Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:11])[NH:9][OH:10])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:20][C:19]=1[O:34][CH2:35][C:36]([OH:38])=[O:37])(=[O:14])=[O:13].[CH2:39](O)[CH2:40][CH2:41][CH3:42].[ClH:44]>>[ClH:44].[CH2:39]([O:37][C:36](=[O:38])[CH2:35][O:34][C:19]1[CH:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([CH3:33])(=[O:32])=[O:31])[CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][NH:15][S:12]([C:3]1[CH:4]=[C:5]([C:8](=[NH:11])[NH:9][OH:10])[CH:6]=[CH:7][C:2]=1[OH:1])(=[O:13])=[O:14])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCO
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C(=N)NO)ccc2O)c(OCC(=O)O)c1
Agent: Cl
Product: CCCCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C(=N)NO)ccc1O

Procedure:
Method 2) A solution of 110 g of [4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetic acid in 1.00 L of 14% hydrogen chloride n-butanol solution was stirred at 100° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give 111 g of crude crystal. The crude crystal was recrystallized from n-butanol-diisopropyl ether to give 83.3 g of n-butyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate hydrochloride.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[C:8](=[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)[C:25]1[CH:30]=[CH:29]C=[CH:27][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:13]2[C:8](=[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]=1)(=[O:3])[C:2]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)OC1=CCc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Reactant: O=C(Cl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: O=C(OC1=CCc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To 500 mg of 3-acetyloxy-7-[(5-nitro-2-pyridinyl)oxy]-1H-indene, 5 ml of benzoyl chloride and 15 mg of p-toluenesulfonic acid were added and the mixture was stirred at 100° C. After 1.5 hours, ethyl acetate was added to the reaction solution and the solution was washed in turn with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution. The solution extracted with ethyl acetate was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (10:1)) to obtain 130 mg of the titled compound as a white powder.
Reaction SMILES: [K].[O-]CCCC.[Cl:7]/[C:8](=[CH:11]/[N:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:13])/[C:9]#[N:10].C(O)(=O)C>C1(C)C=CC=CC=1>[NH2:10][C:9]1[C:8]([Cl:7])=[CH:11][N:12]([CH3:13])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CN(C)/C=C(/Cl)C#N
Agent: CCCC[O-]
Agent: [K]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(N)c(Cl)cn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
Potassium ter.butoxide (0.5 g, 0.0044 mol) is placed in anhydrous toluene (300 ml). At ambient temperature, a solution of (E)-2-chloro-3-[[[(ethoxy)carbonyl]methyl](methyl)amino]-2-propene nitrile (58.0 g, 0.286 mol) (mp. 57° C.) in anhydrous toluene (200 ml) is added dropwise to the resulting suspension and the mixture is stirred for a further 30 minutes. It is then poured into ice water (1 liter), neutralized with acetic acid and then exhaustively extracted with dichloromethane. The combined extracts were dried over sodium sulphate and concentrated in vacuo. The residue remaining is recrystallized from diisopropyl ether/petroleum ether (1:1 v/v) and gives colorless crystals (50.0 g), m.p. 48° C.
Reaction SMILES: [OH-].[Na+].Cl.[CH:4]1([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[NH:15])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:16]([NH:21][CH2:22][CH2:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]>O.CC(C)=O>[C:16]([NH:21][CH2:22][CH2:23][C:24]1[S:28][C:27]([S:29]([N:12]2[CH2:13][CH2:14][N:10]([CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]3)[C:11]2=[NH:15])(=[O:31])=[O:30])=[CH:26][CH:25]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)NCCc1ccc(S(=O)(=O)Cl)s1
Reactant: N=C1NCCN1C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCC(=O)NCCc1ccc(S(=O)(=O)N2CCN(C3CCCCC3)C2=N)s1
Reaction time: 18 h

