Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:6][CH:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:35])C=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[O:35])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1ccc(CSc2ccc3oc(C(C)NC(C)=O)cc3c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOc1ccc(CS(=O)c2ccc3oc(C(C)NC(C)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
To a solution of N-(1-[5-[(4-ethoxybenzyl)sulfanyl]-1-benzofuran-2-yl]ethyl)acetamide (100 mg, 0.271 mmol) obtained in Example 49 in ethyl acetate (2 mL) was added 75% m-chloroperbenzoic acid (79.8 mg, 0.324 mmol), and the mixture was stirred at room temperature for 1.5 hr. Aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to ethyl acetate), and the obtained solid was washed with diethyl ether to give the title compound (25.5 mg, yield 25%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:11][OH:12])=[N:6][CH:7]=1
Reactant: NO
Reactant: O=Cc1ccc(F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 5-fluoro-2-formylpyridine (5.0 g, 41 mmol) and hydroxylamine hydrochloride (3.06 g, 44 mmol) in ethanol (3.2 mL) and water (9.6 mL) was added ice (18.6 g). Then a solution of NaOH (4.0 g, 100 mmol) in water (4.6 mL) was added dropwise over 10 min keeping the temperature between −5° C. and +5° C. The reaction mixture was then stirred at room temperature for 30 min. Then HCl (4N) was added to acidify the mixture and the resulting precipitate was filtered off and washed with water to afford the title compound (4.41 g, 79%) as a light brown solid. MS: m/e=141.0 [M+H]+.
Reaction SMILES: COC1C=C2C(=CC=1)[NH:12][C:11]1[C:10](=[O:16])[CH2:9][CH2:8][CH2:7][C:6]2=1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.Cl.[N+]([O-])([O-])=O.[Na+].[Na].C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[Na+]>CO.O>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][N:12]=[C:11]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2=[O:16])=[CH:21][CH:20]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc2[nH]c3c(c2c1)CCCC3=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: COc1ccc(NN=C2CCCCC2=O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6-methoxy-1,2,3,4-tetrahydrocarbazol-1-one 123 g. (1 mole) of p-methoxyaniline are dissolved in 600 ml. of water with the addition of 260 g. of concentrated hydrochloric acid. After cooling down to 0° C., 69 g. of sodium nitrate dissolved in 130 ml. of water are added dropwise to the solution. The diazotation being complete, 350 ml. of methanol and 148 g. (1 mole) of the sodium salt of the 1-hydroxymethylene-cyclohexanone are added and the temperature is maintained below +3° C. by adding ice. By the addition of 33.5 g. of anhydrous sodium carbonate and 250 g. of crystallized sodium acetate the solution is standardized to pH 5 to 6. After coupling is completed (10 to 12 hours or so), the solution is made up to a pH 9 to 9.5, stirred three hours at room temperature, filtered with suction and washed with water until free from alkali. Thus, cyclohexanedione-mono-p-methoxyphenylhydrazone is obtained which melts at 177° C. and has a yield of 202 g. (=87% of the theoretical).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:8]([C:3]2[CH:4]=[N:5][N:6]([CH3:7])[C:2]=2[Cl:1])=[O:9])=[CH:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cn1ncc(C(=O)Cl)c1Cl
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: ClCCl
Product: Cn1ncc(C(=O)Nc2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 0 °C

