Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19](/[CH:21]=[CH:22]\[C:23]([O:25]CC)=O)#[N:20]>FC(F)(F)C(O)=O>[CH:5]1[C:4]2[CH2:3][C:2]3[C:10]4[NH:11][C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:18]=4[C:21]4=[CH:22][C:23](=[O:25])[N:20]=[C:19]4[C:1]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C1=C(c2cc3ccccc3[nH]2)Cc2ccccc21
Reactant: CCOC(=O)/C=C\C#N
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=c2c(c3c(c4[nH]c5ccccc5c24)Cc2ccccc2-3)=N1
Temperature: 120 °C
Reaction time: 4 h
Yield: 12.2 %

Procedure:
A mixture of 2-(2-indenyl)indole 4 (75 mg; 0.32 mmol) and ethyl cis-β-cyanoacrylate (81 mg; 0.64 mmol) in trifluoroacetic acid (1 mL) was heated in a sealed reaction vial at 120° C. for 1 h., followed by 4 h at 160° C. The mixture was evaporated at reduced pressure and the residue was triturated with ether. The resulting solid was chromatographed (silica gel; EtOAc: hexanes; 1:1) to give 12 mg (12%) of tan solid product; mp 275°-280° C., MS (ES+) 310 (M+). This compound showed identical spectral data as that prepared in Method A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>CN(C)C=O>[C:37]1([S:43]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc2c(Cc3cccc(C(=O)OCc4ccccc4)n3)c(-c3ccccc3)[nH]c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3cccc(C(=O)OCc4ccccc4)n3)c(-c3ccccc3)n(S(=O)(=O)c3ccccc3)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (3.04 g) in N,N-dimethylformamide (34 mL) was added sodium hydride (50 to 72% in oil, 342 mg) in one portion under ice-cooling. This mixture was stirred for 30 minutes under ice-cooling. Then, benzenesulfonyl chloride (1.04 mL) was added dropwise thereto, followed by stirring at room temperature for 4.5 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.10 g). 1H-NMR (CDCl3) δ ppm: 3.92 (3H, s), 4.09 (2H, s), 5.44 (2H, s), 6.62-6.68 (1H, m), 6.80 (1H, dd, J=2.4, 8.6 Hz), 7.21 (1H, d, J=8.6 Hz), 7.24-7.53 (16H, m), 7.85-7.93 (2H, m).
Reaction SMILES: [Na+].[Cl:2][C:3]1[N:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19]([S:9]([C:6]1[CH:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:26])[CH3:25])[CH3:24]
Reactant: O=S([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
The crude 6-chloro-pyridine-3-sulfinic acid sodium salt (4.7 mmol) was suspended in DMF (20 mL). Pyridine (0.8 mL) and ethyl α-bromoisobutyrate (1 mL) were added. The reaction was stirred at 50° C. under nitrogen for 18 h. The reaction mixture was partitioned between diethyl ether (100 mL) and water (50 mL). The organic layer was washed with brine (50 mL) and dried over Na2SO4. Filtration, concentration under reduced pressure, followed by column chromatography (silica, eluent heptanes, 0-25% ethyl acetate) afforded 0.83 g of 2-(6-chloropyridine-3-sulfonyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C([O:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([N:16]2[CH2:20][CH2:19][C@:18]3([CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:17]2=[O:26])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.Cl[C:28]1[N:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C(N(CC)C(C)C)(C)C.CN1CCCC1=O.[OH-].[Li+]>CO>[OH:9][C@@H:10]1[CH2:11][CH2:12][C@H:13]([N:16]2[CH2:20][CH2:19][C@:18]3([CH2:25][CH2:24][CH2:23][N:22]([C:28]4[N:35]=[CH:34][CH:33]=[CH:32][C:29]=4[C:30]#[N:31])[CH2:21]3)[C:17]2=[O:26])[CH2:14][CH2:15]1
Reactant: O=C(O[C@H]1CC[C@@H](N2CC[C@]3(CCCNC3)C2=O)CC1)c1ccccc1
Reactant: N#Cc1cccnc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccnc1N1CCC[C@]2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Temperature: 25 °C

