Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C1C=CC2[O:8]CCOC=2C=1)=C=S.[F:14][C:15]1[CH:20]=[CH:19][C:18](C(=O)C)=[C:17]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1.ClC1C=C(C(OO)=O)C=CC=1>ClCCl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:8])=[C:17]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1
Reactant: S=C=Nc1ccc2c(c1)OCCO2
Reactant: CC(=O)c1ccc(F)cc1OCc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Oc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 93 %

Procedure:
A mixture of 11 parts of 1-[4-fluoro-2-(phenylmethoxy)phenyl]ethanone, 8.48 parts of 3-chlorobenzenecarboperoxoic acid and 260 parts of dichloromethane was stirred for 5 days at room temperature. The precipitate was filtered off and the filtrate was stirred in a saturate thiosulfurate solution for 15 minutes. The organic layer was separated and stirred in a saturate hydrogen carbonate solution for 15 minutes. The organic layer was separated, washed with water, dried, filtered and evaporated. The solid residue was stirred in 240 parts of methanol. 5.3 Parts of sodium methoxide were added portionwise. After complete addition, the whole was stirred for 1 hour at room temperature. After evaporation in vacuo at 50° C., the residue was stirred in water and acidified with a hydrochloric acid solution 3N. Trichloromethane was added, the organic layer was separated, washed twice with water, dried, filtered and evaporated, yielding 10 parts (93%) of 4-fluoro-2-(phenylmethoxy)phenol as a residue (intermediate 77).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.Br[CH2:9][C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)Cl.C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[C:10](=[O:16])[CH2:9][S:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[CH3:15]
Reactant: Cc1nnc(S)s1
Reactant: CCOC(=O)C(=O)CBr
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C(=O)CSc1nnc(C)s1
Yield: 91.3 %

Procedure:
A solution of 5-methyl-1,3,4-thiadiazole-2-thiol (264 mg, 2 mmol) and ethyl bromopyruvate (0.264 mL, 2.1 mmol) in methylene chloride (10 mL) and acetonitrile (10 mL) was stirred at 20° C. for 3 hours under nitrogen. The precipitates were filtered, washed with methylene chloride, and dried under vacuum. This gave the expected product, 3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (450 mg, yield 69%) as a solid.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH2:11]CC)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.BrCC1C=CC(C2C=CC=CC=2C2N=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)N=2)=CC=1>>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCCCCC(=O)CC(=O)OCC
Agent: BrCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Product: CCCC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC

Procedure:
Substituting ethyl butyrylacetate for ethyl 3-oxooctanoate and 4-bromobenzyl bromide for 4-bromomethyl-2'-(2-(triphenylmethyl)tetrazol-5-yl)-biphenyl in Example 4 gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[N:20]O)[CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni].O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([NH2:20])[CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=NO)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(N)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Reaction time: 3 h
Yield: 75.7 %

Procedure:
A solution of 7-(1-hydroxyiminoethyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (1.0 g, 3.44 mmol) in MeOH (50 ml) was hydrogenated for 1 h under a pressure of 44 psi, in presence of 50% RaNi/H2O (2 mL). Additional catalyst was added (1 mL) and the hydrogenation proceeded for 3 hours. The catalyst was filtered off and filtrate evaporated. The crude product was chromatographed (SiO2, 15% of 2.0M NH3/MeOH in CH3CN) to provide 0.72 g (76%) of the title compound as a white solid. m.p: 61-64° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:23][N:24]1[C:33](=[O:34])[C:32]2[CH:35]=[C:36]([OH:38])[CH:37]=[C:30]3[C:31]=2[C:26](=[CH:27][CH:28]=[CH:29]3)[C:25]1=[O:39])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:23][N:24]1[C:33](=[O:34])[C:32]2[CH:35]=[C:36]([O:38][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])[CH:37]=[C:30]3[C:31]=2[C:26](=[CH:27][CH:28]=[CH:29]3)[C:25]1=[O:39])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCCl
Reactant: O=C1c2cccc3cc(O)cc(c23)C(=O)N1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CN(C)CCOc1cc2c3c(cccc3c1)C(=O)N(OCc1ccccc1)C2=O
Yield: 30.7 %