Procedure:
20 ml (0.02 mol) of 1 N sodium hydroxide solution are added dropwise over the course of 10 minutes, whilst stirring, to a mixture of 2.04 g (0.01 mol) of 1-cyclohexyl-2-imino-imidazolidine hydrochloride and 2.96 g (0.01 mol) of 5-(2-butyramido-ethyl)-2-thiophenesulphonyl chloride in 45 ml of water-acetone (1:2), at 25°C. In the course thereof, the reaction temperature rises to 33°C. The reaction mixture is stirred for a further 18 hours at 24°-25°C and the acetone is then evaporated off with the aid of a rotary evaporator. The oil-water mixture which remains is extracted twice with 30 ml of ethyl acetate at a time. The extracts are washed with 20 ml of saturated sodium chloride solution, then combined, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on a column of 120 g of silica gel which is eluted with a mixture of chloroform and methanol (95:5). The eluate is evaporated with the aid of a rotary evaporator and the residue is recrystallized from toluene. Colourless crystals of 1-[5-(2-butyramido-ethyl)-2-thienylsulphonyl]-2-imino-3-cyclohexyl-imidazolidine of melting point 121°-125°C are obtained.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)=[O:7])([O-:3])=[O:2].CO.[BH4-].[Na+]>O.C(OCC)(=O)C>[N+:1]([CH2:4][CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:13]=1)[OH:7])([O-:3])=[O:2]
Reactant: CCCCCCCCc1ccc(C(=O)CC[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCc1ccc(C(O)CC[N+](=O)[O-])cc1
Temperature: 6 °C
Reaction time: 0.17 h

Procedure:
3-Nitro-1-(4-octylphenyl)propan-1-one (75 g) and methanol (750 mL) are charged into a round bottom flask equipped with a condenser and guard tube, stirred to 10 minutes and the mixture is cooled to 6° C. Sodium borohydride (20.2 g) is added in portions over 30 minutes. Allowed the mixture to room temperature, stirred for 3 hours and solvent is removed under reduced pressure to obtain a solid. The solid is diluted with water (1000 mL), ethyl acetate (1000 mL) is added, the separated solid is filtered. The solid, ethyl acetate (200 mL), and water (200 mL) are charged in a round bottom flask and stirred at room temperature, and 6N HCl (100 mL) is added drop-wise. The organic layer is separated, washed with water (200 mL), dried over sodium sulphate, and concentrated under reduced pressure to give the title compound as a yellow liquid. Yield: 30 g.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[OH-].[Na+]>CO>[N:29]1([CH2:28][C:19]2[C:20]([C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][CH2:16][C@H:15]3[O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:35])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCOCC3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCOCC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-morpholin-4-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester by saponification with aq. NaOH in methanol as described above for Examples 1-11.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:32])=[C:18]([C@:20]2([CH3:31])[CH2:25][S:24](=[O:27])(=[O:26])[C:23]([CH3:29])([CH3:28])[C:22]([NH2:30])=[N:21]2)[CH:19]=1>>[NH2:30][C:22]1[C:23]([CH3:28])([CH3:29])[S:24](=[O:26])(=[O:27])[CH2:25][C@:20]([C:18]2[CH:19]=[C:14]([NH:13][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH:2]([F:1])[F:12])=[CH:8][N:7]=3)=[O:11])[CH:15]=[CH:16][C:17]=2[F:32])([CH3:31])[N:21]=1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Reactant: CC1(C)C(N)=N[C@](C)(c2cc(N)ccc2F)CS1(=O)=O
Product: CC1(C)C(N)=N[C@](C)(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)CS1(=O)=O
Yield: 47.9 %

Procedure:
Prepared from commercially available 5-(difluoromethyl)pyrazine-2-carboxylic acid (CAS-no. 1174321-06-2) (48.9 mg, 281 μmol, Eq: 1.2) and (R)-5-(5-amino-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (70 mg, 234 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (51 mg, 112 μmol, 47.9% yield) as a light yellow foam. MS (ISP): m/z=456.5 [(M+H)+].
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[OH:19])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[OH:40]O.[Cl-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N+:12]2([O-:40])[CH2:13][CH2:14][CH:15]([C:18]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=3)([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)[OH:19])[CH2:16][CH2:17]2)=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(CN2CCC(C(O)(c3ccc(C(F)(F)F)cc3)c3ccc(C(F)(F)F)cc3)CC2)cc1
Reactant: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1ccc(C[N+]2([O-])CCC(C(O)(c3ccc(C(F)(F)F)cc3)c3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.1 %

