Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([O:15]C)=O)[CH3:5].O>C1COCC1>[CH3:5][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([NH:2][CH3:1])=[O:15])[CH3:3]
Reactant: CN
Reactant: COC(=O)c1sccc1N=NN(C)C
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1sccc1N=NN(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 76 %

Procedure:
To an ice cold (0-5° C.) solution of methyl amine (3 mL) in THF (5 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (500 mg) in THF (5 mL) for 5 min and stirred at rt for 36 h. The solution was poured into ice cooled water and the solution was extracted with chloroform (3×100 mL). The combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product, which was recrystallized from chloroform-hexane gave the product as a pale orange color solid (380 mg, 76%), mp 98-102° C. IR (neat) νmax 3297, 3082, 2929, 1637, 1380, 1348, 1299, 1221, 1109, 1016, 882, 776 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.35 (1H, br s), 7.29 (1H, d, J=5.2 Hz), 7.27 (1H, d, J=5.2 Hz), 3.57 (3H, br s), 3.21 (3H, br s), 3.00 (3H, d, J=4.8 Hz); LC-MS (positive ion mode): m/z 213 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[C:6](=[O:14])[C:5]2=[CH:15][N:16]([CH3:18])[N:17]=[C:4]12)[CH3:2].[OH-].[K+]>C(O)C>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6](=[O:14])[C:5]2=[CH:15][N:16]([CH3:18])[N:17]=[C:4]12)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nn(C)cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cn(C)nc21

Procedure:
24.9 g. of 7-ethyl-4,7-dihydro-2-methyl-4-oxo-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (0.1 mol.) are treated with 10 g. of potassium hydroxide in 100 ml. of ethyl alcohol at reflux temperature for 12 hours with stirring. The solvent is removed in vacuo and the crystalline, residual potassium salt is dissolved in 100 ml. of water. After acidifying the solution with acetic acid, 7-ethyl-4,7-dihydro-2-methyl-4-oxo-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid crystallizes, yield 19 g. (68%); m.p. 273°-275° (DMF).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Reactant: OB(O)c1ccccc1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(-c2ccccc2)cc1
Yield: 52.1 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (167 mg, 0.43 mmol, prepared in example 17) and phenylboronic acid (62 mg, 0.51 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with methylene chloride. Further purification was achieved by reverse phase C18 chromatography to afford 77 mg (53%) of the title compound as a solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[N:16]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[N:16]=2)[CH2:10]1
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To tert-Butyl-((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (700 mg, 1.56 mmol) was added 20 mL CH2Cl2 followed by addition of 7 mL of TFA. After the reaction was stirred for 1 hour it was neutralized with a 1.0 M aqueous NaOH solution. The mixture was partitioned between H2O and CH2Cl2, and separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to yield 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (400 mg, 74%). LC/MS: m/z 349.3 (M+H)+ at 1.52 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[N:6][CH:7]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:31]=1[C:32]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:18])=[O:33])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(F)ccc1C(=O)O
Product: CC(C)(C)OC(=O)NCCOc1cc(F)ccc1C(=O)Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Yield: 75 %

Procedure:
Using methods substantially equivalent to those described in Example 29-G, the compound was prepared in a 75% yield from N-(5-chloropyridin-2-yl)-2-amino-5-chloro-benzamide and 2-(2-tert-butoxycarbonylaminoethoxy)-4-fluorobenzoic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:29](/B(O)O)=[CH:30]/[CH3:31]>COCCOC.C(O)C.O>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](/[CH:29]=[CH:30]\[CH3:31])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C\B(O)O
Reactant: C[C@]12CCc3c(Br)cccc3[C@@H]1CN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: C/C=C\c1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Temperature: 160 °C
Yield: 67.4 %

