Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O:5][C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8])([OH:4])(=[O:3])=O.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.CN(C=O)C>[OH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[O:5][S:1](=[O:3])(=[O:4])[NH:17][CH:13]1[CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCC1
Reactant: O=S(=O)(O)Oc1ccccc1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(NC1CCC1)Oc1ccccc1O
Reaction time: 3 h

Procedure:
Cyclobutyl-sulfamic acid 2-hydroxy-phenyl ester was prepared by adding a solution of catechol sulphate (1.32 g, 7.7 mmol) in DCM (2 ml) to a stirred solution of cyclobutylamine (600 μl, 7.0 mmol) and TEA (1.07 ml, 7.7 mmol) in DMF at 0° C., and stirring for 3 hours at this temperature. The mixture was quenched with 1M HCl (50 ml) and extracted with diethyl ether. The organic extract was washed with water, brine, dried and concentrated to dryness. Quantitative yield.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]=O)=O)[CH:2]=1.C(O)C.S(O)(O)(=O)=O.[OH:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=1[NH2:28].C([O-])(=O)C.[Na+]>O>[OH:20][C:21]1[C:22]2[C:23](=[N:27][C:7]([C:3]3[CH:2]=[C:1]([CH3:11])[CH:6]=[CH:5][CH:4]=3)=[CH:9][N:28]=2)[N:24]=[CH:25][N:26]=1
Reactant: Cc1cccc(C(=O)C=O)c1
Reactant: Nc1ncnc(O)c1N
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(-c2cnc3c(O)ncnc3n2)c1
Reaction time: 17 h

Procedure:
A solution of 3.6 g. of 3-tolylglyoxal in 15 ml. of ethanol was added to a stirred suspension of 3.26 g. of 6-hydroxy-4,5-diaminopyrimidine sulfate in 30 ml. of hot water containing 6.45 g. of sodium acetate. Stirring was continued for 17 hours at room temperature and the formed precipitate was then filtered, washed twice each with methanol and ether to yield 2.7 (28%) of 4-hydroxy-7-(3-tolyl)pteridine. Recrystallization from DMSO/water produced the pure product; melting point 248-50 degrees C. The test results (100 mg/kg; oral) are shown in Table VI.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][C@@H:27]([C:29]([OH:31])=[O:30])[CH3:28].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][C@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@@H](N)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@@H](NC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), D-alanine (1061 mg, 11.9 mmol) and NaOMe solution (18 mL, 9 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated to give a crude solid. The solid was dissolved in saturated NaHCO3 and washed with ether. 4 M HCl was added to the aqueous layer until pH was about 1, and the resulting precipitate was isolated by filtration to give 23 mg of the title compound as an off-white solid. MS: (+) m/z 393.25 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:8][C:7]2=[O:18].O.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl.[OH-].[Na+]>C(O)(C)C>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:8][C:7]2=[O:18]
Reactant: ClCC1CO1
Reactant: O=c1cc(-c2ccccc2)oc2c(O)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=c1cc(-c2ccccc2)oc2c(OCC3CO3)cccc12
Temperature: 70 °C
Yield: 99 %

Procedure:
8-Hydroxyflavone (17.9 g, 75 mmol) (see Awad et al, J. Org. Chem., 25, 1333 (1960)) was suspended in a solvent consisting of 22 ml of water and 135 ml of isopropanol. Epichlorohydrin (59 ml, 75 mmol) and NaOH (3.0 g, 75 mmol) were added and the reaction mixture was heated at 70° C. for 31/2 hours. The reaction mixture was then cooled and filtered, and the solvent was removed under reduced pressure. The residue was taken up in 600 ml of CH2Cl2, washed twice with 600 ml of H2O, dried and the remaining solvent was removed by evaporation. This gave 21.9 g of light tan solid (99% yield). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@:5]1([CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8][CH2:7][N:6]1[CH3:21])=[O:4]
Reactant: COC(=O)[C@]1(COCc2ccccc2)CCCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@]1(COCc2ccccc2)CCCN1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
A solution of Intermediate 85c (3.37 g, 13.5 mmol) and formaldehyde (37% aqueous, 4.38 mL, 54.1 mmol) in DCM (140 mL) was stirred at RT for 30 min, then sodium triacetoxyborohydride (5.74 g, 27.1 mmol) was added. This mixture was stirred at RT for 18 h then washed with sat. aq. NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound as a clear oil (2.59 g, 72%). LCMS (Method 4): Rt 1.85 min, m/z 263 [MH+].
Reaction SMILES: [OH:1][C:2]1([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].Cl>CO>[CH2:9]([O:8][C:6]([N:4]1[CH2:5][C:2]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[NH2:29])([OH:1])[CH2:3]1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCCCC1C1(O)CN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: NC1CCCCC1C1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.6 %