Procedure:
To a stirred solution of 1.5 grams (0.003 mole) of N-(4-propoxyphenylmethyl)-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine in 25.0 mL of absolute methanol was added 1.4 mL (0.014 mole) of 30% aqueous hydrogen peroxide in one portion. Upon completion of the addition the reaction mixture was stirred at ambient temperature for five hours and then analyzed by thin layer chromatography (TLC), which indicated the reaction was not complete. An additional 3.0 mL (0.029 mole) of 30% aqueous hydrogen peroxide was added, and the reaction mixture was stirred for about 18 hours. At the conclusion of this period the reaction mixture was poured into 100 mL of an aqueous saturated sodium chloride solution. The mixture was extracted with three 100 mL portions of ethyl acetate, and the combined extracts were washed with one 100 mL portion of an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.5 grams of N-(4-propoxyphenylmethyl)-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine N-oxide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[CH2:3][CH2:4][OH:5].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[CH2:3][CH:4]=[O:5]
Reactant: CC(C)C(C)(C)CCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)C(C)(C)CC=O
Temperature: 25 °C

Procedure:
3,3,4-Trimethylpentanol (1 equiv) is dissolved in CH2Cl2. Pyridinium chlorochromate (1.5 equiv) is added and the resulting mixture is stirred at ambient temperature. The liquid is decanted and concentrated by rotary evaporation. The residue is triturated with 1 to 1 diethyl ether/hexane and mixture is filtered and the filtrate is washed with 1 N HCl. The organic layer is dried over Na2SO4, decanted and concentrated. The aldehyde is purified by fractional distillation to yield 3,3,4-trimethylpentanal.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:5]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[Cu](C#N)[C:19]#[N:20]>CN1CCCC1=O.C(=O)(O)[O-].[Na+]>[CH2:14]([CH:13]([C:5]1[C:6]2[N:7]([CH3:12])[C:8](=[O:11])[NH:9][C:10]=2[C:2]([C:19]#[N:20])=[CH:3][CH:4]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Reactant: N#C[Cu]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(C#N)c2[nH]c(=O)n(C)c12
Yield: 85.1 %

Procedure:
A mixture of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (300 mg, 1.01 mmol) and copper cyanide (116 mg, 1.30 mmol) in 1-methyl-2-pyrrolidone (3 mL) was irradiated by microwave (200 w) at 150° C. for 1 h. After cooling, to the reaction mixture was diluted with saturated sodium bicarbonate, and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with 50% diisopropyl ether/n-hexane to give the title compound (209 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][C:3]=1[F:13].[Cl-].[NH4+].O>C(O)(C)C.[Fe]>[Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc(Br)c(F)cc1N
Temperature: 75 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (0.998 g, 3.99 mmol) in isopropanol (20 mL) was added iron (0.7 g, 12 mmol), ammonium chloride (0.64 g, 12 mmol) and water (2 mL). The reaction was stirred at 75° C. for 2 hours, then filtered and concentrated. The residue was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give 4-bromo-5-fluoro-2-methoxyaniline (0.82 g, 93%).
Reaction SMILES: C(B1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])(C)[O:4]1)=C.C(=O)([O-])[O-].[Na+].[Na+].[NH2:18][C:19]1[C:20]([CH3:33])=[C:21]([CH3:32])[C:22]2OC(C)(C)[C:24](=O)[C:23]=2[C:30]=1Br>C(OCC)(=O)C.O.COCCOC.C(O)C>[NH2:18][C:19]1[C:20]([CH3:33])=[C:21]([CH3:32])[C:22]2[O:7][C:6]([CH3:8])([CH3:9])[C:5](=[O:4])[C:11]=2[C:30]=1[CH:23]=[CH2:24]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(C)c2c(c(Br)c1N)C(=O)C(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1c(N)c(C)c(C)c2c1C(=O)C(C)(C)O2
Temperature: 100 °C
Reaction time: 45 h
Yield: 90.3 %