Procedure:
trans-2-Benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.561 mmol, 200 mg) was dissolved in DME (1 ml) and ethanol (0.5 ml). 2 N sodium carbonate solution (1 ml) was added along with (Z)-prop-1-enylboronic acid (0.842 mmol, 72.3 mg) and tetrakis(triphenylphosphine)Pd(0) (0.028 mmol, 32.4 mg). The reaction mixture was heated to 160° C. for 15 minutes in a microwave reactor and then diluted with water. The resulting mixture was extracted with DCM (3×) and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford a crude residue that was purified by silica column chromatography (eluting with 10% EtOAc in heptane) to afford trans-2-benzyl-3a-methyl-6-((Z)-prop-1-enyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (120 mg), m/z: 318.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][NH:30][CH2:31]4)=[CH:26][CH:25]=3)[N:21]=[C:20]([NH2:34])[N:19]=2)[CH2:14][CH2:13]1>>[NH2:34][C:20]1[N:21]=[C:22]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:8]([NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:9])[CH2:31]3)=[CH:26][CH:25]=2)[CH:23]=[C:18]([N:15]2[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]2)[N:19]=1
Reactant: O=C=NC1CCCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCCCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from cyclohexylisocyanate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=450.2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OO)(=[O:17])C>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:14][O:13][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N+:1]2[O-:17])=[CH:6][CH:7]=1)=[O:12]
Reactant: CC(=O)OO
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2ccc[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of methyl quinoline-7-carboxylate (17.8 g, 94.87 mmol) in dichloromethane (315 mL) was added peracetic acid (39.9 mL, 190 mmol, 32% in acetic acid). The reaction was stirred at room temperature overnight. Peracetic acid (10 mL, 48 mmol, 32% in acetic acid) was added and the mixture was stirred for 5 h. The reaction mixture was diluted with a saturated solution of aqueous sodium bicarbonate. The aqueous phase was extracted into dichloromethane (2×1 L). The extracts were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography (2-15% methanol in dichloromethane) gave the title compound (17.4 g, 90%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d, δ): 9.41 (1H, s), 8.56 (1H, dd, J=6.0, 0.8 Hz), 8.24 (1H, dd, J=8.5, 1.7 Hz), 7.93 (1H, d, J=8.6 Hz), 7.75 (1H, d, J=8.6 Hz), 7.39 (1H, dd, J=8.6, 6.0 Hz), 4.01 (3H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][C:9](=N)[C:10](Cl)(Cl)Cl)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]([C@H:21]1[CH2:25][C@@H](O)C[N:22]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:20].CO>C1(C)C=CC=CC=1.[O-]S(C(F)(F)F)(=O)=O.[La+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:17][O:18][C:19]([C@H:21]1[CH2:25][C@@H:9]([O:8][CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][N:22]1[C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[O:20]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [La+3]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1C[C@@H](OCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
Add lanthanum triflate (3.6 g, 6.16 mmol) to a solution of 2,2,2-trichloro-acetimidic acid 4-methoxybenzyl ester (52.2 g, 185 mmol) and (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (30.2 g, 123 mmol) in toluene (200 mL). Stir 2.5 h, add methanol and concentrate. Dissolve in 25:75 dichloromethane:hexanes, filter away the insolubles and purify filtrate (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures) to give the title compound (37.85 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:6]1[CH2:8][CH2:9]OS(C)(=O)=O)=[O:4].[C-:23]#[N:24].[Na+].[Na+].[I-]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:6]1[CH2:8][CH2:9][C:23]#[N:24])=[O:4]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCOS(C)(=O)=O
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CC1CCC#N
Temperature: 80 °C
Yield: 93 %