Procedure:
2-Chloro-N,N-dimethylethylamine hydrochloride (0.5 g, 3.3 mmol), potassium iodide (0.4 g, 2.4 mmol), and potassium carbonate (1.4 g, 10.1 mmol) were added to a suspension of 2-benzyloxy-5-hydroxy-benzo[de]isoquinoline-1,3-dione (0.8 g, 2.5 mmol) in acetone (100 mL). The mixture was refluxed for 8 hours and concentrated in vacuo. The residue was dissolved in water and extracted with 30% methanol in chloroform. The organic layer was dried (Na2SO4), filtered, and concentrated to give 0.3 g of 2-benzyloxy-5-(2-dimethylamino-ethoxy)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-5-(2-dimethylamino-ethoxy)-benzo[de]isoquinoline-1,3-dione (0.2 g) in the presence of 10% Pd/C (0.2 g) in DMA (20 mL) afforded 0.04 g of the title compound, mp 225-229° C.;
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].CC1C=CC(S(O[CH:22]2[CH2:25][CH2:24][CH2:23]2)(=O)=O)=CC=1.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH:22]1[CH2:25][CH2:24][CH2:23]1
Reactant: Sc1ccccc1Br
Reactant: Cc1ccc(S(=O)(=O)OC2CCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccccc1SC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 390 mg, 9.75 mmol) in anhydrous DMF (20 mL) was added 2-bromobenzenethiol (1.03 mL, 8.37 mmol) dropwise over 5 minutes. After stirring for 10 minutes at room temperature a solution of cyclobutyl 4-methylbenzenesulfonate (2.0 g, 8.85 mmol) in dry DMF (3 mL) was added dropwise. The resulting solution was then stirred for 2 hours at room temperature, and 2 hours at 50° C. Water was then added, and the mixture extracted with ethyl acetate (×3). The combined organics were washed with brine (×3), then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with neat petrol) to give (2-bromophenyl)(cyclobutyl)sulfane (1.19 g, 4.89 mmol, 58%) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:14]NC(=O)CCC(N)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([Br:1])[C:11]([CH2:12][Br:14])=[C:10]([Br:13])[CH:9]=1
Reactant: COC(=O)c1cc(Br)c(C)c(Br)c1
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(CBr)c(Br)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of methyl 3,5-dibromo-4-methylbenzoate (5 g, 16.24 mmol) in carbon tetrachloride (50 mL) was treated with N-bromosuccinamide (3.6 g, 20.23 mmol) and 2,2′-azobisisobutyronitrile (0.56 g, 3.410 mmol). The reaction mixture was heated to reflux for 24 h. The reaction was cooled to room temperature and concentrated under vacuum. The resulting mixture was absorbed onto silica and was purified by flash chromatography using silica gel eluted with 3:1 hexanes:ethyl acetate. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 3,5-dibromo-4-bromomethyl-benzoic acid methyl ester (57) (6.22 g, 99%) as a yellow solid; LRMS for C9H7Br3O2 (M+Na) m/z=407. MW=386.8669, Exact Mass=383.7996
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]=[O:22])=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][CH:30]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]([OH:22])[C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:38])([F:37])[F:27])=[CH:30][CH:31]=3)=[C:19]([CH:23]([CH3:24])[CH3:25])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC1(CCC1)O2
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.70 g (1.99 mmol) of 5-(4-fluorophenyl)-7-isopropyl-4-oxo-3,4-dihydrospiro-[chromen-2,1′-cyclobutane]-6-carbaldehyde (Example 51A) is suspended in 30 ml of tetrahydrofuran and cooled to −78° C. 5.25 ml (2.62 mmol) of a freshly prepared 0.5 M solution of [4-(trifluoromethyl)phenyl]magnesium bromide in tetrahydrofuran are added slowly. The mixture is stirred briefly at −78° C. and then warmed to 0° C. After about 30 min, the mixture is hydrolyzed with sodium bicarbonate solution, diluted with water and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified a little at a time by preparative HPLC (method 12). This gives 0.635 g (64% of theory) of the title compound.
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH3:21]>N1C(C)=CC(C)=CC=1C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH2:20][CH3:21])=[CH:24][CH:25]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOc1ccc(O)cc1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Solvent: Cc1cc(C)nc(C)c1
Product: CCOc1ccc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc1

Procedure:
The reaction and workup are carried out in the same manner as described for Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.75g, 5.40 mmol), 4-ethoxy phenol (796 mg, 5.76 mmol) and cuprous oxide (390 mg, 2.73 mmol) in collidine (15 ml). The crude product is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13](C)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26]>CC1C=CC=CC=1C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:23]([O:24][CH2:25][CH3:26])=[O:27])[CH2:12][CH2:11]1)=[O:9]
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc(C(=O)C2CCN(C)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCOC(=O)N1CCC(C(=O)c2cccc(C)c2)CC1
Reaction time: 6 h

