Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:34])C1.C([O-])(O)=O.[Na+]>O.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]=[O:34])[N:8]=[C:7]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2nc(-c3ccccc3)ccc2cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cc2nc(-c3ccccc3)ccc2cc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The CCl4 (45 ml) solution of 6-chloro-7-methyl-2-phenylquinoline (753.3 mg, 2.969 mmol), AIBN (48.8 mg, 0.1 eq.) and NBS (898.4 mg, 1.7 eq.) was heated at 80° C. under N2 for 8 h. After that time, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (60 ml), washed successively with H2O (30 mL), saturated NaS2O3 (30 mL), H2O (30 mL), and brine (30 mL). The organic extract was then dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DMSO (105 mL), and then NaHCO3 (2495 mg, 10 eq.) was added. The reaction mixture was stirred at 90° C. for 3 h. Water (140 mL) was added and the mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with H2O (4×60 mL) and brine (60 mL), and dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from CHCl3/hexane (20:80, 10 mL) to give 6-chloro-2-phenylquinoline-7-carbaldehyde as pale-yellow solid; 1H NMR (CDCl3, 400 MHz) δ 7.51-7.58 (m, 3H), 7.93 (s, 1H), 8.03 (d, 1H, J=8.8 Hz), 8.18-8.20 (m, 3H), 8.75 (s, 1H), 10.63 (s, 1H); MS(ES+): 268.1/270.0 (M/M+2).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:42])([F:41])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:41])([F:42])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Product: CCOC(=O)c1ccc(N2CCN(CCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (a) of Example 93 were used as the starting compounds. Thus, ethyl 4-[4-[3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]propyl]-piperazin-1-yl]benzoate was obtained.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1([C:22]([F:25])([F:24])[F:23])[C:19]2[CH:18]=[C:17]([F:20])[CH:16]=[C:15]([Cl:21])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)C.[OH-].[Na+]>C(O)C>[Cl:21][C:15]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:22]([F:23])([F:24])[F:25])([O:6][CH2:5][C:4]([OH:26])=[O:3])[C:19]=2[CH:18]=[C:17]([F:20])[CH:16]=1
Reactant: CCOC(=O)COC1(C(F)(F)F)c2ccccc2-c2c(Cl)cc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COC1(C(F)(F)F)c2ccccc2-c2c(Cl)cc(F)cc21
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 85.3 %

Procedure:
To a mixture of ethanol (440 ml) and (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid ethyl ester (360 g) was added 2N aqueous sodium hydroxide solution (877 ml), and the mixture was stirred at 80° C. for 3.5 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off through celite, and washed with water (500 ml) and ethanol (60 ml). Water (120 ml) was added to the filtrate and the mixture was ice-cooled, and formic acid (199 ml) was added dropwise. This suspension was stirred at room temperature overnight, and filtered. The obtained solid was washed with 25 v/v % ethanol-water (400 ml), air-dried overnight, and dried under reduced pressure at 60° C. to give the title compound (285 g, 2 steps 90%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].[OH-].[NH4+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccnc2ccccc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
4-Chloroquinoline (5 g, 31 mmol) was dissolved in sulfuric acid (23 mL, 0.42 mol), to which nitric acid (4.5 mL, 0.11 mol) was slowly added dropwise, which was then stirred at room temperature for four hours. When the reaction was completed, the resultant was cooled to 0° C., and neutralized with 1M ammonium hydroxide. The generated solid was dissolved in ethyl acetate, dried with anhydrous sodium sulfate, and then filtered. The solvent was removed by vacuum distillation, and the residue was purified by a column chromatography (ethyl acetate/n-hexane=⅓) to obtain 3.55 g of the desired compound as a white solid (yield 55.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:16]([NH:1][C:2]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 2-amino-4-(trifluoromethyl)benzoate (8.00 g, 0.036 mol), acetic anhydride (11.18 g, 0.109 mol), pyridine (8.62 g, 0.109 mol) and chloroform (20 ml) was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The extracts were washed with 1N hydrochloric acid and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 50% ethyl acetate/n-hexane to give 8.10 g (0.031 mol 86%) of the title compound as a white powder.
