Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.C1C2C(=CC=CC=2)C=CC=1[Mg]Br.N#N.C[C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1C)/[CH:32]=[C:33]1\CC[C:36]2NC(C(OC)=O)=[CH:39][C:40]\1=2>C1COCC1.[Pd].CCOCC>[CH:39]1[C:30]2[C:31](=[CH:45][CH:46]=[CH:47][CH:29]=2)[CH:32]=[CH:33][C:40]=1[CH2:36][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: COC(=O)c1cc2c([nH]1)CC/C2=C\c1ccc(C)c(C)c1
Agent: [Pd]
Agent: Br[Mg]c1ccc2ccccc2c1
Agent: N#N
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc2ccccc2c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (1.00 g, 5.58 mmol) was reacted with 2-naphthalenylmagnesium bromide (55 mL, 21 mmol) according to General Procedure 3. In this example, the 2-naphthalenylmagnesium bromide was first placed in a separate flask and the Et2O was blown off with N2. The residue was then dissolved in 50 mL THF, and added to the 4-oxo solution over 20 min via cannulae. The resulting exo-olefin ((E)-methyl 4-(naphthalen-2-ylmethylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was converted to the title compound by hydrogenation according to General Procedure 6 (with 10% Pd/C). The crude product was used in the next step without further purification. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.16 (ddt, J=12.27, 8.77, 6.00, 6.00 Hz, 1H) 2.51-2.62 (m, 1H) 2.62-2.78 (m, 2H) 2.97 (d, J=7.61 Hz, 2H) 3.37-3.46 (m, 1H) 3.67-3.69 (m, 3 H) 6.27 (d, J=1.71 Hz, 1H) 7.40-7.52 (m, 3H) 7.73 (s, 1H) 7.81-7.91 (m, 3H) 10.47 (br. s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]=[O:13]>N1C=CC=CC=1>[OH:13][CH2:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: C=O
Solvent: c1ccncc1
Product: CC1(C)CC(O)CC(C)(C)N1CO
Temperature: 25 °C

Procedure:
In a 1-liter stainless steel container are placed 79 grams of 2, 2, 6, 6-tetramethyl-4-hydroxypiperidine, 132 grams of paraformaldehyde and 300 milliliters of pyridine. The flask is evacuated, filled with nitrogen and this process repeated 3 times. The flask is then sealed and heated at 135° to 140°C. for 30 minutes with rocking. The flask is then cooled quickly to room temperature, the contents removed and the mixture filtered. The pyridine is removed from the filtrate on a rotary evaporator. The remaining viscous oil is dissolved in ether, treated with activated charcoal, brought to a boil and filtered. The ether is removed from the filtrate on a rotary evaporator to yield 1-hydroxymethyl-2, 2, 6, 6 -tetramethyl-4-hydroxypiperidine as a viscous oil.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11]([NH:13]C(=O)C1C=CC=CC=1)=[O:12])#[N:2].[CH3:22]I>>[CH3:22][O:12][C:11]1[N:13]=[C:1]([NH2:2])[C:3]2[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=2[N:10]=1
Reactant: Cc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C
Reactant: CI
Product: COc1nc(N)c2c(C)c(C)sc2n1
Yield: 86 %

Procedure:
Prepared in a similar manner to Example 25 from N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamoyl)benzamide (Example 4a) and methyl iodide in 86% yield. 1H NMR (400 MHz, CDCl3) δ2.35 (s, 3H), 2.36 (s, 3H), 3.53 (s, 3H), 6.0 (bs, 2H). MS 210 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([CH:12]([CH2:22][CH2:23][CH2:24][CH:25]([OH:38])[CH2:26]OC1C=CC(C(C)(C)C)=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])[CH3:10]>>[C:9]([CH:12]([CH2:22][CH2:23][CH2:24][CH:25]([OH:38])[CH2:26][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])[CH3:10]
Reactant: Oc1ccccc1F
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(C(C)(C)C)cc1
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccccc1F

Procedure:
The synthesis of this compound is carried out by the procedure of Example 10 except that an equivalent amount of 2-fluorophenol is substituted for the 4-tert-butylphenol of Example 10. The title compound is obtained as a viscous oil after purification by silica gel column chromatography.
Reaction SMILES: [Se](O)(O)=[O:2].[CH2:5]([O:7][C:8](=[O:22])[CH2:9][C:10]1[C:11]([Cl:21])=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]2)[CH3:6]>O1CCOCC1.O>[CH2:5]([O:7][C:8](=[O:22])[CH2:9][C:10]1[C:11]([Cl:21])=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH:20]=[O:2])[CH:16]=[CH:15]2)[CH3:6]
Reactant: O=[Se](O)O
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(C)nc12
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(C=O)nc12
Temperature: 100 °C
Yield: 77 %