Procedure:
5-Chloro-1-methyl-1H-pyrazole-4-carbonyl chloride (1.0 g, 5.6 mmol) was dissolved in CH2Cl2 (100 mL) under N2 and cooled to 0° C. 4-t-Butylaniline was added and the reaction was stirred with gradual warming to RT overnight. The reaction was quenched with saturated NaHCO3(aq) and extracted 3× with fresh CH2Cl2. The CH2Cl2 extracts were washed with brine, combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure giving 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (4-tert-butyl-phenyl)-amide as a foamy pink solid.
Reaction SMILES: O1C2(CCNCC2)OCC1.CC1C=C(C=CC=1C)OCCCCN1CCC(=O)CC1.[ClH:31].CN.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)/C=C/C(O)=O.[CH3:56][N:57]([CH:68]1[CH2:73][CH2:72][N:71]([CH2:74][CH2:75][CH2:76][CH2:77][O:78][C:79]2[CH:84]=[CH:83][C:82]([CH3:85])=[C:81]([CH3:86])[CH:80]=2)[CH2:70][CH2:69]1)C(=NC1C=CC=CC=1)SC>>[ClH:31].[ClH:31].[CH3:86][C:81]1[CH:80]=[C:79]([CH:84]=[CH:83][C:82]=1[CH3:85])[O:78][CH2:77][CH2:76][CH2:75][CH2:74][N:71]1[CH2:72][CH2:73][CH:68]([NH:57][CH3:56])[CH2:69][CH2:70]1
Reactant: CSC(=Nc1ccccc1)N(C)C1CCN(CCCCOc2ccc(C)c(C)c2)CC1
Agent: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN
Product: CNC1CCN(CCCCOc2ccc(C)c(C)c2)CC1

Procedure:
1,4-Dibromobutane, condensed with 3,4-dimethylphenol according to Ismaïel et al. (J. Med. Chem., 1993, 36, 2519-25), gives 1-[4-bromobutoxy]-3,4-dimethylbenzene with a yield of 86%. The condensation of this compound (according to the same authors) with 1,4-dioxa-8-azaspiro[4.5]decane gives, after deprotection, 1-[4-(3,4-dimethylphenoxy)butyl]-4-piperidone in the form of an orangey oil with a yield of 61%. The reductive amination of this ketone (4.33 g or 15.7 mmol) with methylamine hydrochloride (1.06 g; 15.7 mmol) in the presence of sodium triacetoxyborohydride (4.33 g; 20.5 mmol) according to the protocol of Example 3.1 makes it possible to prepare 5.95 g (Yd: 63%) of the compound of formula 10:
Reaction SMILES: [P:1]([O-:43])([O-:42])([O:3][C:4](C(C)(C)C)(C(C)(C)C)[N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[CH:7][C:6]1=[O:33])=[O:2].C(O)(C)C>C(O)(=O)C>[P:1]([OH:43])([OH:42])([O:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[CH:7][C:6]1=[O:33])=[O:2]
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(C(OP(=O)([O-])[O-])(C(C)(C)C)C(C)(C)C)c(=O)c1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Reaction time: 0.33 h
Yield: 82.7 %

Procedure:
To a 72 liter jacketed glass reactor fitted with an N2 inlet and a mechanical stirrer, and with a jacket temperature set at 40° C., was added di-tert-butyl((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl) phosphate (20, 2820.9 g, 4.49 moles, 1.0 eq) and isopropyl alcohol (25.4 liters, 9.0 volumes). The mixture was stirred at 200 rpm, and acetic acid (14.1 liters, 5.0 volumes) was added, resulting in a clear solution. The clear solution was polish filtered and transferred to a 50 liter jacketed glass reactor system with stirring at 100 rpm. Water (5.6 liters) was added, and the jacket temperature was ramped to 71° C. over 20 minutes. After 4.5 hours of stirring and heating, HPLC analysis indicated that the reaction was complete. The jacket temperature was ramped down to 19° C. over 3 hours, and the product began crystallizing out of solution. The solid was collected by filtration, rinsed with acetone (5 liters). The solid was added back into the reactor vessel, acetone was added (8.5 liters), the jacket temperature was ramped to 45° C. over 10 minutes, and the suspension was stirred. After 40 minutes, the jacket temperature was ramped to 20° C. over 30 minutes, and the crystalline solid was collected by filtration, rinsed with acetone (5 liters) and dried in vacuo at 50° C. to give 1917.7 g (83%) of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate (9) as a crystalline white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]Br)=[N:3][CH:2]=1.[SH:9][CH:10]([CH3:14])[CH:11]([OH:13])[CH3:12]>>[OH:13][CH:11]([CH3:12])[CH:10]([S:9][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][N:3]=1)[CH3:14]
Reactant: BrCc1ccncn1
Reactant: CC(O)C(C)S
Product: CC(O)C(C)SCc1ccncn1

