Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].C[Si](C)(C)[O:14][C:15]1[CH:16]=[C:17]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:18]=[CH:19][C:20]=1[C:21]([O:23][Si](C)(C)C)=[CH2:22]>CO>[OH:6][CH2:23][C:21]([C:20]1[CH:19]=[CH:18][C:17]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:16][C:15]=1[OH:14])=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(O[Si](C)(C)C)c1ccc(N2CCOCC2)cc1O[Si](C)(C)C
Solvent: CO
Product: O=C(CO)c1ccc(N2CCOCC2)cc1O
Temperature: -78 °C
Reaction time: 16 h

Procedure:
3-Chloroperoxybenzoic acid (1.48 g, 6.0 mmol) was slurried in hexanes (40 mL) and cooled to −78° C. A solution of 4-(3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-phenyl]-morpholine (1.10 g, 3.01 mmol) dissolved in hexanes (5 mL) was added slowly. The resulting suspension was maintained at −78° C. for 60 minutes then slowly warmed to 22° C. After stirring at 22° C. for 16 hours, the reaction mixture was diluted with methanol and concentrated in vacuo. The residue was redissolved in methanol and concentrated two additional times. The solids were resuspended in EtOAc and washed 2 times with saturated NaHCO3, and once with saturated NaCl then dried over Na2SO4. After concentration, the residue was chromatographed on SiO2 using 2:1 hexane/EtOAc then 1:1 hexane/EtOAc. After concentration, the alcohol was recrystallized from EtOAc. (19% yield).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]([OH:15])([CH3:14])[CH3:13])[N:8]2[CH3:11])=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)O1>>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([C:12]([OH:15])([CH3:14])[CH3:13])[N:8]4[CH3:11])=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:3]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: Cn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: Cn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
Crude 2-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)propan-2-ol was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via Procedure A and purified via reverse phase HPLC to give 56.6 mg of 132 as a white solid. MS (Q1) 394.3 (M)+
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:5]=1.Cl[C:18]1[NH:19][C:20]2[C:25]([C:26](=[O:28])[N:27]=1)=[C:24]([CH3:29])[C:23]([O:30][CH3:31])=[C:22]([O:32][CH3:33])[CH:21]=2>CCO>[CH3:31][O:30][C:23]1[C:24]([CH3:29])=[C:25]2[C:20](=[CH:21][C:22]=1[O:32][CH3:33])[NH:19][C:18]([N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH:5]=1)=[N:27][C:26]2=[O:28]
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2c(C)c1OC
Reactant: CNCc1cccc(C2CCN(C)CC2)c1
Solvent: CCO
Product: COc1cc2[nH]c(N(C)Cc3cccc(C4CCN(C)CC4)c3)nc(=O)c2c(C)c1OC
Temperature: 120 °C

Procedure:
In a heavy-walled pressure tube, a mixture of methyl-[3-(1-methylpiperidin-4-yl)benzyl]amine (0.14 g, 0.64 mmol) and 2-chloro-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one (0.155 g, 0.60 mmol) in 4 mL of EtOH, was heated to 120° C. for 5 hours. After solvent removal, the residue was purified by flash chromatography eluting with CH2Cl2:MeOH:NH4OH (94.5:5:0.5), and the above-titled Example H-3 crystallized from CH2Cl2/cyclohexane. mp 155.7–158° C.; IR (KBr) νmax 2933, 1651, 1590 cm−1; 1H NMR (DMSO-d6, 2.49) δ 1.59–1.71 (m, 4H), 1.93 (m, 2H), 2.16 (s, 3H), 2.42 (m, 1 H), 2.60 (s, 3H), 2.82 (m, 2 H), 3.01 (s, 3H), 3.62 (s, 3H), 3.84 (s, 3H), 4.78 (s, 2H), 6.63 (br s, 1H), 7.03 (d, 1H, J=7.44), 7.11–7.13 (m, 2 H), 7.25 (t, 1H, J=7.74), 10.81 (br s, D2O, 1H); 13C NMR (DMSO-d6, 39.50) δ 13.44, 32.94, 35.12, 41.08, 46.09, 51.64, 55.44, 55.65, 59.76, 124.61, 125.32, 125.65, 128.44, 137.54, 146.43; MS (ES+) m/z 437 (M+H); Anal. (C25H32N4O3.0.25H2O)C: calcd, 68.08; found, 68.02; H: calcd, 7.43; found, 7.19; N: calcd, 12.70; found, 12.69.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=2[C:18]([CH3:29])([CH3:28])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH2:30](O)[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=2[C:18]([CH3:29])([CH3:28])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:30][CH3:31])=[O:26])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C2=C(C(C)(C)COCCCCC(=O)O)C(C)(C)CO2)c1
Reactant: CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCOCC(C)(C)C1=C(c2cccc(OC(C)=O)c2)OCC1(C)C
Reaction time: 0.33 h

