Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[N:12]=[C:13](Br)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.C(OCC)(=O)C>CN(C=O)C>[Br:10][C:11]1[N:12]=[C:13]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Brc1cn2ccnc2c(Br)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Nc2nc(Br)cn3ccnc23)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-aminobenzonitrile (220 mg; 1.89 mmol) and 6,8-dibromo-imidazo[1,2-a]pyrazine (500 mg; 1.81 mmol) is slurried in DMF (1 mL) and heated to 140° C. for 20 minutes. The reaction is allowed to cool, and when the bath reaches 75° C., ethyl acetate (40 mL) is added and the slurry is stirred to break up large solid lumps into fine powder. The powdered 4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzonitrile is filtered, washed with diethyl ether (2×50 mL) and dried under vacuum to a fine orange/tan solid (600 mg).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.C(B(CC)CC)C.[CH2:16]([O:18][C@@H:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]2OC(CC3N=C(C4C=CC=CC=4)OC=3C)=C[C:28]=2[CH:45]=1)[C:20]([OH:22])=[O:21])[CH3:17].C([N:49](C(C)C)CC)(C)C.[CH2:55]([O:62][C:63]1[CH:70]=[CH:69][C:66]([CH:67]=[O:68])=C[CH:64]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>ClCCl>[CH2:16]([O:18][CH:19]([CH2:23][C:24]1[CH:45]=[CH:28][C:27]([C:67](=[O:68])[CH2:66][CH2:69][C:70]2[N:49]=[C:55]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[O:62][C:63]=2[CH3:64])=[CH:26][CH:25]=1)[C:20]([OH:22])=[O:21])[CH3:17]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCO[C@@H](Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(=O)O
Agent: CCB(CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(Cc1ccc(C(=O)CCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Trifluoromethanesulfonic acid (5.0 ml, 56 mmol) was added to a solution of triethylborane in hexanes (56 ml of a 1M solution, 56 mmol). After the bubbling stopped, the solution was heated to 40° C. for 1 hour then cooled to 0° C., a solution of (S)-4-benzyl-3-(phenoxyacetyl)oxazolidin-2-one (prepared as in Example 19) (5.0 g, 28 mmol) in dichloromethane (90 ml) was added followed by diisopropylethylamine (12.3 ml, 71 mmol) dropwise. After 30 minutes the solution was cooled to -78° C. and treated with a solution of 4-benzyloxybenzaldehyde (6.0 g, 28 mmol) in dichloromethane (80 ml). After 2 hours at -78° C., the solution was warmed to 0° C., stirred for 30 minutes and quenched with Ph 7 buffer. The layers were separated, the aqueous portion was extracted with dichloromethane, the combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The product was isolated by flash-chromatography (hexanes/ethyl acetate, 1:1) as an oil (6.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1>>[CH3:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Reactant: COC(=O)CCc1ccccc1B1OC(C)(C)C(C)(C)O1
Product: COC(=O)CCc1ccccc1-c1ccc(-c2onc(C)c2C(O)CCCc2ccccc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol and 3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester.