Procedure:
By the same method, 4-pyrimidylmethyl bromide is reacted with 3-mercapto-2-butanol to yield 4-(3-hydroxy-2-butylthiomethyl)pyrimidine, with 3-mercapto-1,2-propanediol to yield 4-(2,3-dihydroxy-1-propylthiomethyl)pyrimidine, with 2-mercaptophenol to yield 4-(2-hydroxyphenylthiomethyl)pyrimidine, with ethyl 2-mercaptoacetate to yield ethyl 2-(4-pyrimidylmethylthio)acetate, with ethyl 2-mercaptopropionate to yield ethyl 2-(4-pyrimidylmethylthio)propionate, with ethyl 2-phenyl-2-mercaptoacetate to yield ethyl 2-phenyl-2-(4-pyrimidylmethylthio)acetate (when ethyl esters are prepared, it is preferable to substitute an equivalent of sodium ethoxide for sodium methoxide), with mercaptoacetone to yield 4-pyrimidylmethylthioacetone, with 1-phenyl-1-mercaptoacetone to yield 1-(4-pyrimidylmethylthio)-1-phenylacetone, and with methyl 3-mercaptopropionate to yield methyl 3-(4-pyrimidylmethylthio)propionate (when methyl esters are prepared it is preferable to substitute methanol for ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:9](C(OC(C)(C)C)=O)[CH:10]1[CH2:12][CH2:11]1)[C:6](=[O:8])[CH3:7])[CH3:2].[ClH:21].C(OCC)C>O1CCOCC1>[ClH:21].[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:9][CH:10]1[CH2:11][CH2:12]1)[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)N(C(=O)OC(C)(C)C)C1CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)C(NC1CC1)C(C)=O
Reaction time: 2 h
Yield: 70 %

Procedure:
To 6.4 g (23 mmol) of 2-(tert-butoxycarbonyl-cyclopropyl-amino)-3-oxo-butyric acid ethyl ester was added 10 ml of 4M hydrochloric acid in dioxane and the mixture stirred for 2 h. Diethyl ether was then added and 3.5 g (70%) of product was isolated by filtration. MS: 186.0 (MH+).
Reaction SMILES: [NH3:1].[C:2]([OH:9])(=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=[O:6]>O>[NH2:1][CH:3]([C:2]([OH:9])=[O:8])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: N
Solvent: O
Product: NC(CC(=O)O)C(=O)O
Yield: 95.7 %

Procedure:
The mother liquor and the washing water from Example 11 are combined. Then water and ammonia are added until 2780 ml of a 20% strength aqueous solution with a pH of 10.5 are obtained. This solution is reacted as described in Example 9 and subsequently concentrated as in Example 10. 1453 ml of a bottom product remain. D,L-aspartic acid is then precipitated as described in Example 11 by adding 323 g (2.78 mol) of maleic acid. Drying results in 382 g (2.87 mol) of D,L-aspartic acid, corresponding to a yield of 95.7% based on the amount of maleic acid added in Example 11.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[K+].C(OCC)(=O)C.CCCCCC>CS(C)=O>[C:22]([O:25][CH2:2][C:3]1[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1c(CBr)cccc1S(=O)(=O)NC(C)(C)C
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(COC(C)=O)cccc1S(=O)(=O)NC(C)(C)C
Yield: 54.6 %

Procedure:
A solution of 5.0 g of 3-bromomethyl-2-carboethoxy-N-(1,1-dimethylethyl)benzenesulfonamide and 1.5 g of potassium acetate in 50 mL of dimethylsulfoxide was stirred at room temperature for 6 hours. The resulting reaction mixture was poured onto ice and extracted with ethyl acetate. The organic phase was washed with a solution of saturated sodium chloride and then dried over magnesium sulfate. Removal of the drying agent by filtration and concentration provided a white solid. Chromatography on silica gel with 1:1 ethyl acetate/hexane provided 2.58 g of a white solid, m.p. 81°-82° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].B(F)(F)F>C1C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=2)[O:13][CH:12]=[CH:11][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(Br)cc1
Agent: FB(F)F
Solvent: c1ccccc1
Product: CC1(c2ccc(Br)cc2)OC=CO1