Procedure:
A mixture of cis-4-[(5S)-1-oxo-2,7-diazaspiro[4.5]dec-2-yl]cyclohexyl benzoate (19.0 mg, 0.0000533 mol), 2-chloronicotinonitrile (8.12 mg, 0.0000586 mol) and N,N-diisopropylethylamine (20.0 μL, 0.000115 mol) in N-methylpyrrolidinone (0.6 mL, 0.006 mol) was irradiated by microwave at 180° C. for 20 min. After cooling to rt, lithium hydroxide aqueous solution (1.0 M, 0.150 mL) was added, followed by methanol (0.2 mL). The mixture was heated at 100° C. for 5 h. The crude reaction mixture was then purified by prep-HPLC under basic conditions to afford the desired product. LC-MS: 355.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1.O>[CH2:26]([NH:33][C:2]1[N:3]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:24])[F:25])[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: NCc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: FC(F)c1nc2ccccc2n1-c1nc(NCc2ccccc2)nc(N2CCOCC2)n1
Yield: 66.8 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (92 mg, 0.25 mmol) and benzylamine (67 mg, 0.625 mmol) in dioxane (5 mL) was heated to reflux for 5 min and cooled. The mixture was diluted with water to give a white precipitate, which was recrystallised from EtOH to give 73 mg (67% yield) of N-benzyl-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 185-188° C.; 1H NMR (CDCl3) (rotamers) δ 8.41 and 8.28 (2d, J=7.4 and 7.7 Hz, 1H), 7.89 (m, 1H), 7.64 and 7.50 (2t, JHF=53.8 and 53.7 Hz, 1H), 7.43-7.29 (m, 7H), 5.62 (m, exchangeable with D2O, 1H), 4.72 and 4.68 (2d, J=6.0 and 5.9 Hz, 2H), 3.89 (m, 4H), 3.78 (m, 4H); Anal. Calc. for C22H21F2N7O: C, 60.4; H, 4.8; N, 22.4. Found: C, 60.6; H, 4.8; N, 22.7%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]2[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][C:16]=1[F:23])=[O:4].O.[OH-].[Li+].Cl>O1CCOCC1.O>[F:23][C:16]1[CH:17]=[C:18]([S:21][CH3:22])[CH:19]=[CH:20][C:15]=1[NH:14][C:13]1[N:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]2=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2ccncn2c1Nc1ccc(SC)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(Nc2c(C(=O)O)cc3ccncn23)c(F)c1
Temperature: 55 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 7-(2-fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid methyl ester (635 mg, 1.9 mmol) in dioxane (8 mL) and water (2.5 mL) was added lithium hydroxide monohydrate (161 mg, 3.8 mmol). The reaction was stirred at 55° C. for 2 hours then cooled to room temperature. Aqueous hydrochloric acid (1M) was added dropwise until pH˜3. The reaction mixture was extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a dark brown solid (600 mg, 99%). LCMS (Method B): RT=3.20 min, M+H+=318.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH:4]=1.C[O:20]C(OC)N(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:20])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH:4]=1
Reactant: COC(OC)N(C)C
Reactant: COc1ccnc(-c2ccc(C)c([N+](=O)[O-])c2)c1
Solvent: CN(C)C=O
Product: COc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(4-methoxypyridin-2-yl)-2-nitrotoluene (2.5 g) in N,N-dimethylformamide (15 ml) was added N,N-dimethylformamide dimethyl acetal (2.72 ml), and the mixture was stirred at 140° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure, and the residue was suspended in tetrahydrofuran (60 ml) and water (60 ml). Sodium metaperiodate (6.57 g) was added to the suspension, and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 150 g, 25-45% ethyl acetate in n-hexane) to give 4-(4-methoxypyridin-2-yl)-2-nitrobenzaldehyde (1.99 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:7])[CH2:5][CH3:6].[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=O>C1COCC1>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH2:3][C:4](=[O:7])[CH2:5][CH3:6]
Reactant: CCC(C)=O
Reactant: COC(=O)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)CCCCCl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil: 8.88 g) in THF (250 mL) was added a mixture of 2-butanone (7.98 g) and methyl 5-chlorovalerate (50.0 g) in THF (100 mL) dropwise via cannula at 0° C. The mixture was stirred at 0° C. for 10 min and at rt for 24 h. After the reaction was quenched with 2 N HCl (200 mL), aqueous layer was extracted with EtOAc (3×). Concentration of the combined organic phase gave a brown colored oil, which was purified by fractional vacuum distillation. The title compound was collected in the temperature range between 95° C. and 110° C. at 10 mmHg. 1H NMR (500 MHz, CDCl3) δ 1.14 (t, 3H, J=7.4 Hz), 1.65–1.90 (m, 4H), 2.30–2.60 (m, 4H), 3.50–3.60 (m, 2H), 5.51 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].[CH3:12][N:13]([CH3:16])[CH:14]=O>C(O)C>[CH3:12][N:13]([CH3:16])/[CH:14]=[CH:11]/[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Solvent: CCO
Product: Cc1cccc(/C=C/N(C)C)c1[N+](=O)[O-]
Reaction time: 46 h

