Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=O)=[CH:16][CH:17]=2)[NH:12][N:11]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(N(CC)CC)C>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[O:21])=[CH:16][CH:17]=2)[NH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Reactant: Nc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(O)cc1)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (208 mg, 0.7 mmol) in dry dimethylformamide (6 mL) was added 4-aminophenol (82 mg, 0.7 mmol) followed by HATU (312 mg, 0.8 mmol) and then triethylamine (20 drops) was added. The reaction was stirred overnight at room temperature. LC/MS showed desired product as major component. The solvent was removed by vacuum. The residue remaining was taken up in water and ethyl acetate. The layers were separated and the organic layer was concentrated under vacuum. The residue was dissolved in methanol (10 mL) and half of this solution was purified by HPLC using a gradient of 5% acetonitrile/water to 55% acetonitrile/water over 60 minutes with 0.1% trifluoroacetic acid in the water. The tide compound was isolated as a solid (20 mg). 1H NMR (methanol-d4) δ 6.87 (2H, d, 8.8 Hz), 7.55 (2H, d, 8.7 Hz), 7.61 (2H, m), 7.87 (2H, br s), 8.00 (1H, d, 8.4 Hz), 8.35 (1H, s), 8.52 (1H, d, 8.6 Hz). MS (APCI pos) 370.1. The starting material was prepared as follows: To 1H-indole-6-carboxylic acid (2.0 g, 12.42 mmol) in water (100 mL) was added NaNO2 (856 g, 124.2 mmol). To this suspension was then slowly added dropwise via addition fuel 6N HCL (16 mL). The resulting slurry was allowed to stir at room temperature overnight The solid precipitate was filtered and washed with water (50 mL) to provide 2.35 g (100%) of 3-formyl-1H-indazole-5-carboxylic acid. 1H NMR (DMSO-d6) δ 14.46 (1H, s), 10.21 (1H, s), 8.26 (1H, s), 8.20 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=8.3 Hz). MS (APCI positive) 205 (methyl ester). To 3-formyl-1H-indazole-6 carboxylic acid (2.35 g, 12.42 mmol) in DMF (60 mL) was added 1,2-phenylenediamine (12.42 mmol, 1.34 g) and sulfur powder (1.1 eq, 13.66 mmol). This mixture was then heated to reflux for 6 hours. The reaction was followed by TLC and LC-MS. After cooling, water (50 mL) was added to the reaction and the brown precipitate which formed was filtered and collected to provide 3.1 g (90%) of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid. 1H NMR (DMSO-d6) δ 14.01 (1H, s), 8.58 (1H, d, J=8.5 Hz), 8.24 (1H, s), 7.87 (1H, d, l=8.7 Hz), 7.64 (2H, m), 7.25 (2H, m). MS (APCI positive) 279.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[NH:8])[NH2:7])[CH3:2].Cl[CH2:11][CH:12]=O>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:12]=[CH:11][NH:8][C:6]=1[NH2:7])=[O:9])[CH3:2]
Reactant: O=CCCl
Reactant: CCOC(=O)CC(=N)N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc[nH]c1N
Reaction time: 0.03 h
Yield: 31 %

Procedure:
Carbamimidoyl-acetic acid ethyl ester (3.357 g, 25.8 mmol) was dissolved in AcOEt (20 mL). Chloroacetaldehyde (50% solution in water, 1.8 mL, 28.7 mmol) was added rapidly at room temperature. The solution stirred for 2 minutes until a precipitant formed. The solution was then brought to 65° C. for 0.5 h. The reaction mixture was then cooled and flash chromatographed with AcOEt. Product containing fractions were concentrated to give the desired material as a green solid. 0.68 g obtained, 31% yield. 