Procedure:
To 4-Bromoacetophenone (50.0 g., 0.25 mol) in 500 ml. benzene was added ethylene glycol (21.7 ml., 24.2 g., 0.39 mol) followed by BF3 etherate (3.69 ml., 4.26 g., 0.03 mol). The mixture was heated at reflux with a Dean-Stark trap, cooled, washed 1×350 ml. saturated NaHCO3, dried and stripped to yield title product as an oil which crystallized on standing 60.2 g., recrystallized from pentane (chilled in an acetone-dry ice bath) 43.6 g.; 1H-nmr 1.6 (s, 3H), 3.75 (m, 2H), 4.0 (m, 2H), 7.3 (d, 2H), 7.45 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26]>CO.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[N:25][OH:26])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C=O)cc2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C=NO)cc2)CC1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)benzaldehyde (3.16 g, 9.89 mmol) and hydroxylamine hydrochloride (1.27 g, 18.3 mmol) in 9:1 MeOH/pyridine (30 mL) was heated at reflux for 18 hours. The mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in EtOAc and washed with 0.1M HCl (3×), water, sat. CuSO4 (2×), water, sat. NaCl, dried (MgSO4) and concentrated, giving 3.19 g (96%) of the oxime; mp: 140.1°-141.8° C.; 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.14 (bs, 2H), 3.80 (d, J=6.2 Hz, 2H), 2.71 (bt, J=12.4 Hz, 2H), 1.95 (m, 1H), 1.80 (bd, J=12.4 Hz, 2H), 1.45 (s, 9H), 1.26 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH2:25][O:26][CH3:27])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[N:4](C(=O)C)[N:3]=1.Cl.OCCOC1C=CC=CC=1C1NC(=O)N=C(C2C=C3C(=CC=2)NN=C3C)C=1>CO>[OH:26][CH2:25][CH2:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[NH:14][C:13](=[O:28])[N:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[CH:16]=1.[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH2:25][O:26][CH3:27])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: COCCOc1ccccc1-c1cc(-c2ccc3c(c2)c(C)nn3C(C)=O)nc(=O)[nH]1
Agent: Cc1n[nH]c2ccc(-c3cc(-c4ccccc4OCCO)[nH]c(=O)n3)cc12
Agent: Cl
Solvent: CO
Product: COCCOc1ccccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Temperature: 60 °C

Procedure:
A flask was charged with 4-(3-methyl-1-acetyl-1H-indazol-5-yl)-6-(2-{[2-(methyloxy)ethyl]oxy}phenyl)pyrimidin-2(1H)-one (2.50 g, 6.2 mmol), MeOH (60 mL) and 10 ml of 4 N HCl in dixoane (Aldrich). The mixture was heated at 60° C. overnight. The reaction was concentrated, and the residue was submitted to preparative HPLC (reverse-phase, acetonitrile/water with 0.01% ammonium acetate) to result in 4-(3-methyl-1H-indazol-5-yl)-6-(2-{[2-(methyloxy)ethyl]oxy}phenyl)pyrimidin-2(1H)-one (1.32 g). 1H NMR (400 MHz, d6-DMSO): δ 12.90 (s, br, 1H), 11.75 (s, br, 1H), 8.60 (s, 1H), 8.15 (d, 1H), 7.75 (d, 1H), 7.60-7.45 (m, 3H), 7.25-7.10 (m, 2H), 4.20 (t, 2H), 3.75 (t, 2H), 3.40 (s, 3H), 2.60 (s, 3H). MS (EI) for C21H20N4O3: 377 (MH+); and 6-{2-[(2-hydroxyethyl)oxy]phenyl}-4-(3-methyl-1H-indazol-5-yl)pyrimidin-2(1H)-one (250 mg) 1H NMR (400 MHz, d6-DMSO): δ 8.88 (s, 1H), 8.09 (d, 1H), 7.80-7.45 (m, 4H), 7.35-7.05 (m, 2H), 4.23 (t, 2H), 3.80 (t, 2H), 2.40 (s, 3H). MS (EI) for C20H18N4O3: 363 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Pd]>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C=CCc2ccccc2Cc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCCc2ccccc2Cc2ccccc2)cc1
Reaction time: 15 h