Procedure:
To 1-tert-butoxycarbonylamino-2 (2-methanesulfonyloxy-1-ethyl)-cyclopropanecarboxylic acid methyl ester (400 mg, 1.19 mmol) from example 109 in DMF (6 mL) was added NaCN (350 mg, 7.14 mmol) and NaI (178 mg, 1.19 mmol). The reaction mixture was heated at 80° C. for 2 h then diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica (20→50% EtOAc/Hexanes) to afford 1-tert-butoxycarbonylamino-2-(2-cyano-ethyl)-cyclopropanecarboxylic acid methyl ester (297 mg, 93%). 1H NMR (300 MHz, CDCl3): δ 5.13 (br s, 1H), 2.44 (m, 2H), 2.05 (m, 2H), 1.70-1.53 (m, 1H), 1.53-1.37 (m, 4H) 1.45 (s, 9H). LCMS found 290.9 [M+Na]+. To this intermediate (297 mg, 1.10 mmol) in CH2Cl2 (2 mL) was added 4N HCl in dioxanes (2 mL). Ater stirring at room temperature for 2 h the reaction was concentrated to afford 225 mg (100%) of the HCl salt of 1-amino-2-(2-cyano-ethyl)-cyclopropanecarboxylic acid methyl ester, which was used in the next step without further purification.
Reaction SMILES: COC(=O)C1C=CC=C([C:10]2[CH:11]=[C:12](C(S(C)(=O)=O)(C)C)[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)C=1.[Li+].[OH-]>C1COCC1.[OH-].[Na+]>[N:18]1[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc2ncccc2c1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
To a solution of 3-[6-(1-methanesulfonyl-1-methylethyl)-quinolin-8-yl]-benzoic acid methyl ester from Step 1 (1.0 eq) in THF (20 mL) was added LiOH (2.5 eq; 2.0N in water). The mixture was stirred at 65° C. for 6 h then poured in NaOH (1N) then extracted with CH2Cl2 (2×). The organic extracts were discarded while the aqueous phase was acidified to pH=5 using AcOH. The latter was extracted with CH2Cl2 (5×). The combined organic extracts were dried over MgSO4, filtered and concentrated. The resulting solid was stirred in a mixture of EtOAc:Hex:Et2O (0.1:1:1) then filtered to afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=4)=[CH:19][C:12]=3[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C(Cl)(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=4)=[CH:19][C:12]=3[N:11]=2)=[CH:3][C:2]=1[N:1]1[CH2:32][CH2:33][CH2:34][CH2:35][C:36]1=[O:37]
Reactant: O=C(Cl)CCCCBr
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2ccc(Cl)c(N)c2)n3C)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2ccc(Cl)c(N4CCCCC4=O)c2)n3C)ccn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To (4-{2-[(3-amino-4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide in chloroform was added 5-bromopentanoylchloride (1.5 eq) and sodium phosphate (3 eq) and stir for 2 hours. Acylation was checked by HPLC/MS. The mixture was partitioned between methylene chloride and water. The organic layer was dried with sodium sulfate and concentrated. The crude N-acylated product was taken in tetrahydrofuran and Potassiumbis(trimethylsilyl)amide (2 eq) was added to it and the mixture was heated at 100° C. for 16 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was dried and concentrated to give 4-[(2-{[4-chloro-3-(2-oxopiperidin-1-yl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]-N-methylpyridine-2-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([O:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:10]([CH3:30])[CH:9]=1)[OH:7])[CH3:2].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([O:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[C:10]([CH3:30])[CH:9]=1)[O:7][S:45]([CH3:44])(=[O:47])=[O:46])[CH3:2]
Reactant: C=CCCOC(C(=O)OCC)C(O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCOC(C(=O)OCC)C(OS(C)(=O)=O)c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of 2-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-hydroxy-propionic acid ethyl ester (150 mg, 0.3 mmol) in dichloromethane (2 ml) at 0° C. was added successively triethylamine (55 μl, 0.4 mmol) and methanesulfonic acid chloride (42 μl, 0.36 mmol). The reaction was allowed to warm to ambient temperature over night and then quenched by the addition of sat. NaHCO3. The layers were separated and the aqueous phase was extracted two times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford crude 2-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-methanesulfonyloxy-propionic acid ethyl ester which was dissolved in THF (2 ml). DBU (139 μl, 0.9 mmol) was added at ambient temperature and the mixture was stirred for 8 h at 50° C. The reaction was quenched by the addition of water, the layers were separated, and the aqueous phase was extracted two times with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure to afford a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=9/1) to give 79 mg (0.166 mmol, 55%) of the title compound as bright yellow oil and 29 mg (61 μmol, 20%) 2E-but-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester as bright yellow oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[C:11]([F:17])[CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:7][CH:3]2[CH2:6][CH2:5][CH2:4]2)=[C:11]([F:17])[CH:10]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1COC1CCC1
Reaction time: 6 h

Procedure:
Sodium hydride (50% in oil; 1.63 g) was cautiously added to a solution of cyclobutanol (2.7 g) in DMF (12 ml). After gas evolution ceased, 4-bromo-1-bromomethyl-2-fluorobenzene (10 g) was added at 0° C. After 6 hours at room temperature, the mixture was cautiously hydrolyzed and then partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. 4-Bromo-1-cyclobutoxymethyl-2-fluorobenzene was obtained as crude product in this way.
Reaction SMILES: [CH3:1][OH:2].C(N(CC)CC)C.Cl[Si:11]([CH2:19][Cl:20])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[Cl:20][CH2:19][Si:11]([O:2][CH3:1])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CO
Reactant: C[Si](Cl)(CCl)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CO[Si](C)(CCl)c1ccccc1
Yield: 79.7 %