Procedure:
To a stirred mixture of 35 parts of (3-methylphenyl) (1-methyl-4-piperidinyl)methanone, 1 part of sodium carbonate and 225 parts of dimethylbenzene are added dropwise 22 parts of ethyl carbonochloridate at 20° C. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated, yielding 12 parts of ethyl 4-(3-methylbenzoyl)-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: Cl.N[CH2:3][CH2:4][SH:5].[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[C:9]([C:24]#[N:25])[C:8]=1[S:26]([CH3:28])=[O:27]>CO>[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:20])([F:21])[F:22])=[CH:14][C:13]=2[Cl:23])[N:10]=[C:9]([CH:24]2[NH:25][CH:3]=[CH:4][S:5]2)[C:8]=1[S:26]([CH3:28])=[O:27]
Reactant: NCCS
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: Cl
Solvent: CO
Product: CS(=O)c1c(C2NC=CS2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A solution of 0.297 gram (0.00261 mole) of 2-aminoethanethiol hydrochloride in 2.5 milliliters of methanol was added to 1.0 gram (0.00261 mole) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile, and the mixture was stirred at room temperature for an approximately 17-hour period. The mixture was partitioned between water and dichloromethane and the organic layer was separated, dried over Na2SO4 and filtered. Solvent was evaporated leaving a residue which was purified by preparative thin-layer chromatography to give 0.186 gram (0.00042 mole) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-(dihydro-2-thiazolyl)-4-methylsulfinyl-1H-pyrazole having a melting point of 189.5° C. (with decomposition). This compound is referred to hereinafter as Compound 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13](OC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+]>C(Cl)(Cl)Cl>[OH:14][CH2:13][C:12]1[CH:11]=[C:10]([CH:19]=[CH:18][CH:17]=1)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Methyl 3-{[(tert-butoxycarbonyl)amino]methyl}benzoate (4.6 g) was mixed with toluene (50 ml), followed by cooling to 0° C. Sodium bis(2-methoxyethoxy)aluminum hydride (65% toluene solution) (20 g) was added dropwise over 30 minutes, followed by stirring at 0° C. for 1 hour. A 1M aqueous NaOH solution (30 ml) was added dropwise to the reaction mixture, and CHCl3 was then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl [3-(hydroxymethyl)benzyl]carbamate (4.1 g).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1.[BH4-].[Na+]>CO>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[C:5]([O:19][CH3:20])[CH:4]=2)=[CH:24][CH:23]=1
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: NCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCc2ccc(F)cc2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 53.7 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 4-fluorophenethylamine (0.374 g, 2.69 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then add EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.545 g, 53.4%): TOF MS ES+ 397.2 (M+H)+, HRMS calcd for C21H22N4O3F 397.1676 (M+H)+, found 397.1689, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.2 min, 100% purity.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=[C:12]2[C:17]=1[N:16]([CH3:18])[C:15](=[O:19])[CH2:14][CH2:13]2.Br[C:30]1[CH:31]=[C:32]([CH2:36][NH:37][S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH:33]=[N:34][CH:35]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:7][C:8]1[CH:9]=[C:10]([C:30]2[CH:31]=[C:32]([CH2:36][NH:37][S:38]([CH2:41][CH3:42])(=[O:39])=[O:40])[CH:33]=[N:34][CH:35]=2)[CH:11]=[C:12]2[C:17]=1[N:16]([CH3:18])[C:15](=[O:19])[CH2:14][CH2:13]2
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(Cl)c21
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCc1cncc(-c2cc(Cl)c3c(c2)CCC(=O)N3C)c1
Temperature: 110 °C
Yield: 33 %