Procedure:
In a nitrogen atmosphere at room temperature, to a THF (2.5 mL) solution having 5-(3-acetoxyphenyl)-4-(7-carboxy-1,1-dimethyl-3-oxaheptyl)-3,3-dimethyl-2,3-dihydrofuran (compound (15)) (209 mg, 0.5167 mmol) dissolved, ethanol (48 mg, 1.042 mmol, 2.0 eq.) and triphenyl phosphine (275 mg, 1.048 mmol, 2.0 eq.) were added, and further diethyl azodicarboxylate (185 mg, 1.062 mmol, 2.1 eq.) dissolved in THF (0.5 mL) was added, followed by stirring for 20 minutes. This reaction solution was put into a 1N hydrochloric aqueous solution and a saturated sodium chloride aqueous solution, and extracted with ethyl acetate. The aqueous layer was again extracted with ethyl acetate, and the extract was put together with the previous organic layer, followed by washing with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain a residue. This residue was subjected to silica gel column chromatography with a developing solvent (ethyl acetate:hexane=1:20). As a result, the desired 5-(3-acetoxyphenyl)-4-(7-ethoxycarbonyl-1,1-dimethyl-3-oxaheptyl)-3,3-dimethyl-2,3-dihydrofuran (compound (17)) was obtained as a colorless oil (172 mg, 0.3976 mmol, 77.0%).
Reaction SMILES: N1(CCN[C:9]2[N:14]=[C:13]([C@@H:15]([NH:25][C:26](=[O:44])[CH2:27][N:28]3[C:36]4[C:35]([F:38])([F:37])[CH2:34][CH2:33][C:32]([F:40])([F:39])[C:31]=4[C:30]([CH:41]([F:43])[F:42])=[N:29]3)[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=2)C=CN=N1.[NH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][C:59]1=[O:63].BrC1C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1>>[F:43][CH:41]([F:42])[C:30]1[C:31]2[C:32]([F:39])([F:40])[CH2:33][CH2:34][C:35]([F:37])([F:38])[C:36]=2[N:28]([CH2:27][C:26]([NH:25][C@H:15]([C:13]2[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=[C:9]([NH:55][CH2:56][CH2:57][N:58]3[CH2:62][CH2:61][CH2:60][C:59]3=[O:63])[N:14]=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[O:44])[N:29]=1
Reactant: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Reactant: NCCN1CCCC1=O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Product: NC(=O)c1cc(-c2cnc(NCCN3CCCC3=O)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (24) was prepared according to the method presented for the synthesis of compound 23F of Example 23 starting with 1-(2-aminoethyl)pyrrolidin-2-one and 23B. MS (m/z) 1H NMR (400 MHz, CD3OD) δ 8.84 (m, 1H), 8.07 (s, 1H), 7.50-7.27 (m, 2H), 7.24-7.11 (m, 1H), 6.97-6.61 (m, 2H), 6.45 (d, J=6.2 Hz, 2H), 5.27 (m, 1H), 5.10 (s, 2H), 3.57 (m, 6H), 3.18-2.87 (m, 2H), 2.51 (m, 4H), 2.41-2.28 (m, 2H), 2.12-1.89 (m, 2H). 783.12 [M+H]+.
Reaction SMILES: [CH:1]1([CH:8](O)[CH:9]2[C:13](=[O:14])[C:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])=[C:11]([O:24]C)[CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CC(C)=O.O>[CH:1]1([CH:8]=[C:9]2[CH2:10][C:11](=[O:24])[CH:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:13]2=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCCCCC2)C1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)c(C2C(=O)CC(=CC3CCCCCC3)C2=O)c(C)c1
Yield: 96.9 %