Procedure:
2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (3.79 g, 24.6 mmol), tetrakistriphenyl phosphine palladium (605 mg, 0.523 mmol), sodium carbonate (1.36 g, 12.8 mmol), water (8 mL) and ethanol (5 mL) were added to a solution of DME (14 mL) containing 5-amino-4-bromo-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (2.00 g, 7.04 mmol) synthesized in Reference Example 21, and the mixture was stirred under argon atmosphere at 100° C. for 45 hours. After cooled to room temperature, water was added to the mixture, and extraction was performed using ethyl acetate. It was dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate: 98:2 to 85:15) to give 1.47 g of the title compound (yield: 91%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].S(Cl)(O[CH2:25][Cl:26])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([O:14][CH2:25][Cl:26])=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)OCCl
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)OCCl)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-((tert-butoxycarbonyl)amino)cyclopropane-carboxylic acid (0.55 g, 2.73 mmol), sodium carbonate (1.449 g, 13.67 mmol) and tetrabutylammonium hydrogen sulfate (0.186 g, 0.547 mmol) in a mixture of DCM (10 mL) and water (5 mL) at 0° C., was added chloromethyl chlorosulfate (0.902 g, 5.47 mmol). The reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with DCM and water and the organic layer was separated, washed with a brine solution and dried over Na2SO4. The mixture was filtered and concentrated in vacuo and the residue obtained was purified by a flash chromatography (SiO2, 0-10% EtOAc in hexane) to afford Preparation 53A (0.5 g, 73.3%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 1.24-1.26 (m, 2H), 1.46 (s, 9H), 1.60-1.61 (m, 2H), 5.13 (s, 1H), 5.71 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:14])[N:4]=1.[C:17]1([CH:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:14][CH2:8][CH:9]([OH:14])[CH2:10][N:29]2[CH2:28][CH2:27][N:26]([C:24](=[O:25])[CH:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30]2)[N:4]=1
Reactant: O=C(C(c1ccccc1)c1ccccc1)N1CCNCC1
Reactant: Cc1cc(C(F)(F)F)nc2cccc(O)c12
Product: Cc1cc(C(F)(F)F)nc2cccc(OCC(O)CN3CCN(C(=O)C(c4ccccc4)c4ccccc4)CC3)c12

Procedure:
Following the same procedures as in Example 1-(a) and (b), reaction and treatment were carried out using 2-trifluoromethyl-4-methyl-5-hydroxyquinoline prepared in Example 54 and N-(α,α-diphenylacetyl)piperazine in order to obtain the desired compound.
Reaction SMILES: ClC(N(C)C)=C(C)C.[C:9]([O:13][C:14]([NH:16][C:17]1[S:21][C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:19][C:18]=1[C:30]([OH:32])=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH2:33][C:34]1[C:35]([N:52]2[CH2:57][CH2:56][CH2:55][C@H:54]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:53]2)=[C:36]2[CH:42]=[CH:41][N:40]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(=[O:45])=[O:44])[C:37]2=[N:38][CH:39]=1.N1C=CC=CC=1>C1COCC1>[C:9]([O:13][C:14]([NH:16][C:17]1[S:21][C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:19][C:18]=1[C:30]([NH:33][C:34]1[C:35]([N:52]2[CH2:57][CH2:56][CH2:55][C@H:54]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])[CH2:53]2)=[C:36]2[CH:42]=[CH:41][N:40]([S:43]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)(=[O:45])=[O:44])[C:37]2=[N:38][CH:39]=1)=[O:32])=[O:15])([CH3:11])([CH3:10])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylpropenylamine (115.7 mg, 0.8659 mmol) in THF (1.0 mL) was added slowly to a solution of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, Step 6, 120.4 mg, 0.3379 mmol) in THF (1.0 mL). The mixture was stirred at room temperature for 5 h. A solution of tert-butyl {(3S)-1-[5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (127.3 mg, 0.2699 mmol) in THF (2.0 mL) was then added, followed by pyridine (227.6 mg, 2.877 mmol) and the mixture was stirred at room temperature for a further 12 h. The mixture was then concentrated and the residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (194.4 mg, 89%). LCMS calc. for C38H42F2N2O2S2 (M+H)+: m/z=810.2. found 810.2.
Reaction SMILES: N12CCCN=C1CCCCC2.C(O[CH2:16][C@H:17]1[C@H:20]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:19][C:18]1=[O:26])(=O)C>O1CCCC1>[C:23]([O:22][CH2:21][CH:20]1[CH2:19][C:18](=[O:26])[C:17]1=[CH2:16])(=[O:25])[CH3:24]
Reactant: CC(=O)OC[C@@H]1CC(=O)[C@H]1COC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C1C(=O)CC1COC(C)=O
Temperature: 25 °C
Yield: 106.6 %