1H NMR (400 MHz, CDCl3) δ 1.32 (t, J=7.2 Hz, 3H), 4.24 (q, J=7.0 Hz, 2H), 5.08 (brs, 2H), 6.10-6.13 (m, 1H), 6.25 (t, J=3.12, 1 Hz), 8.60 (brs, 1H); MS Calcd.: 154. Found 155 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:25]2[C@@H:29]([CH2:30][C:31]([O:33]C)=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:39])([F:38])[F:37])=[N:26]2)[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:11][C@H:10]1[CH3:24].[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([N:25]2[C@@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:37])([F:38])[F:39])=[N:26]2)[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:11][C@H:10]1[CH3:24]
Reactant: COC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(O[C@@H]2CCN(c3cc(OC)ncc3Cl)C[C@H]2C)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)O)cc3Br)[C@H](C)C2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.5 %

Procedure:
To a stirred solution of methyl 2-((4S,5S)-1-(3-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (44 mg, 0.069 mmol) in THF (2.0 mL) and water (0.2 mL) at rt was added 1.0M aqueous lithium hydroxide (0.2 mL, 0.200 mmol). After stirring at rt for 4.5 h, the reaction mixture was partially evaporated to remove most of the THF. The remaining solution was partitioned between water (50 mL) and Hex (15 mL). The aqueous layer was acidified to pH 2 by dropwise addition of 1M HCl, and then extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was dried under vacuum to afford 2-((4S,5S)-1-(3-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (43 mg, 100% yield) as a white solid: LC-MS [M+H] 619, 621. 1H NMR (500 MHz, CD2Cl2) δ 7.97 (s, 1H), 7.36 (d, J=2.8 Hz, 1H), 7.02 (dd, J=9.0, 2.8 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 6.30 (s, 1H), 4.41 (m, 1H), 4.02 (dt, J=3.9, 8.3 Hz, 1H), 3.86 (s, 3H), 3.54 (m, 2H), 3.28 (m, 1H), 2.90 (m, 1H), 2.84 (dd, J=16.5, 3.1 Hz, 1H), 2.18 (m, 2H), 1.86 (m, 2H), 1.35 (d, J=7.1 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H). Analytical HPLC (Zorbax method, 50% Solvent B start): RT=8.55 min, HI: 100%. hGPR40 EC50=45 nM.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[Br:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[Br:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=2)[CH:24]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: Brc1c[nH]cn1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (1.17 g, 4.0 mmol) and commercially available 4-bromo-imidazole (0.88 g, 6.0 mmol) according to the general procedure IVa. Obtained as an off-white solid (1.23 g, 76%). MS (EI) 404.0 [(M)+]; mp 247° C.
Reaction SMILES: F[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:11])[C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]([NH2:22])=[O:21].O>CN(C)C=O>[NH:19]([C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:11])[C:7]=1[N+:8]([O-:10])=[O:9])[C:20]([NH2:22])=[O:21]
Reactant: NC(N)=O
Reactant: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(F)c1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Yield: 92.4 %

Procedure:
A solution of 5-fluoro-1,3-diamino-2,4,6trinitrobenzene (1.57 g, 6 mmol) and urea (1.80 g, 30 mmol) in 30 ml of dry dimethylformamide (DMF) was heated for 1 hour at 90° C. A yellow precipitate formed after about 5 minutes. The mixture was cooled, poured into 150 ml of cold H2O and the solid filtered. Trituration of the solid with warm DMF-H2O (1:1, 100 ml), filtration and drying gave 5-ureido-1,3-diamino-2,4,6-trinitrobenzene (1.67 g, 92.3%): mp 350° C. dec; IR (KBr) 1730 cm-1 (C=O); mass spectrum (CI, CH4) m/z 259 (M+1-HNCO, 100).
