Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C:77](=[O:78])[NH:76][C@@:6]2([O:11][C@@H:10]([CH2:12][C@H:13]([OH:72])[C@H:14]([CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[C@H:23]3[O:58][C:56](=[O:57])[C@@H:54]4[NH:55][N:50]([CH2:51][CH2:52][CH2:53]4)[C:48](=[O:49])[C@H:47]([CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[CH:61]=4)[NH:46][C:44](=[O:45])[C@H:43]([CH:67]([CH3:69])[CH3:68])[NH:42][C:40](=[O:41])[C@@H:32]4[CH2:33][CH2:34][C@:35]([O:38]C)([CH3:37])[O:36][C@@H:31]4[C@@H:30]([CH3:70])[C@@H:29]([OH:71])[CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]3)\[CH3:22])[CH3:15])[C@H:9]([CH3:73])[C@H:8]([OH:74])[C@@H:7]2[CH3:75])[C@@H:5]([CH3:79])[CH2:4]1.S(=O)(=O)(O)O>C1COCC1.O>[CH3:1][CH2:2][C@@H:3]1[C:77](=[O:78])[NH:76][C@@:6]2([O:11][C@@H:10]([CH2:12][C@H:13]([OH:72])[C@H:14]([CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[C@H:23]3[O:58][C:56](=[O:57])[C@H:54]4[NH:55][N:50]([CH2:51][CH2:52][CH2:53]4)[C:48](=[O:49])[C@H:47]([CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[CH:61]=4)[NH:46][C:44](=[O:45])[C@H:43]([CH:67]([CH3:68])[CH3:69])[NH:42][C:40](=[O:41])[C@H:32]([CH2:33][CH2:34][C:35]([CH3:37])=[O:38])[C@H:31]([OH:36])[C@@H:30]([CH3:70])[C@@H:29]([OH:71])[CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]3)\[CH3:22])[CH3:15])[C@H:9]([CH3:73])[C@H:8]([OH:74])[C@@H:7]2[CH3:75])[C@@H:5]([CH3:79])[CH2:4]1
Reactant: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1CC=CC=C[C@H](O)[C@H](C)[C@H]3O[C@](C)(OC)CC[C@H]3C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Agent: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1C/C=C/C=C/[C@H](O)[C@H](C)[C@@H](O)[C@@H](CCC(C)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Agent: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1C/C=C\C=C/[C@H](O)[C@H](C)[C@H]3O[C@](C)(OC)CC[C@H]3C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1CC=CC=C[C@H](O)[C@H](C)[C@@H](O)[C@@H](CCC(C)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Reaction time: 1.5 h

Procedure:
A solution of 550 mg (0.50 mmol) of sanglifehrin C in 5 mL of 4:1 THF-water is treated with 0.5 mL of 2N aqueous sulfuric acid and stirred for 1.5 h. The reaction is quenched with saturated aqueous sodium bicarbonate and the resulting mixture is extracted twice with ethyl acetate. The organic solution is washed with saturated aqueous sodium bicarbonate solution and twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (90:10 methyl-tert.-butyl ether:methanol) to yield sanglifehrin A as a white amorphous powder.
Reaction SMILES: C([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:54]=[CH:53][C:10]([C:11]([O:26][CH2:27][C@@:28]23[C@@H:34]([O:35]CC4C=CC=CC=4)[C@@H:31]([O:32][CH2:33]2)[C@H:30]([N:43]2[CH:51]=[N:50][C:49]4[C:48](=[O:52])[NH:47][CH:46]=[N:45][C:44]2=4)[O:29]3)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>CO.ClCCl.[Pd]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([O:26][CH2:27][C@@:28]23[C@@H:34]([OH:35])[C@@H:31]([O:32][CH2:33]2)[C@H:30]([N:43]2[CH:51]=[N:50][C:49]4[C:48](=[O:52])[NH:47][CH:46]=[N:45][C:44]2=4)[O:29]3)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]2[CH:53]=[CH:54][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cnc5c(=O)[nH]cnc54)O2)[C@@H]3OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cnc5c(=O)[nH]cnc54)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 224.5 %

Procedure:
Sodium formate (1.2 g) was added to a mixture of compound 24 (1.02 g, 0.52 mmol) and Pd/C (10%, 0.5 g) in methanol (20 mL). The mixture was refluxed for 20 min, cooled to room temperature and diluted with dichloromethane (20 mL). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a white solid material, which was crystallised from 50% ethanol/water to yield 680 mg (77%) of compound 25.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:15]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH2:16][CH3:17])[CH3:14].C([N-]C(C)C)(C)C.[Li+].C[O:35][C:36](=O)[C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[N:39][CH:38]=1>O1CCCC1>[CH2:13]([N:15]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[C:36]([OH:35])[C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH3:43])[CH:42]=2)[C:20]1=[O:25])[CH2:16][CH3:17])[CH3:14]
Reactant: CCN(CC)CN1CCCCC1=O
Reactant: COC(=O)c1cncc(C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCN(CC)CN1CCCC(=C(O)c2cncc(C)c2)C1=O
Temperature: 25 °C
Yield: 13.2 %