Procedure:
A 500 -ml. three-necked flask fitted with a thermometer, a 15-cm. Vigreux column connected to a descending condenser and receiver with a nitrogen inlet was charged with 30.23 g. of 2-nitro-m-xylene, 64.77 g. of N,N-domethylformamide diethyl acetal, and 200 ml. of N,N-dimethylformamide. The reaction vessel was then immersed in an oil bath, preheated to 165°, for 46 hours. The pot temperature was maintained above 140° by continuous distillation of the formed ethanol.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15]2([CH2:26][C:25](=O)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:28])[CH:23]=3)[O:18]2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([N:12]1[CH2:17][CH2:16][C:15]2([CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:28])[CH:23]=3)[O:18]2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(Cl)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Clc1ccc2c(c1)CCC1(CCN(Cc3ccccc3)CC1)O2
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a stirred suspension of AlCl3 (3.04 g, 22.8 mmol) in dichloromethane (75 ml) tert-butylamine-borane (1:1) (3.98 g, 45.8 mmol) was added at 0° C., and the stirring was continued for 15 min at this temperature to obtain a clear solution. A solution of 1′-benzyl-6-chlorospiro[chromene-2,4′-piperidin]-4(3H)-one (2.61 g, 7.6 mmol) in dichloromethane (15 ml) was added dropwise. The stirring was continued for 2 h at 0° C. and for 3 h at room temperature. The reaction mixture was quenched by dropwise addition of 0.1 N aq. HCl. After the gas evolution has ceased, the layers were separated. The organic layer was washed with 0.1 N HCl (2×50 ml) and brine (50 ml), and dried over Na2SO4. The solvent was removed in vacuo to afford subtitle compound as colourless solid (1.63 g, 65%).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:36])([F:35])[C@H:29]([OH:34])[CH2:30][C:31](O)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][C@@H:29]([OH:34])[C:28]([F:36])([F:35])[F:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C[C@@H](O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(C[C@@H](O)C(F)(F)F)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (79 mg, 68%), MS (ISP) m/z=467.2 [(M+H)+], mp 166° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (R)-4,4,4-trifluoro-3-hydroxy-butyric acid.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1([NH:11]S(C(C)(C)C)=O)[CH2:10][O:9][CH2:8]1>O1CCOCC1.CO>[ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1([NH2:11])[CH2:10][O:9][CH2:8]1
Reactant: CC(C)(C)S(=O)NC1(c2nccs2)COC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2nccs2)COC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.1 %

Procedure:
A 4.0 M solution of hydrochloric acid (117 μL, 467 μmol) in dioxane was added to a solution of 2-methyl-propane-2-sulfinic acid (3-thiazol-2-yl-oxetan-3-yl)-amide (Example 281a) (81 mg, 311 μmol) in methanol (0.5 mL) at 0° C. The mixture was stirred at 0° C. for 5 min before the solvents were removed under reduced pressure. The resulting white solid was triturated with diethyl ether and filtered off. The solid was further washed with diethyl ether and dried under high vacuum to yield the title compound (42 mg, 70%) as a white solid. MS (EI): m/e=157.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22]Br)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:15][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC(C)(C)CBr
Reactant: COC(=O)c1cc(O)cc(C(C)(C)C)c1
Product: COC(=O)c1cc(OCC(C)(C)COC(C)=O)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 1.79 g) was reacted with 3-bromo-2,2-dimethylpropyl acetate, worked up and purified analogously to O2.85. 1.01 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:15])=[CH:10][CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Cl>>[CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[CH:10][CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1ccccn1
Reactant: CCCCC1CCc2ccc(O)cc2C1=O
Agent: Cl
Product: CCCCC1CCc2ccc(OCc3ccccn3)cc2C1=O

Procedure:
By the method of Example 10, the title product of Example 9 (5.70 g, 34.3 mmol) and 2-picolyl chloride hydrochloride (5.63 g, 34.3 mmol) were converted to present title product, 4.37 g (41%), m.p. 56-60° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].I[C:37]1[C:38](=[O:50])[N:39]=[C:40]2[NH:45][C:44]3[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=3[N:41]2[CH:42]=1.C(O)C.O1CCOCC1>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.O>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:37]2[C:38](=[O:50])[N:39]=[C:40]3[NH:45][C:44]4[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=4[N:41]3[CH:42]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Reactant: O=c1nc2[nH]c3ccccc3n2cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCN(Cc1ccc(-c2cn3c(nc2=O)[nH]c2ccccc23)cc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 31 %