Procedure:
To a solution of 5-(Cycloheptyl-hydroxy-methyl)-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (100 mg, 0.28 mmol) in acetone (4 ml) in a 10 ml vial was added 2M HCl (4 ml). The reaction was capped and heated to 120 C for 30 minutes under microwave irradiation. The reaction was diluted with H2O (20 ml) and extracted with EtOAc (3×15 ml). The combined organic extracts were washed with brine (10 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to give a brown oil (88 mg). The crude material was purified by flash chromatography over SiO2 using a 100% isohexane to 100% EtOAc gradient to give the desired product as a colourless oil (62 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)[CH2:31][CH2:32][CH2:33][N:34]=[C:35]=NCC.O.ON1C2C=CC=CC=2N=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:34]3[CH2:35][CH2:31][CH2:32][CH2:33]3)=[O:26])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[O:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCNC1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (4.7 mg, 0.030 mmol), and CH2Cl2 (2 mL) were added pyrrolidine (3.2 mg, 0.046 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CC(O)=O.[Br:30]Br>O>[Br:30][C:9]1[S:10][C:6]2[CH2:5][CH2:4][N:3]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:2](=[O:1])[C:7]=2[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sccc3C2=O)CC1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sc(Br)cc3C2=O)CC1
Reaction time: 0.17 h

Procedure:
2-4 (0.73 g, 2.0 mmoles) was added to a 50% aqueous HOAc solution (40 ml) and after stirring at 0°-10° for 10 minutes, Br2 (0.32 g, 2.0 mmoles) was added dropwise. After stirring at 0°-10° for 3 hours, the reaction mixture was diluted with 150 ml H2O and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with hexane (85)/acetone (15) to give pure 3-1, Rf 0.3.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH3:10])=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][N:13]([CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])[S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH3:10])=[CH:27][CH:28]=1
Reactant: CN(CC=Cc1ccc(Cl)cc1)CCNS(=O)(=O)c1cccc2cnccc12
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCN(CCN(C)CC=Cc1ccc(Cl)cc1)S(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 1.0 g of the amorphous compound obtained in Example 190, 0.267 g of 2-dimethylamino ethanol and 0.982 g of triphenylphosphine in 5 ml of tetrahydrofuran, was added dropwise a solution of 0.652 g of diethyl azodicarboxylate in 2 ml of tetrahydrofuran with stirring under ice cooling. After 2 hours, the reaction mixture was concentrated under a reduced pressure to remove tetrahydrofuran, and resulting residue was dissolved in 10 ml of ethyl acetate and extracted three times with 10 ml of 1N hydrochloric acid. The aqueous layer was alkalized with sodium bicarbonate and extracted three times with 10 ml of ethyl acetate, and the organic layer was dried over magnesium sulfate and evaporated to removed the solvent under a reduced pressure. The resulting residue was then applied to a silica gel column and eluted with 3% methanol in chloroform, to obtain 0.77 g of the title compound as a colorless oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][CH2:17][C@H:18]1[C@H:22]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:21][CH:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClC(Cl)(Cl)Cl>[C:20]([O:19][C@H:18]([C@H:22]([Br:1])[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:21])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(COC[C@@H]2OC(c3ccccc3)O[C@H]2COCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O[C@@H](COCc1ccccc1)[C@H](Br)COCc1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 72 h