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5]([O:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1)=[O:6].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:20][C:2]([Cl:1])([Cl:19])[CH2:3][O:4][C:5]([O:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=[O:15])[N:13]=1)=[O:6]
Reactant: CCOC(=O)c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 79.2 %

Procedure:
To a solution of ethyl 2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazole-4-carboxylate (23 g) in CH2Cl2 (200 mL) is added a solution of diisobutylaluminum hydride (1.0 M in CH2Cl2, 120 mL) at −78° C. over 30 minutes. The resulting mixture is kept at −78° C. for 10 hours. The excess hydride is quenched with acetic acid (5 mL) and the reaction is warmed to ambient temperature, and the mixture is stirred with sat. aq. Rochelle's salt (150 mL) until the suspension clears. The organic layer is washed with 10% aq NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. Purification by column chromatography on SiO2 (toluene/ethyl acetate, 6:1) affords the product as a light yellow syrup (16 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:21][C:22]1[CH:43]=[CH:42][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:30]([F:41])[CH:29]=2)=[CH:24][CH:23]=1.Cl>CN(C)C=O>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:30]([F:41])[CH:29]=3)=[CH:42][CH:43]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CCc2ccccc2)[nH]n1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3CCc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-tert-butyl-5-(2-phenylethyl)-1H-pyrazole (250 mg, 1.1 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 40 mg, 1.0 mmol) at 0° C., and the mixture was allowed to warm to room temperature and stirred for 30 min. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (350 mg, 1.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:1) to give the title compound as a yellow oil. 1H NMR (CDCl3) δ: 1.22 (3H, t, J=7.2 Hz), 1.33 (9H, s), 2.57 (2H, t, J=7.6 Hz), 2.68-2.76 (2H, m), 2.78-2.83 (2H, m), 2.89 (2H, t, J=7.7 Hz), 4.11 (2H, q, J=7.2 Hz), 4.97 (2H, s), 5.21 (2H, s), 5.98 (1H, s), 6.60-6.69 (2H, m), 6.99-7.12 (5H, m), 7.16-7.30 (3H, m), 7.32 (2H, d, J=8.1 Hz).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)=O)[CH2:7][C:6]=2[CH:25]=1.Cl.O(C(C)C(N1CCN(CC2C=CC=CC=2)CC1)=O)C1C=CC=CC=1>>[O:9]([CH:8]([CH3:7])[CH2:10][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:16][CH2:17]1)[C:5]1[CH:4]=[CH:3][CH:2]=[CH:25][CH:6]=1
Reactant: O=C(C1Cc2cc(F)ccc2O1)N1CCN(Cc2ccccc2)CC1
Agent: CC(Oc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: CC(CN1CCN(Cc2ccccc2)CC1)Oc1ccccc1

Procedure:
By carrying out the preparation as in Example 1, but replacing 1-[(5-fluoro-2,3-dihydrobenzofur-2-yl)carbonyl]-4-benzylpiperazine with the 1-(2-phenoxypropionyl)-4-benzylpiperazine hydrochloride obtained in Example 7, the title product is obtained.
Reaction SMILES: IC.[C:3]([NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[NH:23])[NH:21][OH:22])=[C:16]([F:24])[CH:15]=2)[CH2:9]1)(=[O:5])[CH3:4].[C:25](N=C(N(C)C)N(C)C)(C)(C)C>CN(C=O)C>[C:3]([NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[NH:23])[NH:21][O:22][CH3:25])=[C:16]([F:24])[CH:15]=2)[CH2:9]1)(=[O:5])[CH3:4]
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=N)NO)c(F)c2)C(=O)O1
Solvent: CI
Solvent: CN(C)C=O
