Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25][CH:26]([CH3:28])[CH3:27])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CC(C)CNCC(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1)CC(C)C
Yield: 41.9 %

Procedure:
1.3 g (3.6 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight with 1.6 ml (8.9 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.69 g (42%) of 7-chloro-3-(5-diisobutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 158°-160°, which was converted into the hydrochloride of m.p. 125°-128°.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11](O)=[O:12])=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:6][C:5]=2[N:4]([CH:20]([CH3:22])[CH3:21])[N:3]=1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:11]([C:9]1[C:10]2[C:2]([CH3:1])=[N:3][N:4]([CH:20]([CH3:22])[CH3:21])[C:5]=2[N:6]=[C:7]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:8]=1)=[O:12]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)C)c2nc(-c3ccncc3)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccncc3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 3-methyl-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (20 mg, 0.067 mmol), DMSO (1 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (19.10 mg, 0.101 mmol), N-methylmorpholine (0.030 mL, 0.270 mmol), 1-hydroxy-7-azabenzotriazole (18.37 mg, 0.135 mmol) and EDC (25.9 mg, 0.135 mmol). The final product was collected as 29 mg (100%). LCMS E-S (M+H)=431.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.25 (s, 3H), 2.46 (s, 3H), 4.40 (d, J=5.0 Hz, 2H), 5.29 (quin, J=6.7 Hz, 1H), 5.89 (s, 1H), 7.83 (s, 1H), 8.19 (d, J=6.1 Hz, 2H), 8.64-8.89 (m, 3H), 11.55 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 2.62 g (5.6 mmol) of methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate in 14 ml dioxane is added 11.6 ml of 1N NaOH (11.6 mmol) and the mixture is heated at 60° for 2 h. The solvent is evaporated and the residue dissolved in water. The pH of the aqueous solution is adjusted to 5.0 using 2N aqueous HCl. The resulting mixture is extracted with methylene chloride (3×20 ml). The combined organic extract is dried (MgSO4), filtered and subjected to evaporation to give an oil. Crystallization from ether yields 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoic acid, m.p. 114°-116°.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH:41]([CH:43]1[CH2:45][CH:44]1[C:46]([O:48][CH2:49][CH3:50])=[O:47])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:49]([O:48][C:46]([CH:44]1[CH2:45][CH:43]1[CH2:41][NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:47])[CH3:50]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)C1CC1C=O
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCC3CC3C(=O)OCC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.055 mmol) in DCE (0.5 mL) was added ethyl 2-formyl-1-cyclopropanecarboxylate (9.13 mL, 0.069 mmol) and titanium(IV) isopropoxide (0.020 mL, 0.069 mmol). The mixture was stirred at rt for 1 h and sodium triacetoxyborohydride (23.38 mg, 0.110 mmol) was added. After stirring the mixture for 16.25 h additional ethyl 2-formyl-1-cyclopropanecarboxylate (9.13 mL, 0.069 mmol) and sodium triacetoxyborohydride (23.38 mg, 0.110 mmol) were added and the mixture was again stirred at rt for 24 h. The reaction mixture was loaded directly onto a silica gel column and was purified by flash chromatography using a 0-25% EtOAc in hexanes gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(ethoxycarbonyl)cyclopropyl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (33 mg, 0.049 mmol, 89% yield). LCMS: m/e 670.8 (M+H)+, 2.47 min (method 11).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C:8]1([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=2)[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)=O)C.[Cl-].[NH4+]>O1CCCC1>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([CH2:6][OH:5])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:19][CH:20]=1
Reactant: CCOC(=O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reaction time: 39 h
Yield: 80.3 %

Procedure:
Lithium borohydride (1.71 g) was added at room temperature to a solution of 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester (7.26 g) described in Reference Example 81(2) in tetrahydrofuran (100 ml) and stirred at the same temperature for 39 hours. Then, lithium borohydride (855 mg) was added and stirred at the same temperature for 24 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give [8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4.5]dec-8-yl]methanol (5.17 g) as a colorless transparent oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[C@H:30]1[O:34][C:33](=[O:35])[NH:32][C@@H:31]1[CH3:36].[H-].[Na+].Br[CH2:40][C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=1>C1COCC1>[F:48][C:47]([F:49])([F:50])[C:45]1[CH:46]=[C:41]([CH:42]=[C:43]([C:51]([F:54])([F:52])[F:53])[CH:44]=1)[CH2:40][N:32]1[C@H:31]([CH3:36])[C@@H:30]([C:21]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=2[C:4]2[CH:5]=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=3[CH3:19])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:34][C:33]1=[O:35]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N[C@@H]3C)c2)c(C)c1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 0.17 h