Procedure:
Selenious acid (193 mg, 1.50 mmol, 1.1 equiv) was added to a solution of (7-chloro-2-methyl-quinolin-8-yl)-acetic acid ethyl ester in dioxane (12 ml). The reaction mixture was heated to 100° C. After 20 and 40 minutes, additional portions of selenious acid (88 mg each) were added, and heating was continued for a total of 90 minutes. After cooling, the reaction mixture was diluted with water, filtered, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 80:20) to afford the title compound (292 mg, 77%). 1H NMR (400 MHz, CDCl3): δ=10.18 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 4.61 (s, 2H), 4.22 (q, J=7.3 Hz, 2H), 1.28 (t, J=7.3 Hz, 3H). MS (ES+): 278.2 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34]/[C:35](=[CH:39]\[CH:40]1[C:45]([CH3:47])([CH3:46])[CH2:44][CH2:43][CH:42]=[C:41]1[CH3:48])/[C:36](=O)[CH3:37]>>[CH3:37][C:36](/[C:35](/[CH3:34])=[CH:39]/[CH:40]1[C:45]([CH3:47])([CH3:46])[CH2:44][CH2:43][CH:42]=[C:41]1[CH3:48])=[CH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)/C(C)=C/C1C(C)=CCCC1(C)C
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(=CCc1ccccc1)/C(C)=C/C1C(C)=CCCC1(C)C
Yield: 19.5 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.80 g, 6.26 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.9 mL, 6.26 mmol, 1.0 equiv.) and (E)-3-methyl-4-(2,6,6-trimethylcyclohex-2-enyl)but-3-en-2-one (1.94 g, 9.39 mmol, 1.5 equiv.), 0.36 g (20%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:22][C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[CH3:29].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:32])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Temperature: 40 °C
Yield: 49.6 %

Procedure:
A mixture of 3-(4-aminomethyl-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 3-chloro-4-methylphenyl isocyanate (0.26 g, 1.6 mmol) and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at this temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.35 g of the product in 50% yield: mp>260° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.22 (s, 3H), 2.36-2.43 (m, 1H), 2.57-2.64 (m, 1H), 2.86-2.98 (m, 1H), 4.36 (d, J=5.6 Hz, 2H), 4.40 (d, J=17.3 Hz, 1H), 4.54 (d, J=17.3 Hz, 1H), 5.15 (dd, J=13.1 Hz, J=5.0 Hz, 1H), 6.77 (t, J=5.6 Hz, 1H), 7.09-7.19 (m, 2H), 7.48-7.57 (m, 2H), 7.61-7.64 (m, 2H), 8.72 (s, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 18.7, 22.6, 31.2, 39.7, 46.2, 51.6, 116.5, 117.7, 121.6, 127.5, 128.3, 130.4, 131.0, 131.7, 133.0, 135.5, 139.5, 139.9, 155.1, 168.1, 171.0, 172.8; Anal. calcd for C22H21ClN4O4.0.2H2O: C, 59.45; H, 4.85; N, 12.60. Found: C, 59.28; H, 4.83; N, 12.39.
Reaction SMILES: NCCNC(=O)OCC1C=CC=CC=1.[N:15]([C:18](=[CH:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2)[C:19]([O:21][CH3:22])=[O:20])=[N+]=[N-].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]1[C:24]2=[C:25]3[C:29]([CH:30]=[CH:31][C:32]2=[N:15][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[N:28][CH:27]=[CH:26]3
Reactant: COC(=O)C(=Cc1cccc2[nH]ccc12)N=[N+]=[N-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCCNC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=Cc2c3c(ccc2=N1)=NC=C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 338.3 %

Procedure:
A solution of 1 (47 mg, 0.06 mmol), 2 (40 mg, 0.078 mmol) and BOP (34.5 mg, 0.078 mmol) in DMF (3 ml) was treated with DIPEA (68 uL). The reaction mixture was stirred at 25° C. for 30 min. The solvent was removed and was further dried in high vacuo for 4 h. The solvent was removed under vacuo and the crude product was purified by Prep HPLC (SymmetrPrep C18, 7 μm, 19×150 mm column), eluted at 10 ml/min (0.01% TFA in water/acetonitrile) with a gradient: 10% acetonitrile in 5 min, 10% to 50% acetonitrile in 15 min, maintaining 50% acetonitrile in 5 min, 50% to 100% acetonitrile in 5 min, to give 3 (56 mg, 85%). MS: calcd for C56H54BrN9O8 (M+H) m/z 1060.33 found 1060.44.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][CH:29]([NH2:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)[NH:34][CH:29]([CH3:28])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(N)C(C)(C)C
Reactant: COc1cc(NC(SC)=C(C#N)S(=O)(=O)c2ccc(Cl)cc2)cc(OC)c1
Product: COc1cc(NC(NC(C)C(C)(C)C)=C(C#N)S(=O)(=O)c2ccc(Cl)cc2)cc(OC)c1
Yield: 72 %