Procedure:
10.9 g (61.2 mMol) N-bromosuccinimide are suspended in 150 ml tetrachloromethane, the suspension cooled to 4° C. and 23.9 g (61.2 mMol) of (4S,5S)-4,5-dibenzyloxymethyl-2-phenyl-1,3-dioxolan dissolved in 250 ml tetrachloromethane added dropwise at the same temperature over a period of 50 minutes. The cooling bath is removed, the reaction flask wrapped in aluminium foil and the reaction mixture stirred for 3 days at room temperature. The obtained orange coloured suspension is diluted with 1 liter methylene chloride and shaken with 200 ml saturated sodium bicarbonate solution. The aqueous phase is extracted with 300 ml methylene chloride and the combined organic phases are dried over sodium sulfate, filtered through a layer of talc and evaporated under vacuum. The residue is chromatographed using 1 kg of silica gel 60 and methylene chloride as eluant. The title compound is obtained as a colourless oil: rotation, [α]D22 =+18.7°, (c=1.3 in chloroform).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32])(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-(tetrahydro-2-furanylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.057 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (3 mL) under nitrogen was treated with acetic anhydride (0.06 mL, 0.63 mmol) at 40° C. The reaction was concentrated in vacuo and the resulting residue was treated with 1 N NaHSO4, filtered, washed with water, and dried in vacuo to provide the title compound as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (ddd, J=15.28, 11.80, 7.14 Hz, 1 H), 1.67 (s, 3 H), 1.79-1.89 (m, 2 H), 1.90-2.00 (m, 1 H), 3.26-3.31 (m, 2 H), 3.33-3.40 (m, 1 H), 3.56 (ddd, J=13.91, 5.95, 4.30 Hz, 1 H), 3.64-3.71 (m, 1 H), 3.76-3.84 (m, 1 H), 3.96-4.04 (m, 1 H), 4.15 (s, 2 H), 4.27 (t, J=6.77 Hz, 2 H), 7.11-7.17 (m, 2 H), 7.38-7.44 (m, 2 H), 8.03 (t, J=5.85 Hz, 1 H), 8.19 (d, J=1.46 Hz, 1 H), 8.56 (d, J=1.46 Hz, 1 H), 10.42 (t, J=5.58 Hz, 1 H); ES+ MS: 483 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[C:29]([N:33]1[CH2:37][CH2:36][NH:35][C:34]1=[O:38])([CH3:32])([CH3:31])[CH3:30].N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[C:29]([N:33]1[CH2:37][CH2:36][N:35]([C:6]2[CH:5]=[CH:4][C:3]([N:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:21]=[CH:20][CH:19]=4)=[N:10]3)=[C:2]([F:1])[CH:7]=2)[C:34]1=[O:38])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N1CCNC1=O
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cn(-c2ccc(N3CCN(C(C)(C)C)C3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 39.4 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (488 mg, 1.0 mmol), 1-tert-butylimidazolidin-2-one (171 mg, 1.2 mmol), CuI (19 mg, 0.1 mmol), trans-1,2-diaminocyclohexane (0.024 mL, 0.2 mmol), and K3PO4 (425 mg, 2.0 mmol) in toluene (5 mL) was stirred at 80° C. for 24 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography eluting with hexane/AcOEt (1/1), AcOEt only and then AcOEt/MeOH (10/1) and recrystallized from AcOEt to give the title compound (198 mg, 39% yield) as a white solid: mp 238-239° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 1.36 (9H, s), 3.29 (3H, s), 3.44-3.59 (2H, m), 3.64-3.76 (2H, m), 6.92-7.03 (2H, m), 7.23-7.51 (6H, m), 7.70 (1H, dd, J=14.1, 2.4 Hz), 7.78 (1H, d, J=1.9 Hz), 8.43 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 503 [M+H]+. Anal. Calcd for C27H27FN6O3: C, 64.53; H, 5.42; N, 16.72. Found: C, 64.31; H, 5.38; N, 16.58.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([C:17]2[C:18]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([NH:41]C(=O)C)=[N:39][CH:40]=3)=[N:19][CH:20]=[C:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:22]=2)[N:3]=1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].C(N)(=O)C>C(Cl)Cl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([C:17]2[C:18]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=3)=[N:19][CH:20]=[C:21]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=3)[CH:22]=2)[N:3]=1
Reactant: CC(=O)Nc1ccc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2Nc2ccc(N)nc2)c2nc[nH]c2n1
Yield: 11.2 %

