Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[N:11]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C1COCC1.CO>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)[C:9]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:10]1)([OH:28])=[O:27]
Reactant: COC(=O)CCCCn1cc(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCn1cc(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 100 °C
Yield: 99.3 %

Procedure:
2N NaOH solution (2.0 mL) was added to a solution of methyl 3-cyclohexyl-1-(5-methoxy-5-oxopentyl)-1H-indole-6-carboxylate (410 mg, 1.1 mmol) in THF/Methanol mixture (2.0 mL/2.0 mL). The reaction mixture was heated at 100° C. under microwave condition for 15 min, after which it was concentrated and the pH was adjusted to 4-5 with 1N HCl solution. A precipitate formed which was collected by filtration to give the product as a white powder, (375 mg, 99% yield). MS m/z 344(MH+). 1H NMR (300 MHz, CD3OD) δ ppm 1.24-1.98 (m, 10 H) 2.00-2.15 (m, 2H) 2.25-2.39 (m, 2 H) 2.84 (m, 1 H) 4.16-4.30 (m, 2 H) 4.56-4.72 (m, 2 H) 7.22 (m, 1 H) 7.58-7.78 (m, 2 H) 8.10 (m, 1 H).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Product: COC(=O)C(Oc1cccc(Cl)c1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 95.3 %

Procedure:
As described in Example 44, 8.28 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate is reacted with 2.96 g of m-chlorophenol to give 8.8 g of the product as a viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1)#[N:2].C[Si]([N:27]=[N+:28]=[N-:29])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:27]1[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]3)[CH:4]=2)=[N:2][N:29]=[N:28]1
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C#N)ccn2)CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)N1CCN(c2cc(-c3nnn[nH]3)ccn2)CC1

Procedure:
2,2-Dimethylpropyl 4-(4-cyanopyridin-2-yl)piperazine-1-carboxylate (120 mg) obtained in Example 2 was dissolved in toluene (5 mL), and trimethylsilylazide (0.105 mL) and a catalytic amount of dibutyltin (IV) oxide were added thereto and heated under reflux for 8 hours. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=9/1) to obtain 16.5 mg of the entitled compound as a colorless solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]1[CH2:33][CH2:32][O:31][C:30]2[CH:34]=[C:35]([C:38]([OH:40])=O)[CH:36]=[CH:37][C:29]1=2.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@@H:53]([C:64]([O:66][CH3:67])=[O:65])[CH2:52]1>CN(C=O)C.O>[O:28]1[CH2:33][CH2:32][O:31][C:30]2[CH:34]=[C:35]([C:38]([NH:50][C@@H:51]3[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])[C@@H:53]([C:64]([O:66][CH3:67])=[O:65])[CH2:52]3)=[O:40])[CH:36]=[CH:37][C:29]1=2
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: COC(=O)[C@H]1C[C@H](N)CCN1C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc3c(c2)OCCO3)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
BOP (6.59 g, 14.9 mmol) was added to a solution of 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (2.68 g, 14.9 mmol) and DIEA (5.3 mL, 30 mmol) in DMF (50 mL). Then (2R,4R)-1-tert-butyl 2-methyl 4-aminopiperidine-1,2-dicarboxylate (3.5 g, 13.5 mmol) was added to the mixture and the resulting solution was stirred at room temperature for 18 hours. Water (100 mL) was added to quench the reaction, and extracted with ethyl acetate (2×100 mL), organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was purified by Companion (ReadySep, 120 g, silica gel packed) with ethyl acetate/heptane from 20-50% to give the amide as off-white solid 5.4 g (95%). LC-MC: 421.2 (t=2.4 min).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH3:35])[C:10]([NH:12][C@@H:13]([CH2:31][CH:32]1[CH2:34][CH2:33]1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11].[O:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43](O)=[O:44])[CH2:38][CH2:37]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:32]1([CH2:31][C@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:43](=[O:44])[CH2:42][N:39]2[CH2:40][CH2:41][O:36][CH2:37][CH2:38]2)[CH3:35])[C:14]([NH:16][C@@H:17]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:18]([C@@:20]2([CH3:23])[CH2:22][O:21]2)=[O:19])=[O:15])[CH2:34][CH2:33]1
Reactant: O=C(O)CN1CCOCC1