Procedure:
The starting methyl 4′-methoxy-2-methyl-2″-[(4R,5R)-4-methyl-2-oxo-1,3-oxazolidin-5-yl]-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (40 mg, 0.080 mmol) was dissolved in anhydrous THF (1 mL) and cooled in an ice bath. Sodium hydride (60% w/w in mineral oil, 3.5 mg, 0.088 mmol) was added into the mixture. The reaction mixture was stirred cold (ice bath) for 10 min followed by addition of 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (22 μL, 36.8 mg, 0.120 mmol). The resulting mixture was stirred cold for 20 min then the cold bath was removed. Aliquot at reaction time 2.5 hours indicated about 50% conversion. Reaction crude was cooled (ice bath) and quenched by NH4Cl (aq., sat.). The resulting bi-phasic mixture was worked up with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford an oil. This oil was purified by a preparative reverse-phase HPLC (Kromasil 100-5C18, 100×21.1 mm) eluted with a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixture. Related fractions were pooled and evaporated to afford methyl 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. Un-reacted starting material was also recovered. LCMS calc.=725.18; found=726.19 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][C:30]([OH:32])=O)[CH:28]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:65]([NH2:70])[C:66]([CH3:69])([CH3:68])[CH3:67]>CN(C)C=O>[CH3:67][C:66]([CH3:69])([CH3:68])[CH2:65][NH:70][C:30](=[O:32])[CH2:29][N:27]1[CH:28]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[CH:10][CH:11]=4)[N:33]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:25]=[N:26]1
Reactant: O=C(O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Reactant: CC(C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)CNC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-pyrazol-1-yl)-acetic acid (0.60 g, 0.128 mmol) in dimethylformamide (1 ml) was added EDCl (50 mg, 0.256 mmol), diisopropylethylamine (112 μl, 0.640 mmol), HOBT (35 mg, 0.256 mmol) and finally neopentylamine (30 μl, 0.256 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The title compound was purified by preparatory HPLC to yield the desired product. LCMS method: 2, RT: 2.51 min, MI: 517 [M+1]; 1H NMR (300 MHz, DMSO) 9.40 (s, 1H), 8.85 (s, 1H), 8.42 (s, 1H), 8.16 (s, 2H), 7.61 (d, 2H), 7.54 (d, 1H), 7.40 (dd, 2H), 6.92 (d, 2H), 4.98 (s, 2H), 4.02 (t, 2H), 2.93 (d, 2H), 2.87 (t, 2H), 2.63 (s, 4H), 1.69 (s, 4H), 0.83 (m, 9H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:18]([O:22][C:23](=O)[O-:24])([CH3:21])([CH3:20])[CH3:19].O>O1CCOCC1>[C:18]([O:22][C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH2:2][CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: c1cc2[nH]ncc2cc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]ncc3c2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a solution of 5-Piperazin-1-yl-1H-indazole (0.34 g, 1.3 mmol) in 1,4-dioxane (5 mL) was added 3N NaOH (0.42 mL, 1.3 mmol). After cooling to 0° C., a solution of tert-butylcarbonate (0.25 g, 1.3 mmol) in 1,4-dioxane (1 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight and then poured into water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography (EtOAc:hexanes, 1:1) to give 4-(1H-Indazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.31 g, 82%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 10.01 (s, 1H), 7.80 (s, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.21 (dd, J=9.2 Hz, J=2.0 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 3.62 (m, 4H), 3.09 (m, 4H), 1.50 (s, 9H). LCMS (APCI+) m/z 303 [M+H]+; Rt=2.50 minutes.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:52][OH:53])[C:11]([CH3:51])([CH3:50])[O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:52][OH:53])([C:11]([CH3:51])([CH3:50])[O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC(C)(C)[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: CO
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC(C)(C)[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
To a solution of [(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-7,7-dimethyl-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 9d (50.00 mg, 0.07 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 5 mL) were added o-dichlorobenzene (0.04 mL, 0.35 mmol) and 10% Pd/C (42.40 mg, 0.04 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 2 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 9 as colorless oil (13.00 mg, 46.0%, HPLC: 94.04%). The compound was characterized by the following spectroscopic data: MS (ESI, neg. ion) m/z: 509 [M+HCOO]−; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.40 (m, 2H), 7.29 (dd, 1H), 7.10 (d, 2H), 6.84 (d, 2H), 5.00 (d, 1H), 4.93 (d, 1H), 4.82 (d, 1H), 4.63 (t, 1H), 3.99 (s, 2H), 3.96 (m, 1H), 3.92 (m, 1H), 3.79 (m, 1H), 3.60 (m, 1H), 3.42 (m, 2H), 3.28 (m, 1H), 1.42 (s, 3H), 1.30 (t, 3H), 0.95 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:15][C:16](Cl)=[O:17].[OH-].[Na+]>[N+](C1C=CC=CC=1)([O-])=O>[F:1][C:2]1[C:3]([OH:9])=[CH:4][C:5]2[O:8][CH2:15][C:16](=[O:17])[C:6]=2[CH:7]=1
Reactant: Oc1ccc(F)c(O)c1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1COc2cc(O)c(F)cc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 14.5 %