Procedure:
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-methylsulfanyl-2-propenenitrile (0.34 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 22 h at 75° C. under nitrogen. Work up as described in EXAMPLE 1, 2) gave 264 mg (72%) of the title compound. Mp 177.5-179° C. 1H NMR (200 MHz, CDCl3): δ=0.82 (s, 9H), 0.95 (d, 3H), 3.2 (m, 1H), 6.13 (d, 2H), 6.32 (t, 1H), 7.45 (d, 2H), 7.82 (d, 2H); EI SP/MS: 478 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[N:32]=[C:33]([I:34])[C:26]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[N:32]=[C:33]([I:34])[C:26]=12
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Reactant: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 150 °C
Reaction time: 72 h
Yield: 77.1 %

Procedure:
A mixture of 5-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.009 g, 0.03 mmol, prepared in Example 45, step F), 4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (0.010 g, 0.0250 mmol) and DMAP (0.006 g, 0.05 mmol) in bromobenzene (0.300 mL) under N2 was stirred at 150° C. for 3 days. The reaction was concentrated in vacuo to remove as much bromobenzene as possible and then purified directly by flash column chromatography, eluting with 10:1 CH2Cl2/MeOH. The desired product (0.013 g, 76%) was obtained as a yellow solid. LRMS (APCI pos) m/e 675 (M+1).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=O)(=[O:3])[CH3:2].BrC[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:35])[CH:24]=2)[CH:19]=1.O>C(O)C>[C:1]([NH:4][CH:5]([CH2:6][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=3[Cl:34])[CH:24]=2)[CH:19]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Clc1cccc(Cl)c1-c1ccc2cc(CBr)ccc2c1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1ccc2cc(-c3c(Cl)cccc3Cl)ccc2c1)NC(C)=O
Reaction time: 1 h

Procedure:
To a solution of Na (0.092 g) in ethanol (5 ml) is added diethyl 2-(acetylamino)malonate (0.870 g). The mixture is stirred for 1 h. A solution of 2-(bromomethyl)-6-(2,6-dichlorophenyl)naphthalene 288 (0.978 g) in ethanol (5 ml) is added, under argon. The mixture is stirred under reflux for 5 h. After addition of water (5 ml), the solution is concentrated under vacuum and then diluted with AcOEt (5 ml). The aqueous phase is extracted with AcOEt (3×15 ml). The organic phases are dried over MgSO4, filtrated and evaporated under vacuum. The residue is purified by silica gel chromatography using AcOEt/cyclohexane 20/80 then (40/60) as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([O:39][CH3:40])=[O:38])=[N:35][CH:36]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([O:39][CH3:40])=[O:38])=[N:35][CH:36]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: COC(=O)c1ccc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (200 mg, 0.48 mmol) and methyl 5-aminopicolinate (73 mg, 0.48 mmol) in dichloromethane (30 mL) were added the solution of 1-methyl-1H-imidazole (158 mg, 1.92 mmol) and EDCI (368 mg, 1.92 mmol) in dichloromethane (10 mL), the reaction mixture was stirred at room temperature for 15 hours, the solvent was removed in vacuo and methanol (6 mL) was added and stirred for 30 minutes, the solid was collected by filtration and washed with methanol to afford methyl 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)picolinate (230 mg, 87.1%) as an orange solid. LC-MS: 550 [M+H]+, tR=1.58 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=2[O:19][CH3:20])=[CH:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 4-Benzyloxy-phenol following the Standard Procedure J. MS (ES) for C27H30O7 [M+Na]+: 489.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27](F)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])=[CH:16][CH:15]=1>>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])=[CH:16][CH:15]=1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(O)cc2)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(O)cc2)c(=O)n1OCc1ccccc1
Yield: 22.3 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.04 mL, 0.5 mmol), triethylamine (0.07 mL, 0.5 mmol), and 1-(4-hydroxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example J-1, 0.065 g 0. 16 mmol) provided 0.05 g of the title compound as a solid.
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16](O)=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2].S(Cl)(Cl)=O.[CH3:34][NH2:35]>C(Cl)(Cl)(Cl)Cl>[CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([NH:35][CH3:34])=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CN
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)O)c(=O)oc12
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)NC)c(=O)oc12
Reaction time: 0.67 h