Procedure:
A solution of benzyl 3-hydroxy-3-(2-oxocyclohexyl)azetidine-1-carboxylate (100 mg, 330 mmol) in methanol (1.60 mL) in the presence of ammonium acetate (191 mg, 2.48 mmol was cooled to 0° C. for 1 hour. Sodium cyanoborohydride (81.5 mg, 1.30 mmol) was added and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 6 N hydrogen chloride (800 μL) and extracted with ethyl acetate. The aqueous layer was basified with aqueous sodium bicarbonate (pH 9) and extracted with dichloromethane. The combined organic portion was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford benzyl-3-(2-aminocyclohexyl)-3-hydroxyazetidine-1-carboxylate (73.7 mg, 73%). MS (EI) for C17H24N2O3: 305 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][CH2:24][N:25]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:26][CH2:27]2)[CH:17]=1
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2cccc(-c3ccccc3)c2)CC1
Yield: 58.5 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (249 mg, 0.923 mmol), 1-biphenyl-3-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. To the reaction solution was added water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and then recrystallized from a mixed solvent of hexane and ethyl acetate to give the titled compound (176 mg, 58.6%) as solid product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.[OH-].[Li+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a solution of methyl 4-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}benzoate of Example 87 (0.315 g, 0.656 mmol) in methanol (4 mL) and water (2 mL) was added lithium hydroxide (31.4 mg, 1.31 mmol) and the reaction mixture heated to reflux for 1 hour. The cooled reaction mixture was diluted with water (20 mL) and washed with ethyl acetate (2×20 mL). The aqueous phase was then acidified to pH 4.5 by the addition of 2 M hydrochloric acid and the resulting milky suspension allowed to stand at 4° C. for 16 hours. The solid product was filtered, washed with water, and dried at 50° C. in vacuo overnight to afford the title compound (0.271 g, 89%) as a white solid.
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].[CH2:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].OO>C(O)C.S(=O)(=O)(O)O>[CH2:6]([PH:2](=[O:4])[OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=[PH2][O-]
Reactant: C=CCCCCCC
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCC[PH](=O)O
Yield: 84.8 %

Procedure:
To a mixture of 95.1 g (0.897 mol) of sodium hypophosphite hydrate in 600 mL 95% ethanol, 23.8 mL of concentrated sulfuric acid was added. 1-Octene (33.6 g, 0.299 mol) was added to the stirred mixture followed by 1.69 g (0.0149 mol) of 30% hydrogen peroxide. The resulting mixture was refluxed for 8 hs, and then another 1.15 g (0.010 mol) of hydrogen peroxide was added and the reaction mixture was continued to reflux for another 8 hs. The resulting mixture was cooled, filtered, and then the ethanol was removed using a rotary evaporator. To the resulting residue, 200 mL water was added and then 50% sodium hydroxide solution was added until the solution became alkaline. The mixture was extracted twice with 200 mL diethyl ether, and the aqueous phase was then acidified with concentrated sulfuric acid. The aqueous layer was extracted with 200 mL ethyl acetate, and the organic layer was washed with saturated sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer was decanted and the drying agent was washed with another 50 mL ethyl acetate. The combined organic layers were evaporated on a rotary evaporator. 45.2 g of n-octylphosphinic acid (84.8% yield) was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[C:8]([CH3:11])([CH3:10])[CH3:9].O.[OH-].[Na+]>O1CCCC1>[CH2:7]([C:12]1[CH:20]=[CH:19][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)Cc1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of lithium aluminum hydride (1.13 g, 29.9 mmol) in tetrahydrofuran (50 ml) was added dropwise a solution of 4-neopentylbenzoic acid (3.830 g, 19.92 mmol) in tetrahydrofuran (30 ml) under ice-cooling, and the mixture was stirred overnight at room temperature. After ice-cooling the reaction solution, water (1 ml), a 15% aqueous sodium hydroxide solution (1 ml) and water (2.5 ml) were successively added dropwise to decompose excess lithium aluminum hydride. The mixture was stirred as it was at room temperature for 2 hrs. The resulting precipitate was removed by filtration, and the precipitate was washed with ethyl acetate. The solvent of the recovered filtrate was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][N:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[C:22]2[CH:27]=[CH:26][C:25]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:24][N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2ccc(Br)cn2)C1
Reactant: OB(O)Oc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2ccc(-c3ccc(F)cc3)cn2)C1
Temperature: 100 °C
Reaction time: 10 h
Yield: 0.8 %