Procedure:
A solution of 4-fluorobenzene-1,3-diol (1.00 g, 7.81 mmol) in nitrobenzene (15 mL) was added with aluminum chloride (3.12 g, 23.4 mmol), and the reaction vessel was cooled to 0° C. The reaction mixture was added dropwise with a solution of chloroacetyl chloride (1.06 g, 9.37 mmol) in nitrobenzene (2 mL), and the mixture was stirred at 40° C. for 6 hours. The reaction mixture was cooled to room temperature, and added with 2 N aqueous sodium hydroxide until the aqueous layer became basic. The aqueous layer was separated, then made acidic with 3 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 5-fluoro-6-hydroxybenzofuran-3(2H)-one (0.190 g, 14%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.IC[C:45]1[N:49](C)[C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]([CH3:45])[C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[N:47][N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Cn1c(CI)nnc1S(C)(=O)=O
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cn1c(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)nnc1S(C)(=O)=O

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazole and isolated as white solid. MS (m/e): 456.3 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3]([Br:5])Br.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8].O>CN(C=O)C>[Br:5][C:3]1[CH2:8][CH:7]([C:6]([O:10][CH2:11][CH3:12])=[O:9])[O:1][N:2]=1
Reactant: ON=C(Br)Br
Reactant: C=CC(=O)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(Br)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vigorously stirred mixture of hydroxycarbonimidic dibromide (15.5 g, 76.4 mmol) and ethyl acrylate (15.3 g, 153 mmol) in DMF (200 mL) was added a solution of 15 wt % aqueous KHCO3 (102 mL, 153 mmol). The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted twice with methyl tert-butyl ether. The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.B(O)(O)[C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C1COCC1.[Pd](Cl)Cl>[O:22]1[C:19]2[CH:20]=[CH:21][C:16]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)=[CH:17][C:18]=2[O:24][CH2:23]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCO4)ccc2c1
Yield: 27.2 %

Procedure:
2-chloro-6-nitroquinoline (5.2 g, 25 mmol) (prepared according to Byoung S. L. et al. Heterocycles. 1998, 48.12, 65), 3,4-(methylenedioxy)phenylboronic acid (5.0 g, 30 mmol), palladium dichloride bis(triphenilphosphine) (350 mg, 0.5 mmol) and barium hydroxide octahydrate (18.9 g, 60 mmol) in 150 ml of anhydrous THF are stirred at 65° C. for 20 hours. The mixture of reaction is evaporated under vacuum and the residue is chromatographed on silica gel (CH2Cl2) to afford 2.0 g (27%) of the titled product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:49]=[CH:50][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:57]=[C:58]([F:63])[CH:59]=[C:60]([F:62])[CH:61]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:64][CH:65]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cc(F)cc(F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 91 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(3,5-difluoro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 4 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 97 mg off-white solid (71%). MS (ISP) 447.3 (M+H)+.
Reaction SMILES: [Br-].[Li+].[CH2:3]([Mg]Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:28][C:29](Cl)=[O:30])[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1.ClCCl>[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:28][C:29](=[O:30])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
In a baked-out, argon-purged flask, 3.7 g of lithium bromide (2.4 eq.) and 4.38 g (1.2 eq) of CuBr-Me2S were dissolved in 55 ml of abs. THF and stirred at RT for 20 min. The resulting yellow solution was cooled to −70° C. and admixed with 16.2 ml (1.2 eq.) of benzylmagnesium chloride solution (20% in THF). After a further 20 min at −70° C., a solution of 5.32 g of methyl (S)-2-benzyloxycarbonylamino-3-chlorocarbonylpropionoate (example 1) (17.75 mmol) in 15 ml of THF was added. After 2 h, the mixture was heated slowly to −35° C. and 50 ml of a sat. NH4Cl solution were added. The reaction mixture was diluted with 400 ml of dichloromethane and washed with 100 ml of a 2 M HCl solution. The aqueous phase was washed twice more with 50 ml of dichloromethane. The combined organic phases were washed successively with 2 M HCl solution, sat. NaHCO3 solution and sat. NaCl solution, dried over MgSO4 and concentrated under reduced pressure. Methyl (S)-2-benzyloxycarbonylamino-4-oxo-5-phenylpentanoate was obtained as a yellow oil which was used in the next stage without further purification.