Procedure:
To a solution of diisopropylamine (4.4 mL, 31.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (12 mL, 30 mmol). The solution was allowed to warm to rt over 30 min and was re-cooled to −78° C. A solution of 1-diethylaminomethyl-piperidin-2-one (3.87 g, 21.0 mmol) in tetrahydrofuran (10 mL) was added to the lithium diisopropylamide via syringe. The reaction mixture was maintained at −78° C. for 1 h and was treated with a solution of 5-methylnicotinic acid methyl ester (2.12 g, 14.0 mmol) in tetrahydrofuran (20 mL) via syringe. The reaction mixture was allowed to warm to rt and was maintained overnight. The reaction mixture was quenched with water (30 mL) and was extracted with ether (2 x). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography [1/0 to 1/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] to provide 560 mg (13%) of 1-diethylaminomethyl-3-[hydroxy-(5-methylpyridin-3-yl)methylene]piperidin-2-one. To a solution of the piperidin-2-one (550 mg, 1.8 mmol) in acetone (101 mL) was added conc. hydrochloric acid (2 L) and the reaction mixture was heated at 100° C. overnight. The reaction mixture was allowed to cool to rt, diluted with isopropyl alcohol, and allowed to stand at 0° C. The product was isolated by filtration, thus providing 400 mg (85%) of 5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl dihydrochloride.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.[CH:33]1([CH2:36][N:37]2[C:45]([N:46]3[CH2:51][CH2:50][NH:49][C@@H:48]([CH3:52])[CH2:47]3)=[N:44][C:43]3[C:38]2=[N:39][C:40]([C:59]2[CH:60]=[N:61][C:62]([NH2:65])=[N:63][CH:64]=2)=[N:41][C:42]=3[N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)[CH2:35][CH2:34]1.[C:66](O)(=[O:70])[C@@H:67]([CH3:69])[OH:68]>C(Cl)Cl.CO.CN(C)C=O>[NH2:65][C:62]1[N:63]=[CH:64][C:59]([C:40]2[N:39]=[C:38]3[C:43]([N:44]=[C:45]([N:46]4[CH2:51][CH2:50][N:49]([C:66](=[O:70])[C@H:67]([OH:68])[CH3:69])[C@@H:48]([CH3:52])[CH2:47]4)[N:37]3[CH2:36][CH:33]3[CH2:35][CH2:34]3)=[C:42]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[N:41]=2)=[CH:60][N:61]=1
Reactant: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CCN1
Reactant: C[C@@H](O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](O)C(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@@H]1C
Reaction time: 18.5 h
Yield: 50.6 %