Reactant: C[C@H](N)C(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To (S)-2-((S)-2-aminopropanamido)-3-cyclopropyl-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (377 mg, 0.779 mmol) was added 2-morpholinoacetic acid (226 mg, 1.56 mmol), HATU (622 mg, 1.64 mmol), and DMF (4 mL). The mixture was cooled to 0° C. and DIEA (0.68 mL, 3.9 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) provided (S)-3-cyclopropyl-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (320 mg, 80%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J=7.6 Hz, 1H), 7.32-7.22 (m, 3H), 7.16-7.14 (m, 2H), 6.67 (d, J=7.6 Hz, 1H), 6.47 (d, J=7.6 Hz, 1H), 4.86-4.81 (m, 1H), 4.43 (q, J=6.8 Hz, 2H), 4.34 (dd, J=14.4, 6.8 Hz, 1H), 3.74-3.72 (m, 4H), 3.30 (d, J=4.8 Hz, 1H), 3.14 (dd, J=14.0, 5.2 Hz, 1H), 3.04 (d, J=4.8 Hz, 2H), 2.92 (d, J=4.8 Hz, 1H), 2.83 (dd, J=14.0, 7.8 Hz, 1H), 2.54-2.52 (m, 4H), 1.56 (t, J=6.8 Hz, 2H), 1.50 (s, 3H), 1.35 (d, J=7.2 Hz, 3H), 0.41-0.36 (m, 2H), 0.05-0.00 (m, 2H). MS (EI) for C27H38N4O6, found 515.4 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[CH3:12][O:13][C:14](=[O:40])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:25]([O:36][CH3:37])=[CH:24][C:23]=2[CH:38]=O)=[CH:17][CH:16]=1.[CH2:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42]1.[O-]S(C(F)(F)F)(=O)=O.[In+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[CH3:12][O:13][C:14](=[O:40])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]([O:36][CH3:37])=[CH:24][C:23]=2[CH:38]2[CH:42]3[CH2:43][C:44]4[C:49]([CH:41]3[C:11]3[C:3](=[CH:4][CH:5]=[C:6]([C:7](=[NH:9])[NH2:8])[CH:10]=3)[NH:2]2)=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:19][CH:20]=1
Reactant: C1=Cc2ccccc2C1
Reactant: N=C(N)c1ccc(N)cc1
Reactant: COC(=O)c1ccc(Oc2cc(OCc3ccccc3)c(OC)cc2C=O)cc1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [In+3]
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2cc(OCc3ccccc3)c(OC)cc2C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)cc1
Temperature: 75 °C

Procedure:
4-amino-benzamidine mono HCl salt (120 mg, 0.7 mmole) was suspended in acetonitrile (4 mL). The suspension was treated with 4-(5-Benzyloxy-2-formyl-4-methoxy-phenoxy)-benzoic acid methyl ester (274 mg, 0.7 mmole) and indene (162 mg, 1.4 mmole). Indium triflate (79 mg, 0.14 mmole) was added and the reaction was heated at 75° C. for 18 hours to give 4-[5-Benzyloxy-2-(2-carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-4-methoxy-phenoxy]-benzoic acid methyl ester which was purified by column chromatography (10%methanol in ethyl acetate).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8].S(=O)(=O)=O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:1][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:11][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: CC(=O)OC(C)=O
Reactant: C1COCCO1
Agent: O=S(=O)=O
Solvent: Cc1ccccc1
Product: CC(=O)OCCOCCNC(C)(C)C
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
The reaction time for cleavage of 1,4-dioxane was 2 hours at 120-125° C. and for animation with t-butyl amine was 30 minutes at 140-145° C. A 50 mL one-necked flask was charged with 1,4-dioxane (12 mL, 12.4 g, 140 mmol) under a nitrogen atmosphere. Then sulfur trioxide (2.6 g, 32.5 mmol, polymer) was added followed by addition of acetic anhydride (6.2 mL, 6.6 g, 65 mmol) at 10-15° C. The reaction mixture was stirred at 20-25° C. for 15 minutes to dissolve sulfur trioxide (time may very depending on size of pieces of SO3). The reaction mixture was then transferred to a sealed tube and heated at 120-125° C. for 2 hours. After cooling, the mixture was transferred to one neck 100 mL flask and concentrated under vacuum (1 mm) at 60-65° C. 1,4-dioxane (5 mL, 5.2 g, 58.7 mmol) and tert-butylamine (20 mL, 14 g, 190 mmol) were added to the residue with stirring and cooling. The mixture was transferred to a sealed tube and heated at 140-145° C. for 30 minutes. Then the reaction mixture was cooled to room temperature. Toluene (40 mL) was added with stirring and the mixture was filtered under vacuum. The precipitate was washed with toluene (10 mL) and then concentrated under vacuum to 25-30 mL. The toluene layer was separated from the insoluble bottom oil and the solvent was removed under vacuum to give crude product 2-(2-tert-butylaminoethoxy)ethyl acetate (3.8 g, 20 mmol, approximately 62.5%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([NH2:14])[CH:10]=[C:11]([NH2:13])[CH:12]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(Cl)Cl>[NH2:14][C:9]1[CH:10]=[C:11]([NH:13][C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])[CH:12]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=1
Reactant: Nc1cc(N)cc(N2CCOCC2)c1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cc(NC(=O)C2CC2)cc(N2CCOCC2)c1

Procedure:
A solution of 5-morpholinobenzene-1,3-diamine (0.074 g, 0.383 mmol), triethylamine (0.080 mL, 0.574 mmol), cyclopropanecarbonyl chloride (0.035 mL, 0.383 mmol), and DCM (2 mL) was stirred at 23° C. for 3 h, then concd. The concentrate was partitioned between EtOAc and water, and the products were extracted twice with 25% 2-propanol in chloroform. The combined organics were dried over magnesium sulfate and concd, affording N-(3-amino-5-morpholinophenyl)cyclopropanecarboxamide as a brown amorphous solid. Mass Spectrum (ESI) m/e=262.2 (M+1).