Procedure:
A solution of 4-[3-(2-benzylphenyl)prop-1-enyl]benzoic acid (6.43 g) in THF (50 ml) containing 10% palladium on carbon (1 g) was stirred under an atmosphere of hydrogen (balloon) for 15 hours. The catalyst was removed by filtration and the residue obtained on removal of the solvent was purified by chromatography on silica, eluting with 5% methanol in dichloromethane, to give 4-[3-(2-benzylphenyl)propyl]benzoic acid, m.p. 135-6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21](=[O:43])[N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[CH:32][N:31]=[C:30]4[NH:40][CH:41]=[CH:42][C:29]=34)[CH2:24][CH2:23]2)[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[CH:32][N:31]=[C:30]4[NH:40][CH:41]=[CH:42][C:29]=34)[CH2:24][CH2:23]2)=[O:43])=[CH:4][CH:3]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3cccnc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2c(-c3cccnc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Yield: 77.6 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate (25 mg, 0.041 mmol) in TFA (3 mL) was stirred for 30 minutes and then concentrated to dryness. The resulting residue was dissolved in minimal DCM (0.2 mL) and added to 2N HCl in ether. The resulting solid was filtered and dried under nitrogen to yield (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (16 mg, 77% yield) trihydro chloride. 1H NMR (400 MHz, DMSO-d6) δ 12.40 (br s, 1H), 8.96 (s, 1H), 8.77 (d, 1H), 8.45 (m, 1H), 8.13 (s, 1H), 7.89-7.84 (m, 1H), 7.52-7.45 (m, 3H), 7.41-7.32 (m, 3H), 6.74 (s, 1H), 4.66-4.61 (m, 1H), 3.90-3.15 (m, 10H), 3.00-2.96 (m, 1H), 2.82-2.75 (m, 1H), 1.23 (dq, 6H); m/z (APCI pos) 503.3 (100%) [M].
Reaction SMILES: [C:1]1([C@@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17]>>[CH2:19]([C@@H:15]1[S:11][C:10]([NH:9][CH2:8][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])[CH3:20]
Reactant: C[C@@H](CNC(N)=S)c1ccccc1
Reactant: CCC(Br)C(=O)O
Product: CC[C@@H]1SC(NC[C@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2R)-2-phenylpropyl]thiourea and 2-bromo-butyric acid according to Method D3.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=2[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].C[O:28][C:29](=[O:39])[CH:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)O>>[CH2:1]([C:5]1[O:6][C:7]2[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=2[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:30]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]([OH:39])=[O:28])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(O)Cc1ccccc1
Reactant: CCCCc1oc2ccccc2c1-c1ccc(-c2ccc(O)cc2)cc1
Product: CCCCc1oc2ccccc2c1-c1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-butyl-benzofuran-3-yl)-biphenyl-4-ol, and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 169-170° C.; MS m/e 491 (M+H)+;
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2NCCCO)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 161.1, 72 mg, 0.15 mmol), (6-methylpyridin-3-yl)boronic acid (20.7 mg, 0.15 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (5.3 mg, 0.0075 mmol) and the mixture subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=1.87 min, m/z=447.1 [M+H]+, m/z=445.2 [M−H]−.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[CH:29]1[C:38]2[C:33](=[C:34]([NH:39][NH2:40])[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>>[CH2:24]([N:23]([CH2:26][CH3:27])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:39]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]5[C:33]=4[CH:32]=[CH:31][N:30]=[CH:29]5)[N:40]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21])[CH3:25]
Reactant: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1cccc2cnccc12
Product: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4cnccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-diethyl-benzenesulfonamide (A-21) and isoquinolin-5-yl-hydrazine according to the method described for example 91. MS: M=501.2 (M+H)+