Procedure:
A solution of N-(5-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-ylamino)pyridin-2-yl)acetamide (24.5 mg, 0.040 mmol) in DCM (3 mL) was treated with TFA (0.5 mL). The reaction was monitored by LCMS and, upon completion, some hydrolyzed acetamide was also observed. The mixture was concentrated and purified by prep HPLC to give N5-(3-(2-methyl-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-yl)pyridine-2,5-diamine bis(trifluoroacetate) (3.2 mg, 4.48 μmol, 11.20% yield) followed by N-(5-(3-(2-methyl-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-ylamino)pyridin-2-yl)acetamide trifluoroacetate (8.4 mg, 0.013 mmol, 32.7% yield).
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1.[C:19]1([CH2:25][CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[OH:1][CH:2]([CH2:18][NH:27][CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCC(c2cccc(OCC3CO3)c2)=NN1
Reactant: NCCc1ccccc1
Product: O=C1CCC(c2cccc(OCC(O)CNCCc3ccccc3)c2)=NN1

Procedure:
6-[3-(2,3-Epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone was reacted with phenylethylamine in a similar manner to that described in Example 1(ii) to give 6-[3-(2-hydroxy-3-phenethylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: OO.O.[OH-].[Li+].C(OC(N([C@@H](C1C=CC=C(OC)C=1)C)[C:12](=[O:23])[CH:13]([CH2:20][CH:21]=[CH2:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=O)C.S([O-])([O-])=[O:35].[Na+].[Na+]>C1COCC1.O>[CH2:20]([CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:23])=[O:35])[CH:21]=[CH2:22]
Reactant: O=S([O-])[O-]
Reactant: C=CCC(CCCCCC)C(=O)N(C(=O)OCC)[C@H](C)c1cccc(OC)c1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(CCCCCC)C(=O)O
Reaction time: 3 h

Procedure:
An aqueous solution of hydrogen peroxide (31% by weight; 0.5 ml, 55.0 mmol) and 0.043 g (1.0 mmol) of lithium hydroxide monohydrate were added dropwise to a solution of 0.20 g (0.50 mmol) of N-ethyloxycarbonyl-N-(2-allyloctanoyl)-(R)-1-(3-methoxyphenyl)ethylamine ((1R,2S):(1R,2R)=77:23) in a mixture of 4 ml of THF and 1 ml of water on an ice bath. The mixture was stirred on an ice bath for 3 hours and then at room temperature for 20 hours. A 2 N aqueous solution of sodium sulfite (5 ml) was added dropwise to the reaction mixture on an ice bath, and the resulting mixture was stirred at room temperature for 2 hours. Water (15 ml) was added to the reaction mixture, and the whole mixture was washed with 5 ml of ethyl acetate. To the aqueous layer was added 2 ml of a 1 N aqueous solution of hydrochloric acid (pH=2), and the resulting mixture was extracted with two 40-ml portions of ethyl acetate. The organic layer was concentrated under reduced pressure to give 0.078 g (83%, 62% ee) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:26][CH2:25][CH2:24][CH2:23][Br:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(O)ccc21
Reactant: BrCCCCBr
Product: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(OCCCCBr)ccc21

Procedure:
In analogy to example 1.4, 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless oil, MS: 438 (MH+, 1Br, 1Cl);