Reaction SMILES: F[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([N:14]=2)=[C:12](F)[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[CH:17]1[CH:22]=[CH:21][C:20]([P-:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1.[K+].O>O1CCOCC1.O1CCCC1>[C:24]1([P:23]([C:20]2[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=2)[C:2]2[C:15]3[C:6](=[CH:7][C:8]4[C:13]([N:14]=3)=[C:12]([P:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:20]3[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=3)[CH:11]=[CH:10][CH:9]=4)[CH:5]=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc([P-]c2ccccc2)cc1
Reactant: Fc1cccc2cc3cccc(F)c3nc12
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(P(c2ccccc2)c2cccc3cc4cccc(P(c5ccccc5)c5ccccc5)c4nc23)cc1
Yield: 79 %

Procedure:
To a solution of 0.51 g (2.37 mmol) of 4,5-difluoroacridine (XIII) in 50 ml of 1,4-dioxane was added dropwise 9.3 ml (4.65 mmol) of a 0.5 M solution of potassium diphenylphosphide (Ph2P−K+) in tetrahydrofuran at room temperature. After the addition was completed, the mixture was heated at reflux for one hour. After cooling, 30 ml of distilled water was added to the brown reaction solution. The resulting precipitate was filtered off, washed thoroughly with distilled water, ethanol and n-pentane, and dried under high vacuum to obtain 1.02 g (79% of theory) of 4,5-bis(diphenylphosphino)acridine (Ia) as a yellow powder which will decompose from 255° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=O.Cl.N[C:10]1[NH:14][CH:13]=[N:12][C:11]=1[C:15]([NH2:17])=[O:16]>CO>[F:1][C:2]([F:7])([F:6])[C:3]1[NH:17][C:15](=[O:16])[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[N:5]=1
Reactant: NC(=O)C(F)(F)F
Reactant: NC(=O)c1nc[nH]c1N
Agent: Cl
Solvent: CO
Product: O=c1[nH]c(C(F)(F)F)nc2[nH]cnc12
Temperature: 110 °C
Yield: 65.3 %

Procedure:
A 1 L round-bottom flask (three neck) containing 340 g of trifluoroacetamide was heated in an oil bath at 110° C. After the trifluoroacetamide melted, 50 g of 5-aminoimidazole-4-carboxamide-HCl was added. The mixture was warmed to reflux (bath temp 160 to 165° C.) for 4 hours, cooled to room temperature, and the rocky solid was triturated with 1 L of ether. The ether was decanted off and the remaining solid was warmed until melted and 200 mL of ether was introduced by a dropping-funnel through a water-cooled condenser. The mixture was cooled to room temperature and an additional 200 mL of ether was added with stirring. The solid was removed by filtration, triturated with 3×500 mL of ether, washed with 200 mL of H2O, and filtered to provide 89 g of crude product. The product was treated with 3 L of MeOH and 9 g of activated carbon, warmed to reflux for 20 minutes, filtered through a pad of celite, and concentrated to a volume of 2.5 L. The material was warmed to dissolve all the precipitate that formed and then cooled slowly to room temperature. The crystalline material was isolated by filtration and dried in vacuo to provide 41 g of the desired hypoxanthine as a white solid. 1H NMR (DMSO-d6) δ 8.34 (s, 1H), 7.18 (bs, 2H). MS (ES+), 205.0 (100%, M+H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH2:34][CH2:35][CH3:36])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH2:34][CH2:35][CH3:36])[N:27]=2)[CH:6]=1
Reactant: CCCc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-methoxy-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (96 mg, 192 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (438 mg, 296 μL, 3.84 mmol) and the mixture stirred at room temperature overnight. The mixture was concentrated in vacuo then diluted with 25% aqueous NH4OH and dichloromethane. The phases were separated and the organic phase washed with water. The organic layer was concentrated in vacuo then purified by chromatography (silica, 3 to 20% methanol in dichloromethane) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (59 mg, 148 μmol, 77%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.36 (s, 1H), 8.30 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 3.96 (s, 1H), 3.79 (s, 3H), 3.28 (s, 1H), 2.72 (t, J=7.3 Hz, 2H), 1.54-1.74 (m, 8H), 1.35 (m, 2H), 0.94 (t, J=7.4 Hz, 3H); MS (EI/CI) m/z: 400.2 [M+H].