Product: CONC(=N)c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (0.02 ml, 0.39 mmol) was added to a solution of 5-(S)-acetamidomethyl-3-[4′-(N-hydroxyamidino)-3′-fluorophenyl]oxazolidine-2-one (0.080 g, 0.26 mmol) and tert-butyl-1,1,3,3-tetramethylguanidine (0.058 ml, 0.39 mmol) in DMF (1.0 ml), and the mixture was stirred at r.t. overnight. Solvent was removed under vacuum, and the crude product purified by silica gel PTLC (10% methanol in DCM). HPLC: Rt 3.6 min. MS (m/z): [M+H]+=325.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([C@@H:19]([NH2:41])[CH:20]([OH:40])[CH:21]([NH:23][S:24]([C:27]1[CH:39]=[CH:38][C:30]2[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:29]=2[CH:28]=1)(=[O:26])=[O:25])[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O>[C:1]([NH:11][C@H:12]([C:17]([C@H:19]([NH2:41])[C:20](=[O:40])[CH:21]([NH:23][S:24]([C:27]1[CH:39]=[CH:38][C:30]2[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:29]=2[CH:28]=1)(=[O:25])=[O:26])[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)[C@@H](N)C(O)C(C)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)[C@H](N)C(=O)C(C)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-ol (240 mg, 0.4 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml, 1.5 M) was added dropwise and the reaction as stirred at RT overnight. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction as diluted with EtOAc (20 ml) and was extracted with water (2×20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOH/methylene chloride) to give the title compound as a white solid (70 mg, 29%). MS(ES) M-H+ =578.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][NH:18]C(OC(C)(C)C)=O)=[N:16][C:12]=2[CH:11]=1)=[O:9].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][NH2:18])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNC(=O)OC(C)(C)C)n2C)c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN)n2C)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4.81 g (0.10 mol) of 1-methyl-2-(N-tert-butoxycarbonylaminomethyl)benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide were dissolved in 25 mL of methylene chloride, mixed with 5 mL of trifluoroacetic acid and stirred for 5 hours at ambient temperature. Then the solvent was evaporated off and the residue was stirred with ether. The crystals thus formed were filtered off, washed with ether, and dried. Yield: 3.15 g (68% of theory), C20H23N5O3 (381.4); Rf value: 0.18 (silica gel; methylene chloride/ethanol=9:1).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[O:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (21 mg, 0.046 mmol, racemic intermediate from Example 2, Step 1)), tetrahydro-4H-pyran-4-one (from Aldrich, 4.6 μL, 0.050 mmol), and triethylamine (20 μL, 0.14 mmol) in methylene chloride (0.32 mL) was added resin of sodium triacetoxyborohydride (40 mg, 0.091 mmol). The resulting mixture was stirred overnight at rt. The mixture was filtered and concentrated and then purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C24H32ClN6O2 (M+H)+: m/z=471.2; Found: 471.2.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([C:41]1[CH:46]=[C:45]([CH:47]([CH3:49])[CH3:48])[C:44]([F:50])=[CH:43][C:42]=1[O:51][CH3:52])[C:13]([CH2:19][N:20]1[C@@H:24]([CH3:25])[C@@H:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[O:22][C:21]1=[O:40])=[CH:14]2.C(Cl)(Cl)Cl.C(I)[I:58]>>[F:34][C:32]([F:35])([F:33])[C:30]1[CH:31]=[C:26]([C@H:23]2[O:22][C:21](=[O:40])[N:20]([CH2:19][C:13]3[C:12]([C:41]4[CH:46]=[C:45]([CH:47]([CH3:49])[CH3:48])[C:44]([F:50])=[CH:43][C:42]=4[O:51][CH3:52])=[CH:11][C:10]4[C:15](=[CH:16][CH:17]=[CH:18][C:9]=4[I:58])[CH:14]=3)[C@H:24]2[CH3:25])[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=1
Reactant: ICI
Reactant: COc1cc(F)c(C(C)C)cc1-c1cc2c(N)cccc2cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: COc1cc(F)c(C(C)C)cc1-c1cc2c(I)cccc2cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 80 °C