Procedure:
3(S)-[(5-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.64 mmol), 4-fluorophenylboric acid (98 mg, 0.7 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and a 2 M aqueous sodium carbonate solution (0.83 ml) were added to toluene (3 ml), followed by stirring under a nitrogen atmosphere at 100° C. for 10 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution to separate the reaction solution into layers. The organic layer was washed with saturated saline, followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1). The solvent was distilled off from the purified product under reduced pressure to thereby obtain 2.55 mg of white solid 3(S)-{(3-chloro-4-fluorophenyl)-[5-(4-fluorophenyl)pyridin-2-yl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[C:6]([NH2:13])=[N:5]2.[C:14](OC(=O)CC)(=O)[CH2:15][CH3:16]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:14]([CH2:15][CH3:16])=[N:13][C:6]1=[N:5]2
Reactant: CCC(=O)OC(=O)CC
Reactant: Nc1nc2ccc(Cl)cc2nc1N
Solvent: C1CCOC1
Product: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1

Procedure:
Four parts of 6-chloro-2,3-diaminoquinoxaline was combined with 3 parts of propionic anhydride in 2 parts of tetrahydrofuran. The mixture was heated for three hours during which time a thick slurry formed. The solid was collected from the hot mixture by filtration and washed twice with two parts of tetrahydrofuran. The gray solid was air-dried to give four parts of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline, m.p. 298°-300°.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3cccc(C(F)(F)F)c3)c2c1

Procedure:
The titled compound (38 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 3-(trifluoromethyl)benzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [CH2:1]=[C:2]([Mg]Br)[CH3:3].B(OC(C)C)(OC(C)C)OC(C)C.C([O-])([O-])=O.[K+].[K+].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:46][C:35]3=[N:36][C:37]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[C:38](I)[CH:39]=[C:34]3[C:33]=2[C:47]([NH:49][CH3:50])=[O:48])=[CH:28][CH:27]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:46][C:35]3=[N:36][C:37]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[C:38]([C:2]([CH3:3])=[CH2:1])[CH:39]=[C:34]3[C:33]=2[C:47]([NH:49][CH3:50])=[O:48])=[CH:28][CH:27]=1
Reactant: C=C(C)[Mg]Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C([O-])[O-]
Product: C=C(C)c1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To prop-1-en-2-ylmagnesium bromide (0.5 M THF solution, 6.1 ml, 5 eq.) in a heatgun-dried microwave tube at 0° C. was added triisopropyl borate (0.71 ml, 5 eq.). The mixture was stirred at 0° C. for 15 min and warmed to rt. K2CO3 (2 M aq. solution, 1.5 ml, 5 eq.) was added. The mixture was stirred at rt for 15 min. 2-(4-Fluorophenyl)-5-iodo-N-methyl-6-(methylsulfonamido)furo[2,3-b]pyridine-3-carboxamide (300 mg, 1 eq.) and Pd(PPh3)4 (106 mg, 0.15 eq.) were added. The mixture was degassed, stirred in a microwave reactor at 120° C. for 20 min and cooled. Water was added followed by LiOH (1 M aq. solution, 1.8 ml). The mixture was washed with ether. (It took a long time for layers to settle. There may be a solid meta-phase which can be filtered out as pure product.) Aq. layer was acidified to pH 3.5 using saturated citric acid. Precipitate was filtered, washed with water and lyophilized to give the title compound as an off-white solid (180 mg, 73%). MS (ESI) m/z 404.2 (M+1). Retention time=1.23 min (Method A).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:9]1[CH:10]=C([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1)C(O)=O)#[N:8].CN(C)C=O>ClCCl>[C:7]([C:9]1[CH:10]=[C:1]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1)[C:2]([Cl:4])=[O:3])#[N:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(C(=O)O)ccc1OCC1CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(C(=O)Cl)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Oxalyl chloride (0.040 ml, 0.460 mmol) was added to a stirred solution of 3-cyano-4-[(cyclopropylmethyl)oxy]benzoic acid (D24; 50 mg, 0.230 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at room temperature under nitrogen, and the mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to give the title compound (54.2 mg) which was used in the subsequent step (D49) without purification.
Reaction SMILES: [CH:1]1([S:7]([CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.O>[CH:1]1([S:7]([CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:33][CH2:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[O:23])=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])(=[O:8])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCCCC1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCCCC1
Yield: 39.9 %