Procedure:
A solution of 1.6 ml (1.3 g, 0.040 mol) of methanol and 3.0 ml (2.2 g, 0.022 mol) of triethylamine in 100 ml of ether was stirred while a solution of 4.1 g (0.020 mol) of chloro(chloromethyl)methyl(phenyl)silane in 10 ml of ether was added dropwise. The resulting slurry was refluxed for 2 hours, cooled, washed with water, 0.1N aqueous HCl, saturated aqueous NaHCO3, water, and brine, dried over magnesium sulfate, and evaporated to leave 3.2 g of a pale yellow liquid. Distillation provided 1.7 g (42%) of the title compound as a colorless liquid: bp 46°-49° (0.05 mm); nD22 1.5207; nmr (CDCl3): 0.5 (3H, s), 3.0 (2H, s), 3.5 (3H, s) and 7.3-7.8 (5H, m).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14][C@H:13]1[O:31][CH2:32][CH3:33])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:14][C@H:13]1[O:31][CH2:32][CH3:33]
Reactant: CCO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Product: CCO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1N

Procedure:
The same operation as in Example (40e) was performed using tert-butyl cis(±)-3-(4-{[(benzyloxy)carbonyl]amino}-3-ethoxypiperidin-1-yl)benzoate obtained in Example (48d) (100 mg, 0.22 mmol) and a 10% palladium-carbon catalyst (40 mg) to obtain the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C@@H:9]1[C:14]2=[C:15]3[C:24](=[C:25]([O:27][CH3:28])[CH:26]=[C:13]2[O:12][C:11]([CH3:36])([CH3:35])[C@@H:10]1[O:37][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23](=[O:29])[C:22]1[CH:21]=[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]2=[CH:18][C:17]=1[N:16]3[CH3:34]>N1C=CC=CC=1>[C:1]([O:8][C@@H:9]1[C:14]2=[C:15]3[C:24](=[C:25]([O:27][CH3:28])[CH:26]=[C:13]2[O:12][C:11]([CH3:36])([CH3:35])[C@@H:10]1[O:37][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23](=[O:29])[C:22]1[CH:21]=[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]2=[CH:18][C:17]=1[N:16]3[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)[C@@H](O)[C@@H](OC(=O)c1ccccc1)C(C)(C)O2
Solvent: c1ccncc1
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)[C@@H](OC(C)=O)[C@@H](OC(=O)c1ccccc1)C(C)(C)O2
Reaction time: 12 h

Procedure:
2.5 ml of acetic anhydride are added to a solution of 0.1 g of the compound of Example 20 in 2.5 ml of pyridine. After reacting for 12 hours at room temperature, the reaction mixture is concentrated under reduced pressure. Chromatography on silica gel (eluant: dichloromethane) allows the expected product to be isolated.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:51][CH2:50][CH2:49]3)=[CH:44][CH:43]=2)O1>C1(C)C=CC=CC=1>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:42]2[CH:43]=[CH:44][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:56])[CH3:57])[CH2:51][CH2:50][CH2:49]3)=[CH:46][CH:47]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.800 g, 1 eq.) in a mixture of toluene (10 mL), ethanol (10 mL), and saturated sodium bicarbonate (2 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (1.15 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.08 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (100 mL). The aqueous phase was extracted with dichloromethane (2×75 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl (1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.6 g, 52%). 1H NMR (DMSO-d6) 400 MHz δ 8.41 (s, 1H), 8.04 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 7.96 (dd, JA=7.6 Hz, JB=1.6 Hz, 1H), 7.53-7.48 (m, 2H), 7.45-7.08 (m, 11H), 6.91-6.86 (m, 1H), 6.67-6.62 (m, 1H), 2.45-2.32 (m, 4H), 2.07-1.94 (m, 1H), 1.85-1.73 (m, 1H), 1.28 (bs, 9H); LCMS: 556 [M+H].