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH2:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:35]([N:1]([C:18]([O:20][CH2:21][CH:22]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:19])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC[C@@H](C(=O)O)N(Cc1ccccc1)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a mixture of Fmoc-Lys(Boc)-OH (47, 2.0 g, 4.27 mmol) and benzyl alcohol (531 μL, 5.12 mmol) in CH2Cl2 (8.5 mL) at 0° C. was added DMAP (52 mg, 0.43 mmol) and DCC (1.06 g, 5.12 mmol). The mixture was stirred for 2 h at 0° C. and 3 h at room temperature, then filtered. Solids were washed with small portions of CH2Cl2 and the combined filtrates were concentrated, redissolved in EtOAc, washed with H2O, 0.5 N aqueous HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on a Biotage™ flash chromatography system, using a gradient of 0-10% EtOAc in CH2Cl2 to furnish compound 48 (2.3 g, 96%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.25-1.39 (m, 2H), 1.40-1.52 (m, 2H), 1.43 (s, 9H), 1.66-1.75 (m, 1H), 1.82-1.90 (m, 1H), 3.02-3.11 (m, 2H), 4.20-4.24 (m, 1H), 4.35-4.52 (m, 4H), 5.16 (d, J=12.0 Hz, 1H), 5.22 (d, J=12.0 Hz, 1H), 5.39 (bd, J=8.0 Hz, 1H), 7.29-7.42 (m, 9H), 7.60 (d, J=7.5 Hz, 2H), 7.77 (d, J=7.5 Hz, 2H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CS(OS(C)(=O)=O)(=O)=O.[CH:56]([NH2:59])([CH3:58])[CH3:57]>C1COCC1.C(Cl)(Cl)Cl>[CH:56]([NH:59][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)([CH3:58])[CH3:57]
Reactant: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCOc2cc(CO)ccc21
Reactant: CC(C)N
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)NCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
N-(7-Hydroxymethyl-chroman-4-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Step A) (0.050 g, 0.010 mmol) and DIEA (0.038 g, 0.030 mmol) were dissolved in THF (1.5 mL). The solution was cooled to 0° C. and methanesulfonic anhydride (0.023 g, 0.014 mmol) was added. After the reaction was stirred for 3.5 h, isopropylamine (0.14 g, 2.3 mmol) was added and the solution was stirred at RT overnight. The reaction was diluted with CHCl3 and washed with brine. The aqueous phase was extracted once with CHCl3. The organic phases were combined, dried over MgSO4, filtered, and concentrated in vacuo to provide a residue which was purified by column chromatography (silica, 0.2% TEA in acetone) to provide the title compound. MS (ESI) m/z 558 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[S:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[NH:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31]([CH3:36])=[CH:30]3)[CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:17]1[S:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[NH:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31]([CH3:36])=[CH:30]3)[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccn5C(=O)OC(C)(C)C)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from N-tert-butoxycarbonylpyrrole-2-boronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.08 (d, 1H), 7.36 (m, 2H), 7.28, s, 1H), 7.27 (d, 1H), 6.94 (dd, 1H), 6.60 (d, 1H), 6.40 (m, 1H), 6.22 (dd, 1H), 6.10 (s, 1H), 2.40 (s, 3H), 1.90 (s, 9H); RP18-HPLC RT: 6.73 minutes; API MS: 445 (M+1).