Procedure:
1-Hydroxybenzotriazole (31:3 mg, 0.23 mmol), N,N′-dicyclohexylcarbodiimide (71.6 mg, 0.35 mmol), and triethylamine (64.5 μl, 0.46 mmol) were added to an N,N-dimethylformamide solution (3.0 ml) of 5-{9-(cyclopropylmethyl)-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (115.6 mg, 0.26 mmol) and D-lactic acid (25.3 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred for 18.5 hours followed by the addition of N,N′-dicyclohexylcarbodiimide (71.6 mg, 0.35 mmol) and the resulting mixture was stirred at 40° C. for 22 hours. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (68.7 mg, 57%) as a pale yellow solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[C:16](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:16][O:9][C:8]([C@H:5]1[CH2:6][CH2:7][C@@H:2]([OH:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cis-4-hydroxy-cyclohexanecarboxylic acid (10.0 g, 69.4 mmol) and a catalytic amount of concentrated sulfuric acid in methanol (700 ml) was heated at reflux over night. After cooling to room temperature the reaction mixture was neutralized by the addition of solid sodium carbonate. The mixture was stirred for 30 min, filtered and concentrated in vacuo. The residue was triturated in ethyl acetate (150 ml). The solids were removed by filtration. The filtrate was concentrated in vacuo to give the crude product (10.3 g, 94%) as colorless oil, which was used in the following steps without further purification. MS m/e: 159 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:31]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:10]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C(F)(F)F)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3-trifluoromethylphenylboronic acid (105 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate. (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 7-trifluoromethyl-4-(3-trifluoromethyl-phenyl)-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1.OB(O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:9][C:5]1[CH:4]=[CH:3][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: Cc1cc(-c2ccccc2)ccc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
A mixture of 5.00 g (24.3 mmol) of 5-bromo-2-chlorotoluene, 3.56 g (29.2 mmol) of dihydroxyphenylborane, 546 mg (2.43 mmol) of palladium acetate (II), 9.41 g (29.2 mmol) of tetrabutylammonium bromide, 8.40 g (60.8 mmol) of potassium carbonate and 50 ml of water was stirred for 5 hours at 80° C. under nitrogen flow. The reaction solution was filtrated through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, then, concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane) to obtain 3.92 g of 4-chloro-3-methylbiphenyl.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH2:9][CH:10]([CH2:14]C=C)[CH2:11][CH:12]=[CH2:13])[CH3:8].[C:17]([O-:20])(=[O:19])[CH3:18].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C.Cl.C(O)(=O)CC(O)=O.N1CCCC1>[OH-].[Na+].ClCCl.O1CCCC1>[CH2:9]([CH:10]([CH2:11][CH:12]=[CH2:13])[CH:14]=[CH:18][C:17]([OH:20])=[O:19])[CH:7]=[CH2:8]
Reactant: CC(=O)[O-]
Reactant: C=CCC(CC=C)CCC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(=O)O
Solvent: C1CCNC1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C=CCC(C=CC(=O)O)CC=C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (0.74 g, 20 mmol) was added to a tetrahydrofuran solution (30 mL) of ethyl 2-allylpent-4-ene-acetate (2.20 g, 13.1 mmol) under ice cooling, and the mixture was stirred in this state for 1 hour. To the reaction solution, a 1 N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 1 hour and then filtered through Celite. The filtrate was diluted with saturated saline and ethyl acetate and separated into aqueous and organic layers. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A dichloromethane solution (20 mL) of oxalyl chloride (1.6 mL, 13.1 mmol) was added dropwise to a dichloromethane solution (10 mL) of dimethyl sulfoxide (2.7 mL, 19.5 mmol) under cooling to −78° C. To the reaction solution, a dichloromethane (10 mL) solution of the above-obtained residue was added, and this mixture was stirred at −78° C. for 1 hour. To the reaction solution, triethylamine (7.1 mL, 52.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 1 N hydrochloric acid and saturated saline were added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in pyridine (2.3 mL). To the solution, malonic acid (1.55 g, 14.95 mmol) and pyrrolidine (0.43 mL) were added, and the mixture was stirred overnight at room temperature and further stirred for 6 hours under heating to reflux. The mixture was allowed to cool, then diluted with a 2 N aqueous sodium hydroxide solution, and then washed with dimethyl ether. The aqueous layer was made acidic using concentrated hydrochloric acid under ice cooling, followed by extraction with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (1.49 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[CH2:26][O:25]4)=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(O)C>[CH:27]1([NH:33][CH2:26][CH:24]([OH:25])[CH2:23][O:22][C:16]2[CH:15]=[C:14]3[C:19]([C:20](=[O:21])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:12][O:13]3)=[CH:18][CH:17]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1OC
Reactant: NC1CCCCC1
Solvent: CCO
Product: COc1ccc(-c2coc3cc(OCC(O)CNC4CCCCC4)ccc3c2=O)cc1OC
Yield: 52.9 %

Procedure:
A mixture of compound 4 (obtained from example 2) (0.35 g, 1 mmol), cyclohexylamine (0.50 g, 5 mmol), and ethanol (30 mL) was refluxed for 6 hrs (TLC monitoring). After removal of solvent in vacuo, the residue was treated with H2O (50 mL). The resulting precipitate was collected and purified by column chromatography (MeOH/CH2Cl2=1:25) to give the title compound 6c (0.24 g, 54% yield). M.p.: 70-71° C.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2=[N:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][NH2:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][NH:24][C:14]([C:3]1[N:4]=[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:6]2[C:7](=[O:8])[C:2]=1[OH:1])=[O:16]
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CN1C(=O)Cn2c1nc(C(=O)NCc1ccc(Cl)c(Cl)c1)c(O)c2=O
Yield: 59.6 %