Procedure:
t-Butyl nitrite (90%, 6.5 mg, 8.3 μL, 0.0627 mmol) was added to a suspension of (4S,5R)-3-{[5-amino-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2-naphthyl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (19.9 mg, 0.0314 mmol) in CH2I2 (1 mL). Dry CHCl3 (0.5 mL) was added to dissolve the precipitate formed. The solution was heated at 80° C. for 5 h. The reaction mixture was concentrated in vacuo and the resulting slurry was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-5-iodo-2-naphthyl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.47 (20% EtOAc/hexanes). LCMS calc.=746.1; found 745.8 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 8.11 (d, J=7.2 Hz, 1H); 7.92 (d, J=4.7 Hz, 1H); 7.88-7.85 (m, 1.5H); 7.84 (s, 1H); 7.75 (s, 0.5H); 7.67 (s, 2H); 7.22 (t, J=7.7 Hz, 1H); 7.16 (d, J=8.5 Hz, 0.5H); 7.12 (d, J=8.5 Hz, 0.5H); 6.76-6.70 (m, 1H); 5.54 (d, J=8.1 Hz, 0.5H); 5.34 (d, J=8.0 Hz, 0.5H); 5.01 (d, J=15.7 Hz, 0.5H); 5.00 (d, J=15.7 Hz, 0.5H); 4.22 (d, J=15.7 Hz, 0.5H); 3.98 (d, J=15.7 Hz, 0.5H); 3.81-3.72 (m, 4H); 3.28-3.20 (m, 1H); 1.32-1.24 (m, 4.5H); 1.21 (d, J=6.9 Hz, 1.5H); 0.57 (d, J=6.5 Hz, 1.5H); 0.37 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C@@H:13]([NH:19][C:20]([C:22]1[O:23][C:24]3[CH:30]=[C:29](Br)[CH:28]=[CH:27][C:25]=3[CH:26]=1)=[O:21])[CH2:12]2.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]1)[C@@H:13]([NH:19][C:20]([C:22]1[O:23][C:24]3[CH:30]=[C:29]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH:28]=[CH:27][C:25]=3[CH:26]=1)=[O:21])[CH2:12]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccc(F)cc3)cc2o1
Temperature: 82.5 °C

Procedure:
A mixture of 120 mg (0.86 mmol) of 4-fluorophenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.72 ml (1.72 mmol) of 1N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 80-85° C. for 18 h. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane/methanol 20:1, dichloromethane/methanol-/ammonia 80:20:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 155 mg (68% of theory) of the title compound are isolated.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:34])[N:4]2[C:16](=[CH:17][C:18]=1[CH:19]([O:22][C:23](=[O:33])[CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:20][CH3:21])[C:7]1=[N:8][C:9]3[C:14]([CH:15]=[C:6]1[CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=3.FC(F)(F)C(O)=O>COC1C=CC=C(OC)C=1>[NH2:25][CH2:24][C:23]([O:22][CH:19]([C:18]1[CH:17]=[C:16]2[N:4]([CH2:5][C:6]3[C:7]2=[N:8][C:9]2[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:34])[C:2]=1[CH3:1])[CH2:20][CH3:21])=[O:33]
Reactant: CCC(OC(=O)CNC(=O)OC(C)(C)C)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Agent: COc1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CCC(OC(=O)CN)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of (±)-8-methyl-7-[1-[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one (1.15 g, 2.5 mmol) in 1,3-dimethoxybenzene (12 mL) under an argon atmosphere was added trifluoroacetic acid (13 mL). After stirring for 1.5 h at room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in H2O, extracted with Et2O, filtered and lyophilized to afford the title compound as a pale yellow solid. 1H NMR (DMSO-d6) d 8.68 (s, 1H), 8.24 (m, 1H), 8.13 (m, 1H), 7.86 (apparent br t, 1H), 7.70 (apparent br t, 1H), 7.19 (s, 1H), 5.91 (apparent br t, 1H), 5.26 (s, 2H), 4.02 (br s, 2H), 2.25 (s, 3H), 2.06-1.81 (m, 2H), 0.96 (t, J=7.2Hz, 3H). Anal. Calcd for C21H21N3O3.CF3CO2H.9/4 H2O; C, 53.33; H, 5.16; N, 8.11. Found: C, 53.09; H, 4.91; N, 7.74.