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[Cs+].[Cs+].Cl[C:8]1[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH:9]=1.CO[CH2:29][CH2:30][O:31][CH3:32]>O.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>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][NH:16][C:10]1[N:11]=[C:12]([O:14][CH3:15])[N:13]=[C:8]([C:21]2[CH:20]=[C:19]([C:18]3([C:1]([OH:4])=[O:2])[CH2:17][CH2:32][O:31][CH2:30][CH2:29]3)[CH:24]=[CH:23][CH:22]=2)[CH:9]=1
Reactant: COCCOC
Reactant: O=C([O-])[O-]
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Cs2CO3 solution (1.5 g, 4.6 mmol in 15 mL of water) is added to a stirred solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (0.61 g, 1.84 mmol) and 3-(4-tetrahydro-pyran-4-carboxylic acid)-phenylboronic acid (0.6 g, 2.4 mmol) in 1,2-dimethoxyethane (45 mL). The mixture is degassed over nitrogen for 10 minutes, tetrakis(triphenylphosphine)palladium (0) (64 mg, 0.03 mmol) is added and the reaction mixture is refluxed at 90° C. overnight. The reaction is cooled to room temperature, diluted with water (150 mL), filtered over a pad of celite and the volatiles are removed in vacuo. The aqueous solution is slowly acidified (pH 4-5, 0.1N HCl) with vigorous stirring, which is continued for 2 hours. The formed precipitate is suction filtered and air dried to afford 4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid [605 mg, Example 80(a)]. LCMS: Rt=2.26 minutes, MS: 502. 504 (M+H), H′ NMR [300 MHz, (CD3SO)2SO]: □12.75 (1H, b) 8 (1H, s), 7.8 (1H, b), 7.55 (2H, b), 7.45 (2H, s), 7.35 (2H, s), 6.55 (1H, s), 3.85 (3H, s), 3.82 (2H, m), 3.5 (4H, m), 2.95 (2H, t, J=2 Hz), 2.4 (2H, m), 1.85 (2H, m). IC50=0.05 nM
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH:15](=[N:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCO[Si](CCCN=Cc1ccccc1)(OCC)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
(Imine-TEOS) To a 2000 mL 3-neck round bottom flask placed in an ice water bath and equipped with a stirbar was added 70 g of 5 Å molecular sieves. The flask was then equipped with a reflux condenser and the remaining necks were sealed with rubber septa. The reaction flask was evacuated and backfilled with dry nitrogen three times. After the final backfill cycle, 200.1 g (903.9 mmol) of 3-aminopropyltriethoxysilane was added to the flask, along with 300 mL of anhydrous toluene. With rapid stirring, 95.9 g (903.9 mmol) of benzaldehyde was added dropwise via cannula over 30 minutes. The contents were allowed to stir at room temperature under nitrogen overnight. After an overnight stir, the contents were filtered. An additional 50 mL of anhydrous toluene was added to facilitate the filtration. The filtrate was filtered a second time and collected. The collected filtrate was concentrated via rotary evaporation to yield a pale gold oil (274.9 g, 98%). This solid was isolated in >98% purity, as characterized by 1H NMR spectroscopy and was not purified further. 1H NMR (CDCl3, 400 MHz): 0.68 (m, 2H); 1.22 (m, 9H); 1.85 (m, 2H); 3.61 (m, 2H); 2.82 (m, 6H); 7.40 (m, 3H); 7.72 (m, 2H); 8.27 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:12][C:13]1[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][NH2:22])[N:16]2[N:23]=[CH:24][N:25]=[C:15]2[N:14]=1.O>CS(C)=O>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:22][CH2:21][CH2:20][NH:19][C:17]1[N:16]2[N:23]=[CH:24][N:25]=[C:15]2[N:14]=[C:13]([CH3:12])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(NCCN)n2ncnc2n1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(NCCNCC(O)COc2ccccc2)n2ncnc2n1
Reaction time: 48 h

Procedure:
3.6 g. Phenyl glycidyl ether and 9.0 g. 5-methyl-7-(2-aminoethylamino)-s-triazolo[1,5-a]pyrimidine are dissolved in dimethyl sulphoxide and left to stand for 48 hours at 45° C. The reaction mixture is then poured into water, extracted with methylene chloride, dried and purified chromatographically in the manner described in Example 28. There are obtained 2.0 g. (24% of theory) of the desired product in the form of colorless crystals; m.p. 126°-127° C., after recrystallization from isopropyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[O:26][CH2:27][CH2:28]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][O:26][C:25]2[CH:24]=[C:23]([O:22][CH3:21])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: COc1cc(OCCO)cc(OC)c1OC
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(3,4,5-trimethoxyphenoxy)ethanol (1.8 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material form dichloromethane extraction was purified by HPLC (dichloromethane-diethyl ether, 50:1) and crystallized from dichloromethane-hexane to provide 1 g of 4-[[2-(3,4,5-trimethoxyphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 82°-83° C. Analysis Calculated for C20H22O8 : C, 61.53; H, 5.68. Found: C, 60.82; H, 5.71.