Procedure:
Under argon protection, bis(triphenylphosphine)palladium(II)chloride (4 mg, 0.05 mmol) followed by 1 N aqueous Na2CO3 solution (1 mL), was added to a solution of 8-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (160 mg, 0.5 mmol) and ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 158 mg, 0.6 mmol) in DMF (3 mL). The resulting reaction mixture was then heated in a microwave at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc (5 mL) and poured into a satd. aq. solution of NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (3×5 mL). Combined organics were washed with water and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (65 mg, 45%) as a white solid. MS: 394.1 (M+H+)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(F)cnc1Cc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorobenzyl)nicotinic acid (step 3) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 8.49 (1H, d, J=2.8 Hz), 8.01–7.97 (2H, m), 7.44 (1H, dd, J=7.9, 2.8 Hz), 7.27 (2H, dd, J=4.6, 4.0 Hz), 7.14–7.09 (2H, m), 6.93–6.86 (2H, m), 6.08 (1H, br.s), 4.56 (2H, d, J=5.9 Hz), 4.29 (2H, s), 3.92 (3H, s); MS (ESI) m/z 397 (M+H)+, 395 (M−H)−.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][S:15]([CH2:18][CH2:19][CH:20](O)[CH2:21][CH3:22])(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1>[C:10]([NH:14][S:15]([CH2:18][CH2:19][CH:20]([O:8][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH3:22])(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(O)c1ccccc1
Reactant: CCC(O)CCS(=O)(=O)NC(C)(C)C
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: C1CCOC1
Product: CCC(CCS(=O)(=O)NC(C)(C)C)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
Under nitrogen atmosphere, N,N′-carbonyldiimidazole (90.0 g) was added to a solution of benzoic acid (67.7 g) in tetrahydrofuran (400 ml) in an ice bath and the solution was stirred for 1 hour at room temperature. N-t-butyl-3-hydroxy-1-pentanesulfonamide (59.0 g) was added thereto at room temperature. Subsequently, diazabicycloundecene (84.5 g) was added thereto in an ice bath. The mixture was stirred overnight at room temperature. About ½ volume of tetrahydrofuran was removed under reduced pressure. The reaction solution was made acidic with dilute hydrochloric acid in an ice bath and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate. Deposited solid was separated by filtration. After washing the organic layer with saturated brine and drying it over sodium sulfate, the solvent was removed under reduced pressure to obtain N-t-butyl-3-benzoyloxy-1-pentanesulfonamide (90.42 g) as oil.
Reaction SMILES: ClCCl.C(=O)([O-])[O-].[K+].[K+].Br[C:11]1[CH:20]=[C:19]2[C:14]([C:15]([C:22]([OH:24])=[O:23])=[CH:16][C:17]([CH3:21])=[N:18]2)=[CH:13][CH:12]=1.[CH3:25][C:26]([CH3:48])([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1)[C:27]([O:29][CH3:30])=[O:28]>C(O)(C)C.O1CCOCC1>[CH3:30][O:29][C:27](=[O:28])[C:26]([CH3:25])([CH3:48])[CH2:31][O:32][C:33]1[N:34]=[CH:35][C:36]([C:11]2[CH:20]=[C:19]3[C:14]([C:15]([C:22]([OH:24])=[O:23])=[CH:16][C:17]([CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:37][CH:38]=1
Reactant: Cc1cc(C(=O)O)c2ccc(Br)cc2n1
Reactant: COC(=O)C(C)(C)COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: ClCCl
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(C(=O)O)cc(C)nc3c2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (40.8 mg, 0.05 mmol) and an aqueous solution of potassium carbonate (0.72 g, 4 mmol in 1.0 mL of water) were successively added to a solution of 7-bromo-2-methylquinoline-4-carboxylic acid B-14 (0.26 g, 1.00 mmol) and methyl 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)propanoate A-7 (0.43 g, 1.50 mmol) in isopropanol (5.0 mL) and 1,4-dioxane (20 mL). The reaction was degassed several times under reduced pressure, placed under a nitrogen atmosphere and stirred at room temperature for 24 h. After quenching with a 1 N aqueous hydrogen chloride solution (2.0 mL), the mixture was filtered through a celite pad, washed with ethyl acetate (100 mL) and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (20:1 CH2Cl2:MeOH) to give 7-(6-(3-methoxy-2,2-dimethyl-3-oxopropoxy)pyridin-3-yl)-2-methylquinoline-4-carboxylic acid B-15 as a brown solid (0.32 g, Yield=82%). MS (ESI), [M+1]+ 395.
Reaction SMILES: [NH2:1][C:2]1C=N[N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)[CH:6]=1.C1(C(C2C=CC=CC=2)[CH2:50][NH:51]C2N=C(N3C=C([N+]([O-])=O)C=N3)N=C3C=2N=CN3[C@@H]2C[C@H](NC(=O)CO)[C@@H](O)[C@H]2O)C=CC=CC=1>>[NH2:1][C:2]1[N:51]=[CH:50][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:8]=2)[CH:6]=1
Reactant: Nc1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc([N+](=O)[O-])cn4)nc32)[C@H](O)[C@@H]1O
Product: Nc1cn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)cn1

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(4-amino-pyrazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP3), by substituting N-{(1S,2R,3S,4R)-4-[6-(2,2-Diphenyl-ethylamino)-2-(4-nitro-imidazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZU1) for N-{(1S,2R,3S,4R)-4-[6-(2,2-Diphenyl-ethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP2).