (S)-2-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-(2-(methylthio)pyrimidin-4-yl)pyridazin-3(2H)-one (0.25 g, 79%). m/z (APCI-pos) M+1=393.0, 395.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[C:5]([C:7]1[CH:8]=[C:9]([NH:13]C(C2C=CN3C=2CSC3C2C=NC=CC=2)=O)[CH:10]=[CH:11][CH:12]=1)=[O:6].COC1C=CC=CC=1C(C1C=CC=C([N+]([O-])=O)C=1)=O.[OH-].[Na+]>C(O)C>[NH2:13][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[C:4]2[CH:30]=[CH:31][CH:32]=[CH:33][C:3]=2[O:2][CH3:1])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccccc1C(=O)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Agent: COc1ccccc1C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1C(=O)c1cccc(N)c1
Temperature: 62 °C
Reaction time: 16 h

Procedure:
The 3'-amino-2-methoxybenzophenone may be prepared as follows: Stannous chloride in the dihydrate form (10.3 g) is added, at a temperature between 62° and 66° C., to a suspension of 2-methoxy-3'-nitrobenzophenone (3.9 g) in a mixture of ethanol (40 cc) and concentrated (11.7N) hydrochloric adid (15.2 cc) which is heated to a temperature in the vicinity of 62° C., in the course of 5 minutes. The solution obtained is heated at a temperature in the vicinity of 80° C. for 4 hours, treated with stannous chloride in the dihydrate form (1 g) and heated at a temperature in the vicinity of 80° C. for a further period of 1 hour and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue is dissolved in distilled water (40 cc) and the solution obtained is adjusted, while maintaining the temperature in the vicinity of 10° C., to a pH in the region of 13 by adding an aqueous 10N sodium hydroxide solution (50 cc) and then extracted 3 times with methylene chloride (150 cc in total). The organic extracts are combined, washed twice with distilled water (200 cc in total), dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa at a temperature in the vicinity of 40° C. 3'- Amino-2-methoxybenzophenone (3.4 g) in the form of greenish yellow crystals, m.p. 81° C., is thereby obtained.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[CH:21]1([CH2:24][O:25][C:26]2[CH:31]=[C:30](O)[CH:29]=[CH:28][C:27]=2[CH2:33][CH2:34][C:35]([O:37]C)=[O:36])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][O:25][C:26]2[CH:31]=[C:30]([O:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:8][CH:9]=3)[CH:29]=[CH:28][C:27]=2[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:22][CH2:23]1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1OCC1CC1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(OCC3CC3)c2)cc1)c1ccccc1
Yield: 4.2 %

Procedure:
Compound 58 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.656 g, 2.4 mmol) and methyl 3-[2-(cyclopropylmethoxy)-4-hydroxyphenyl]propanoate (0.6 g, 2.4 mmol) by following the procedure described in scheme 18 (0.04 g, yield: 4.20%); Purity: 98.15%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55]C(OC(C)(C)C)=O)[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH2:55])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reaction time: 1 h

Procedure:
[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.211 g, 0.244 mmol) was dissolved in DCM (2.439 mL). HCl in dioxane (4N, 0.610 mL, 2.44 mmol) was added at room temperature and the resulting solution was stirred for approximately one hour. Upon completion, the reaction was concentrated in vacuo to giving [1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester as a white solid (assumed 0.244 mmol) that was used without further purification in subsequent reactions. LCMS-ESI+: calc'd for C45H48N8O4: 764.43 (M); Found: 765.31 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][C:13]([C:16]3[CH:21]=[C:20]([Br:22])[C:19]([O:23]CC4C=CC(OC)=CC=4)=[C:18]([Br:33])[CH:17]=3)=[N:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][C:13]([C:16]3[CH:21]=[C:20]([Br:22])[C:19]([OH:23])=[C:18]([Br:33])[CH:17]=3)=[N:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(COc2c(Br)cc(C3=NN(C(=O)c4ccc(Cl)c(Br)c4)CC3)cc2Br)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(Cl)c(Br)c1)N1CCC(c2cc(Br)c(O)c(Br)c2)=N1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66.6 %

Procedure:
To a stirred solution of (3-bromo-4-chlorophenyl)(3-(3,5-dibromo-4-(4-methoxybenzyloxy)phenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone (F) (51.8 mg, 0.0788 mmol) in anhydrous dichloromethane (5 ml) under nitrogen was added trifluoroacetic acid (0.1 mL) and the solution was stirred at room temperature for 1 h 40 min. The solvent was evaporated and more dichloromethane was added to the residue and evaporated. The residue was then recrystallised from EtOAc-CH2Cl2 and the resulting solid was collected by filtration, washed with 50% EtOAc/pet. ether and dried at 55° C. under vacuum to leave 28.2 mg (67%) of the title compound as a light-brown solid. 1H NMR δ (ppm) (DMSO-d6): 4.13 (2 H, t, J=9.8 Hz), 7.81 (1 H, d, J=8.4 Hz), 7.86 (2 H, s), 7.86-7.93 (1 H, m), 8.24 (1 H, d, J=2.0 Hz), 10.62 (1 H, br s). LCMS (10 cm_apci_formic) Rt 4.29 min; m/z 535/537/539/541/543 [M+H].