Procedure:
To a mixture of 2-iodo-3-methoxy-acrylic acid methyl ester (1, 1.21 g, 5 mmol), 1H-benzoimidazol-2-ylamine (2, 0.67 g, 5 mmol) and ethanol (30 mL) was added a solution of sodium methoxide (10 mL, 0.5 M in methanol, 5 mmol). The resulted mixture was refluxed for 3 h and concentrated to afford 3-iodo-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-2-one (3). A mixture of (3-tert-butoxycarbonylamino-propyl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]carbamic acid tert-butyl ester (4, 490 mg, 1 mmol), 3 (311 mg, 1 mmol), K2CO2 (414 g, 3 mmol), Pd(PPh3)4 (0) (41 mg, 0.05 mmol), ethanol (6 mL), dioxane (2 mL) and water (2 mL) was degassed and heated at 80° C. for 20 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (0%-6% MeOH in methanechloride) to give desired product 5 (170 mg, 31%) as light yellow solid. LCMS (EI) m/z: 570 (M+Na+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:35]([O:39][C:40](=[O:80])[CH2:41][N:42]([CH2:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76])[C:43](=[O:71])[CH2:44][N:45]1[CH:49]=[CH:48][N:47]=[C:46]1[CH2:50][N:51]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]#[CH:70])=[CH:63][CH:62]=1)[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57](O)=[O:58])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCCl>[C:75]([O:74][C:73](=[O:79])[CH2:72][N:42]([CH2:41][C:40](=[O:80])[O:39][C:35]([CH3:38])([CH3:37])[CH3:36])[C:43](=[O:71])[CH2:44][N:45]1[CH:49]=[CH:48][N:47]=[C:46]1[CH2:50][N:51]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]#[CH:70])=[CH:63][CH:62]=1)[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57](=[O:58])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:78])([CH3:76])[CH3:77]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C#CCOc1ccc(CN(CCCCCC(=O)O)Cc2nccn2CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(CN(CCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2nccn2CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc1
Yield: 76.7 %

Procedure:
A solution of (5)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate (0.742 g, 1.52 mmol), 6-(((1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-(prop-2-yn-1-yloxy)benzyl)amino)hexanoic acid (0.244 g, 0.38 mmol), EDCI (0.290 g, 1.52 mmol), HOBt (0.051 g, 0.38 mmol) and DIPEA (0.40 mL) in DCE (5.0 mL) was stirred at room temperature for 4 h. The solvent was evaporated to give a residue, which was purified by Biotage SP4 eluting with DCM/MeOH to give (14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (0.3237 g, 77%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.64 (t, J=5.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.74 (s, 1H), 6.26 (d, J=8.4 Hz, 1H), 6.22 (d, J=8.0 Hz, 1H), 5.02 (s, 2H), 4.72 (d, J=2.0 Hz, 2H), 4.24 (s, 2H), 4.03-3.89 (m, 4H), 3.51 (t, J=2.0 Hz, 1H), 3.48 (s, 2H), 3.39 (s, 2H), 2.95 (q, J=6.3 Hz, 2H), 2.22-2.15 (m, 4H), 1.94 (t, J=7.4 Hz, 2H), 1.85-1.04 (m, 34H); MS (ESI), 1111.6 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH:22]1([NH:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:27]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:28][CH:29]([CH3:31])[CH3:30])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: CC(C)CNC1CCCC1
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(N(CC(C)C)C2CCCC2)ncn1
Yield: 80 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)-amide (Intermediate 17) and cyclopentyl-isobutyl-amine (Intermediate 27), the title compound was obtained as a white solid in 80% yield.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1([CH3:31])[C:21]([CH3:23])([CH3:22])[O:20][B:19]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[O:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([B:19]3[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:31])([CH3:16])[O:18]3)=[CH:29][CH:28]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC3CCC(O[Si](C)(C)C(C)(C)C)CC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanone (1.72 ml, 6.85 mml) [C.A.S.55145-45-4], 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1 g, 4.56 mmol) and sodium triacetoxy-borohydride (1.44 g, 6.85 mmol) in DCM (25 ml) was stirred at r.t. for 1 day. Then, the mixture was washed with NH4Cl (aqueous sat. solution). The organic layer was collected, dried (MgSO4) and evaporated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; heptane/EtOAc up to 5% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D32-a (trans) (0.566 g, 31%) and D32-b (cis) (1.089 g, 61%).