Procedure:
Reaction of intermediate 13, ethyl 6-hydroxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate, (0.050 g, 0.197 mmol) with 3,4-dichlorobenzylamine (0.11 g, 0.57 mmol) as described in the preparation of example 1 gave 0.045 g (59% yield) of the title amide as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.15 (3H, s, NCH3), 4.48 (2H, s, CH2), 4.50 (2H, d, J=6.9 Hz, NCH2), 7.32 (1H, dd, J=1.4 Hz and J=8.3 Hz, aromatic), 7.58 (1H, d, J=1.4 Hz, aromatic), 7.62 (1H, d, J=8.3 Hz, aromatic), 9.52 (1H, broad t, NH), 12.13 (1H, s, OH). MS (ESI+) m/z 383 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)(=[O:20])=[O:19]
Reactant: OCc1ccc(Br)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)cn1
Reaction time: 2.5 h

Procedure:
A solution of (5-bromo-pyridin-2-yl)-methanol (20.0 g, 106 mmol) in 150 mL of dichloromethane was cooled to 0° C. under nitrogen. Triethylamine (19.3 mL, 138 mmol) was added, followed by methanesulfonyl chloride (9.95 ml, 128 mmol). After 2.5 hours, the mixture was quenched with 50 mL of water and diluted with 100 mL of dichloromethane. The organic layer was washed with an additional 50 mL of water and then the aqueous layer was extracted with 100 mL of methylene chloride. The organic extracts were dried over sodium sulfate, filtered and concentrated to provide (5-bromopyridin-2-yl)methyl methanesulfonate as a red solid that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 268.1 for M+H+(81Br).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[N+:30]([O-:32])=[O:31].[Cl-].[NH4+]>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:24]3[C:23]([N+:30]([O-:32])=[O:31])=[CH:22][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[N:9]=[C:10]([C:11]([F:14])([F:12])[F:13])[C:3]=12
Reactant: FC(F)(F)c1n[nH]c2nccc(I)c12
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1cccc([N+](=O)[O-])c1-n1nc(C(F)(F)F)c2c(I)ccnc21
Temperature: 70 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
Compound (153a) (5.00 g), cesium carbonate (6.72 g), and 4-chloro-3-nitrobenzonitrile (3.21 g) were suspended in acetonitrile (50 mL), followed by stirring at 70° C. for 4 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the precipitate was collected by filtration and dried under reduced pressure to obtain 4-{(4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-nitrobenzonitrile (7.19 g, 98%). The obtained 4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-nitrobenzonitrile (7.19 g) was suspended in THF (50 mL), MeOH (50 mL), and water (50 mL), and ammonium chloride (7.20 g) and iron powder (8.76 g) were added to the resulting suspension, followed by stirring at 80° C. for 2 hr. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered by celite. The solvent of the filtrate was distilled away, and water was added to the residue. Insoluble matters were collected by filtration and dried under reduced pressure to obtain compound (158a) (6.44 g, 96%).
Reaction SMILES: [CH2:1]([C:4]1([C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15]C)=[O:14])=[CH:12][C:7]=2[O:6][CH2:5]1)[CH:2]=[CH2:3].[OH-].[Na+].[OH-].[Li+]>>[CH2:1]([C:4]1([C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[O:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)COc2cc(C(=O)OC)ccc21
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Product: C=CCC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 3-allyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2H-1-benzofuran-6-carboxylate (240 mg, 0.61 mmol), sodium hydroxide (0.12 g, 3 mmol) and lithium hydroxide (0.06 g, 3 mmol) is stirred at room temperature for 3 days. The mixture is concentrated on a rotary evaporator under vacuum at 40° C. 10 ml of water and 10 ml of ethyl acetate are added. The mixture is acidified with concentrated hydrochloric acid solution to pH 1. After separation of the phases by settling, the organic phase is washed twice with 10 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is obtained by recrystallization from a heptane/ethyl ether mixture (3/1).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C@H:24]1[N:29]([CH3:30])[CH2:28][CH2:27][N:26]([C:31]2[C:36]([F:37])=[C:35]([NH:38][NH2:39])[N:34]=[C:33]([CH3:40])[N:32]=2)[CH2:25]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:39][NH:38][C:35]2[C:36]([F:37])=[C:31]([N:26]3[CH2:27][CH2:28][N:29]([CH3:30])[C@H:24]([CH3:23])[CH2:25]3)[N:32]=[C:33]([CH3:40])[N:34]=2)=[O:10])[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Cc1nc(NN)c(F)c(N2CCN(C)[C@H](C)C2)n1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)[C@H](C)C2)n1
Yield: 50.5 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.079 g, 0.30 mmol), 4-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (0.079 g, 0.31 mmol), NMM (0.10 mL, 0.90 mmol), HOAt (0.042 g, 0.31 mmol), and EDC (0.059 g, 0.31 mmol) were dissolved in DMF (4 mL) and treated in a manner similar to General Procedure A, Part B, to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.082 g, 49%). LCMS: (M+H)+=542.7.