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[C:22]([O-:25])([O-])=O.[Cs+].[Cs+].[CH3:28][CH2:29][CH:30](O)C>CN(C=O)C>[CH2:22]([O:25][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1)[CH2:30][CH:29]=[CH2:28]
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: CCC(C)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCCOc1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O
Temperature: 125 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
10 g (0.036 mol) of 2-fluoro-5,12-naphthacenequinone, 26 g (0.028 mol) of Cs2CO3 and 10.41 g (0.14 mol) of 3-butanol are introduced into 200 ml of DMF under nitrogen. The reaction mixture is heated to 125° C. and stirred for 41/2 h. After precipitation in 4000 ml of water containing hydrochloric acid, the product is filtered off (crude yield 94%). Chromatography on silica gel (CH2Cl2) gives 63% pure product; melting point 149° C. The procedure in Examples 25-27 is analogous (see Table 2).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.C(O[CH:12]=[C:13]([CH3:16])[CH:14]=O)C.C([N:19](CC)CC)C>CCOCC.C([O-])(=O)C.[NH4+]>[CH3:14][C:13]1[CH:12]=[N:19][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:16]=1
Reactant: CCOC=C(C)C=O
Reactant: CCN(CC)CC
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cnc2c(c1)C(=O)CCC2
Reaction time: 12 h
Yield: 48 %

Procedure:
A mixture of cyclohexane-1,3-dione (11.2 g. 0.1 m), 3-amino-2-methylacrolein (8.5 g. 0.1m) triethylamine (5 ml.) and ammonium acetate (100 mg) were heated with stirring at 120° in an oil bath for 12 hours. The cooled reaction mixture was diluted with ether (50 ml.) and the solution washed with 2N HCl (3 × 15 ml.) The combined washings were adjusted to pH 9.0 with sodium carbonate and extracted with ether (3 × 50 ml.) The combined extracts were dried, evaporated in vacuo and the residual oil distilled at 0.2 mm Hg to give the title compound as a colourless crystalline solid b.p. 80° (7.5 g. 48%).
Reaction SMILES: [CH3:1][C@H:2]1[C@:6]23[CH2:11][C@H:10]([C:12]([CH3:14])([CH3:13])[C@@H:5]2[CH2:4][CH2:3]1)[C@@:9]([OH:16])([CH3:15])[CH2:8][CH2:7]3.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].[OH2:29]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[C@:6]23[CH2:11][C@H:10]([C:12]([CH3:14])([CH3:13])[C@@H:5]2[CH2:4][CH2:3]1)[C@@:9]([OH:16])([CH3:15])[CH2:8][CH2:7]3.[C:24]([O-:27])(=[O:29])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: O
Agent: C[C@@H]1CC[C@H]2C(C)(C)[C@H]3C[C@@]12CC[C@@]3(C)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In 200 ml of tetrahydrofuran, 25 g of (+)-Cedrol (manufactured by Lancaster) was dissolved, and to the solution were added 22.8 g of triethylamine and 1 g of N,N-dimethylaminopyridine. To the solution was dropwise added 15.2 g of acrylic chloride under cooling with ice over a period of 30 minutes and the mixture was stirred at room temperature for 2 days. To the reaction solution was added 100 ml of distilled water under cooling with ice, and the mixture was stirred for 30 minutes and 300 ml of ethyl acetate was added thereto. The water layer was removed by separation and the organic layer was washed with water, dried and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain 18.2 g of the desired compound which is a raw material monomer for repeating unit (b5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]2)=[CH:4][CH:3]=1.[C:27]([C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([NH:37][C:38](=[O:41])[CH2:39]Cl)=[C:32]([Cl:42])[CH:31]=1)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C)C=O>[ClH:36].[ClH:36].[C:27]([C:30]1[CH:31]=[C:32]([Cl:42])[C:33]([NH:37][C:38](=[O:41])[CH2:39][N:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:14][CH:15]2[CH3:19])=[C:34]([Cl:36])[CH:35]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Reactant: CC1CN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2C)c(Cl)c1
Product: Cl
Temperature: 70 °C
Reaction time: 20 h
Yield: 22.8 %

Procedure:
A mixture of 3.6 parts of 1-[5,5-bis(4-fluorophenyl)pentyl]-3-methylpiperazine, 3 parts of N-(4-acetyl-2,6-dichlorophenyl)-2-chloroacetamide, 1.9 parts of N,N-diethylethanamine and 45 parts of N,N-dimethyformamide was stirred for 20 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in a mixture of sodium carbonate and water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried in vacuo at 40° C., yielding 1.74 parts (22.8%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[5,5-bis(4-fluoro-phenyl)pentyl]-2-methyl-1-piperazineacetamide dihydrochloride, 2-propanol(1:1), sesquihydrate; mp. 176.3° C. (compound 54).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:27][C:28]([C:30]2[C:39]([NH:40]C(=O)OCC3C=CC=CC=3)=[CH:38][C:37]3[C:32](=[CH:33][C:34]([C:51]4[CH2:52][CH2:53][O:54][CH2:55][CH:56]=4)=[CH:35][CH:36]=3)[N:31]=2)=[O:29])[CH2:10]1)=O)(C)(C)C.C1COCC1.Cl.O1CCOCC1>CO>[NH2:40][C:39]1[C:30]([C:28]([NH:27][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[N:11]2[CH2:12][C@H:13]([CH3:20])[C@H:14]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[C@H:9]([NH2:8])[CH2:10]2)=[O:29])=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)[CH:33]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4CCOCC4)ccc3cc2N)C[C@@H](N)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of benzyl [2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate (4.0 mg, 0.005 mmol) in MeOH (0.3 mL) and THF (0.3 mL) 10% Pd on carbon (2 mg) was added. The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 1 h. The mixture was filtered and concentrated under reduced pressure to give an intermediate. The intermediate was treated with 4.0 M HCl in dioxane (0.053 mL, 0.21 mmol) and stirred at room temperature for 30 min. then concentrated under reduced pressure. The residue was diluted with MeOH and NH4OH, filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (1.8 mg, 65%). LCMS calc. for C28H34N9O2 (M+H)+: m/z=528.3. Found: 528.3.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].[CH2:12]1COCC1.C[Mg]Br.[NH4+].[Cl-]>C(OCCCC)CCC.C(OCC)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]([OH:5])[CH3:12]
Reactant: C1CCOC1
Reactant: O=Cc1c(F)ccc(F)c1Cl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCOCCCC
Solvent: CCOCC
Product: CC(O)c1c(F)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry 18×250 mm test tube, 2-Chloro-3,6-difluorobenzaldehyde (1.00 g, 5.66 mmol) and THF (10.0 mL, 123 mmol) were added. The reaction tube was evacuated and filled with N2 3 times. Methylmagnesium bromide (0.810 g, 6.80 mmol) 1.0 M in butyl ether was added slowly at 0° C. The reaction mixture was stirred at room temperature overnight. 5 mL of sat. aq. NH4Cl was added to quench the reaction at 0° C. Diethyl ether was added and aq. layer was extracted with ether 3 times. The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo. The material was not further purified and ready for the next step.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[C:8](Cl)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>CCOCC.O>[C:8]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(=O)Cl
Reactant: CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCC(=O)NC(C)(C)C(=O)O
Yield: 48.7 %

Procedure:
2-Aminoisobutyric acid (2.0 g, 19.4 mmol) and n-hexanoyl chloride (3.0 g, 22.4 mmol) were reacted in the presence of NaOH (1.6 g, 40 mmol) in a mixture of ether and water using the method described in Example 5, Part A. The title compound (1.90 g, 49%) was obtained after crystallization from benzene, m.p. 141°-143° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH:15]=[CH2:16])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7]>C1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH2:15][CH3:16])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=Cc1cc(O)c(C(=O)OC)c(C(=O)OC)c1C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc(O)c(C(=O)OC)c(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.4 %

Procedure:
6-Hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester (1.27 g, 5.11 mmol) was dissolved in benzene (10 mL) and EtOAc (10 mL). Tristriphenylphosphine rhodium chloride (150 mg) was added and the reaction was placed under an atmosphere of hydrogen. Stirring at room temperature was continued. After 14 hrs, the solvents were removed in vacuo and the crude material was purified by silica gel chromatography to provide 1.14 g (88%) of the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ=1.19 (t, J=7.8 Hz, 3H), 2.10 (s, 3H), 2.60 (q, J=7.8 Hz, 2H), 3.89 (s, 6H), 6.87 (s, 1H), 10.79 (s, 1H) ppm.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.[NH:39]1[CH2:47][CH2:46][CH:42]([C:43]([OH:45])=[O:44])[CH2:41][CH2:40]1>C(Cl)Cl>[C:2]([O:4][CH:5]1[C:14]2[C:15]3([CH3:30])[C:16]([C:17](=[CH:18][N:39]4[CH2:47][CH2:46][CH:42]([C:43]([OH:45])=[O:44])[CH2:41][CH2:40]4)[C:23](=[O:24])[O:25][CH:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: O=C(O)C1CCNCC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCC(C(=O)O)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added isonipecotic acid (60 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 561 (M+H).