Procedure:
A solution of 4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoic acid (500 mg, 1.38 mmol, 1.00 equiv), pyridin-3-ylmethanamine (180 mg, 1.67 mmol, 1.20 equiv), EDCI (320 mg, 1.68 mmol, 1.20 equiv), HOBt (220 mg, 1.63 mmol, 1.20 equiv) and triethylamine (420 mg, 4.16 mmol, 3.00 equiv) in N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with 15 mL of water and ice. The precipitate was collected by filtration, washed with water and dried in a vacuum oven to give 0.25 g (40%) of 4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid LC-MS: (ES, m/z): 454 [M+H]+, 347, 306, 238, 120 1HNMR (400 MHz, CDCl3, ppm) δ 8.97 (s, 1H), 8.57 (s, 2H), 8.21-8.05 (t, 4H), 7.54 (s, 2H), 4.73 (s, 2H), 4.17 (s, 2H), 3.02-2.98 (d, 2H), 2.90-2.50 (m, 6H), 2.31-2.20 (d, 2H), 1.95 (s, 2H), 1.74-1.61 (m, 3H), 1.29 (s, 3H
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][C:22]3[CH:23]=[N:24][C:25]([O:28]C)=[CH:26][CH:27]=3)=[N:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].O.CCOC(C)=O>C(Cl)(Cl)Cl.CO>[CH:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][C:22]3[CH:23]=[N:24][C:25]([OH:28])=[CH:26][CH:27]=3)=[N:13][N:12]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Cc2nnc(N[C@H]3CC[C@H](C(C)C)CC3)c3ccccc23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1CC[C@H](Nc2nnc(Cc3ccc(O)nc3)c3ccccc23)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Under N2 atmosphere, 0.35 ml (2.6 mMol) of Me3Sil are added to 500 mg (1.3 mMol) of trans 1-(4-isopropyl-cyclohexylamino)-4-[6-methoxy-(pyridin-3-yl)-methyl]-phthalazine in 15 ml of chloroform, followed by stirring for 16 h at 60° C. After cooling to RT, 15 ml of sat. NaHCO3 solution, 10 ml of water, EtOAc and a small amount of methanol are added, followed by agitation. From the resulting solution, the aqueous phase is removed and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and evaporated to dryness. Crystallization by partial evaporation of a solution in methanol results in the title compound: M.p. 271-272° C. (decomposition); FAB-MS: (M+H)+=377; HPLC(Grad20-100) tRet=10.2.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][O:8][CH3:9])[C@H:4]([OH:6])[CH3:5].C(N(CC)CC)C.[Br:17][C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1>C(#N)C>[Br:17][C:18]1[C:19]([NH:2][C@H:3]([CH2:7][O:8][CH3:9])[C@H:4]([OH:6])[CH3:5])=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1
Reactant: COC[C@@H](N)[C@@H](C)O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC[C@@H](Nc1nc(Cl)ncc1Br)[C@@H](C)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
311 mg (2.6 mmol) of (2R,3R)-3-amino-4-methoxy-butan-2-ol hydrochloride (production according to A. I. Meyers, D. Hoyer, Tet. Lett. 1985, 26, 4687) in 2 ml of acetonitrile is mixed with 0.28 ml of triethylamine and shaken. It is filtered, and the filter cakes are washed with 2 ml of acetonitrile. The filtrate is added in drops to a solution of 455 mg (2.0 mmol) of 5-bromo-2,4dichloro-pyrimidine in 26 ml of acetonitrile at −30° C. By removal of the cooling bath, it is slowly heated to room temperature while being stirred. After 16 hours, the solvent is drawn off in a rotary evaporator, and the remaining residue is purified by chromatography (hexane/ethyl acetate: 4:1-1:1). 509 mg (1.6 mmol, corresponding to 80% of theory) of the product is obtained.