Procedure:
After tetrahydrofuran (3 ml) and 1,8-diazabicyclo[5.4.0]-undeca-7-ene (25.5 mg, 0.168 mmol) was added to Compound (c) (30 mg, 0.14 mmol), the mixture was stirred at room temperature for an hour. The reaction solution was purified by silica gel column chromatography (10 ml, hexane:ethyl acetate=2:1) to give Compound (d) (23 mg, yield: 95.5%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[N:24]([O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([CH3:37])([CH3:36])[CH2:22]2)[N:5]=[C:4]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]2[CH2:56][C:55]([CH3:58])([CH3:57])[N:54]([O:59][CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)[C:53]([CH3:67])([CH3:66])[CH2:52]2)[N:3]=1.[CH2:68]([CH2:70][NH2:71])[OH:69]>>[OH:69][CH2:68][CH2:70][NH:71][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[N:24]([O:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[C:23]([CH3:37])([CH3:36])[CH2:22]2)[N:5]=[C:4]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]2[CH2:56][C:55]([CH3:57])([CH3:58])[N:54]([O:59][CH:60]3[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]3)[C:53]([CH3:67])([CH3:66])[CH2:52]2)[N:3]=1
Reactant: NCCO
Reactant: CC1(C)CC(CCCCCCCCCCCCNc2nc(Cl)nc(NCCCCCCCCCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(CCCCCCCCCCCCNc2nc(NCCO)nc(NCCCCCCCCCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)dodecylamino]-1,3,5-triazine with ethanolamine according to the procedure of Example 1.
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:24]O>>[CH:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]3)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1ccc2cc(OCCCCSC3CCCCC3)ccc2[nH]1
Reactant: OO
Product: O=c1ccc2cc(OCCCCS(=O)C3CCCCC3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-(4-cyclohexylmercapto-butoxy)-carbostyril and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2[C-](N(C)C)C=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: OB(O)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1-c1ccccc1
Yield: 73.3 %

Procedure:
According to General Procedure A, a mixture of o-chloronitrobenzene (79 mg, 0.50 mmol), phenylboronic acid (91 mg, 0.75 mmol), CsF (228 mg, 1.50 mmol), Pd(OAc)2 (2 mg, 0.01 mmol) and 12f (8 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) has heated to reflux, cooled and filtered. Evaporation of the solvent under reduced pressure and column chromatography of the pre-adsorbed crude material (1% Et2O in hexane, silica gel) gave 51d (73 mg, 73%) as a bright yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.86 (d, 1H, J=8.0 Hz), 7.62 (t, 1H, J=7.5 Hz), 7.51-7.40 (m, 5H), 7.34-7.31 (m, 2H); 13C NMR (75.5 MHz, CDCl3) δ 149.3, 137.4, 136.3, 132.2, 131.9, 128.7, 128.2, 128.1, 127.9, 124.0.