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][C@@H:11]([N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46](=[O:48])[NH2:47])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[CH:30]1)[C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O>[C:46]([C:43]1[CH:42]=[CH:41][C:40]([C:37]2[CH:36]=[CH:35][C:34]([C:31]3[CH:32]=[CH:33][N:29]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)[C:16]([CH3:18])([CH3:19])[CH3:17])=[O:13])[CH2:10][C:9]([OH:49])=[O:8])[CH:30]=3)=[CH:39][CH:38]=2)=[CH:45][CH:44]=1)(=[O:48])[NH2:47]
Reactant: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1)C(=O)Nc1ccncc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 81 %

Procedure:
According to the procedure described in Example 5(a), 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-(2,2-dimethyl-1(S)-(N-(pyridin-4-yl)carbarnoyl)propyl]succinamic acid benzyl ester was hydrogenolyzed in MeOH/EtOAc to provide 35 mg (81%) of 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(N-(pyridin-4-yl)carbamoyl)propyl]succinamic acid as a yellow solid, mp 194-6° C. 1H NMR (CD3OD): δ 8.35 (d, 2H, J=6.5 Hz), 7.95 (d, 2H, J=8.4 Hz), 7.75 (d, 3H, J=8.4Hz), 7.70-7.52 (m, 6H), 7.28 (t, 1H, J=2.0 Hz), 6.90 (t, 1H, J=2.8Hz), 6.52 (dd, 1H, J=6.9, 16.8 Hz), 1.20 (s, 9H). IR (KBr): 3400, 2962, 1665, 1606, 1511, 1402 cm−1. HRFABMS: Calculated for C32H34N5O5 (M+H+): 568.2560. Found: 568.2575. Anal. Calculated for C32H33N5O5•0.7 HOAc•0.5 CHCl3: C, 60.83; H, 5.47; N, 10.46. Found: C, 60.93, H, 5.88; N, 10.19.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][N:19]2[C:23](=[O:24])[CH2:22][O:21][C:20]2=[O:25])[CH2:13][CH2:12]1.[NH3:26]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][NH:19][C:20](=[O:25])[O:21][CH2:22][C:23]([NH2:26])=[O:24])[CH2:13][CH2:12]1
Reactant: N
Reactant: O=C1COC(=O)N1CCC1CCN(c2ccc3ccccc3n2)CC1
Solvent: CO
Product: NC(=O)COC(=O)NCCC1CCN(c2ccc3ccccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 3 (step 3.4). Starting with 1.14 g (3.36 mmol) of 3{2-[1-(2-quinolyl)-4-piperidyl]-ethyl}-1,3-oxazolidine-2,4-dione, described in Example 8 (step 8.2), and 9.60 ml (67.20 mmol) of a solution (7M) of aqueous ammonia in methanol, and after chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, followed by recrystallization from ethyl acetate, 0.360 g of pure product is obtained in the form of a white solid.