Procedure:
To a suspension of (E)-8-sec-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylic acid of the formula (V) (0.5 g, 1.28 mmol) in CCl4 (15 mL), added thionyl chloride (1.0 mL), was refluxed for 2.5 h. The resulting solution was evaporated to dryness under reduced pressure, and the residue was dispersed in CCl4 (10 mL). The solvent was eliminated under reduced pressure. Dispersion in CCl4 and solvent elimination was repeated twice. The residue was dissolved in CCl4(10 mL) and added with stirring to a solution of the methyl amine (0.04 g, 1.28 mmol). After 40 min at room temperature, the solvent was removed by evaporation under reduced pressure and extracted 3-fold with CHCl3 (25 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides (E)-8-sec-butyl-N-methyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxamide (General Formula VI). (0.33 g, 65% yield). White solid, m. p. 215-216° C.; 1H NMR (CDCl3 300 MHz): δ 8.93 (s, 1H), 8.72, (brd, J=4.6 Hz, 1H) 7.96 (d, J=8.1 Hz, 2H), 7.83-7.77 (m, 3H), 7.55 (d, J=15.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 3.49-3.37 (m, 1H), 3.04 (d, J=4.9 Hz, 3H), 2.45 (s, 3H), 1.80-1.71 (m, 2H), 1.35 (d, J=6.9 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 189.5, 1610, 161.2, 153.1, 148.5, 144.1, 142.2, 136.5, 135.4, 132.2, 131.4, 129.5, 128.8, 127.1, 123.2, 119.0, 118.8, 33.6, 29.8, 26.7, 21.8, 20.6, 12.1; ESI-MS (m/z): 404 (M+H)+.
Reaction SMILES: [O:1]1[CH2:4][CH2:3][CH2:2]1.[Br-:5].[CH3:6][N+:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][CH2:10][NH:11][CH3:12]>O>[Br-:5].[OH:1][CH2:2][CH2:3][CH2:4][N:11]([CH2:10][CH2:9][CH2:8][N+:7]([CH3:14])([CH3:13])[CH3:6])[CH3:12]
Reactant: C1COC1
Reactant: CNCCC[N+](C)(C)C
Agent: [Br-]
Solvent: O
Product: CN(CCCO)CCC[N+](C)(C)C

Procedure:
A mixture of 20 g. of oxetane (0.34 mole), 32.8 g. of N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide (0.156 mole) and 22 ml. water is heated in a sealed tube at 100° for 15 hours. The solution is evaporated in vacuo and the residue is dissolved in 50 ml. of acetonitrile and filtered. Upon evaporation the desired product crystallizes. The product may be recrystallized from acetonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:39][CH2:40]O)[CH2:31][CH2:30]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[S:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:39][CH2:40][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: OCCN1CCSc2ccccc21
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCN2CCSc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.4 %

Procedure:
To a mixture of 4-hydroxy benzaldehyde (1.8 g, 14.8 mmol) and triphenyl phosphine (4.85 g, 18.5 mmol) in tetrahydrofuran (15 ml) was added 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethanol (2.39 g, 12.3 mmol) and diisopropyl azodicarboxylate (3.74 g, 18.5 mmol) in THF (20 ml) at 25° C. The reaction mixture was stirred for 12 h at 25° C. Water (100 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The organic extracts were dried (Na2SO4) and solvent was evaporated under reduced pressure. The crude product was chromatographed over silica gel using a mixture of methanol and chloroform (5:95) as an eluent to afford the title compound (1.6 g, 44%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:31])[N:7]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:26][CH:25]=2)=[CH:21][CH:22]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(N)cc2)cc1)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(NC(=O)c3ccccc3)cc2)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
Add a solution of {2-[4-(4-amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (100 mg, 0.24 mmol) in dichloromethane (5 mL) dropwise to a solution of benzoyl chloride (40 mg, 0.29 mmol) in dichloromethane (5 mL) at room temperature. Upon complete addition of the amine, add triethylamine (48 mg, 0.48 mmol) and a crystal of DMAP to the reaction and stirred at room temperature for 18 hours. Concentrate on a rotary evaporator then purify by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield {2-[4-(4-benzoylamino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (120 mg). Add trifluoroacetic acid (0.23 mL) dropwise to a solution of [4-(4-benzoylamino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (120 mg, 0.23 mmol) in dichloromethane (5 mL) at room temperature and stir overnight. Concentrate on a rotary evaporator, dilute with saturated aqueous sodium bicarbonate then extract with dichloromethane (3×50 mL). Dry the dichloromethane extracts over sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield N-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-benzamide, (27 mg): 1H NMR (CDCl3, 300.00 MHz): 7.96-6.93 (m, 18H), 3.85 (s, 2H), 2.99-2.80 (m, 4H), 1.56 (s, 2H); m/z=423.4(M+1); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.