Reaction SMILES: C1C(=O)N(OC(CCSSCCC(NCCN[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]2[S:33][CH2:32][C@@H:31]3[NH:34][C:35]([NH:37][C@H:30]23)=[O:36])=[O:24])=O)=O)C(=O)C1.C(=O)([O-])[O-:39]>P([O-])([O-])([O-])=O>[OH:39][C:23]([CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]1[C@@H:30]2[C@@H:31]([NH:34][C:35]([NH:37]2)=[O:36])[CH2:32][S:33]1)=[O:24]
Reactant: O=C([O-])[O-]
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCNC(=O)CCSSCCC(=O)ON1C(=O)CCC1=O
Agent: O=P([O-])([O-])[O-]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
BSA (manufactured by Oriental Yeast K.K., F-V; 30 mg) was dissolved in 0.1M phosphate buffer (pH 7.0; 1 ml), and thereto was added an NHS-SS-biotin solution (manufactured by Pierce Chemical Co., 16.8 mg/ml in 0.1M phosphate buffer, pH 7.0; 1 ml) and the mixture was reacted at 30° C. for 1 hour. The reaction solution was centrifuged and the supernatant was subjected to Sephadex G-25 column (φ1.5 cm×30 cm, eluent: 50 mM carbonate buffer, pH 9.6) to give a biotin-BSA fraction.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:23])[NH:7][S:8]([C:11]1[C:16]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1)(=[O:10])=[O:9])CCC.C(Cl)(Cl)=O.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32](NC)[N:31]=1>ClC1C=CC=CC=1.ClCCl>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32]([N:5]([CH3:1])[C:6](=[O:23])[NH:7][S:8]([C:11]2[C:16]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:19])=[O:20])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:9])=[O:10])[N:31]=1
Reactant: CCCCNC(=O)NS(=O)(=O)c1ncccc1N(C)S(C)(=O)=O
Reactant: CNc1nc(OC)cc(OC)n1
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)nc(N(C)C(=O)NS(=O)(=O)c2ncccc2N(C)S(C)(=O)=O)n1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
63.0 g (0.17 mol) of 3-butyl-1-[3-(N-methyl-N-methylsulfonylamino)-2-pyridylsulfonyl]urea are suspended in 1 l of chlorobenzene, and the suspension is heated to 70° C. At this temperature, the experiment starts to pass a gentle stream of phosgene into the suspension, and heating is continued for approx. 20 minutes until an internal temperature of 120° C. is reached. After phosgene has been passed in for a further 20 minutes (approx. 50 g (0.5 mol) in total), the lower-boiling components together with approx. 300 ml of chlorobenzene are removed from the reaction mixture by distillation over a period of 30 minutes. After the mixture has cooled to room temperature, 29.0 g (0.17 mol) of 4,6-dimethoxy-2-methylaminopyrimidine dissolved in 500 ml of dichloromethane are added, and the mixture is heated for 7 hours at 40° C. The mixture is cooled, the organic phase is washed with 1×250 ml each of 1N HCl and water, dried and evaporated. After the crude product has been triturated with diethyl ether, 66.6 g (85% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-3-methyl-1-[3-(N-methyl-N-methylsulfonyl-amino)-2-pyridylsulfonyl]-urea of m.p. 167°-168° C. (decomp.) remained.
Reaction SMILES: Cl.[CH3:2][NH2:3].[OH-].[K+].[CH:6]([C:8]1[N:9]2[CH:15]=[N:14][CH:13]=[C:10]2[S:11][CH:12]=1)=O.C#N.[B].[Na]>CO>[CH3:2][NH:3][CH2:6][C:8]1[N:9]2[CH:15]=[N:14][CH:13]=[C:10]2[S:11][CH:12]=1
Reactant: CN
Reactant: O=Cc1csc2cncn12
Agent: C#N
Agent: Cl
Agent: [B]
Solvent: CO
Product: CNCc1csc2cncn12
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To 0.5 ml of methanol containing 120 mg of methylamine hydrochloride, 46 mg of potassium hydroxide and 90 mg of 3-formylimidazo[5,1-b]thiazole were added, followed by stirring at room temperature for 6.5 hours. Further, 64 mg of sodium boron cyanohydride was added thereto, and the mixture was then stirred at room temperature for 17 hours. Afterward, the solvent was evaporated under reduced pressure. To the resulting residue, 20 ml of water was added, and extraction was then carried out twice with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was then evaporated under reduced pressure to obtain 47.6 mg of 3-(N-methylamino)methylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:17]([OH:19])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1)=[CH:8]2.[CH3:20][C:21]1[C:25]([NH2:26])=[C:24]([CH3:27])[O:23][N:22]=1>>[CH3:20][C:21]1[C:25]([NH:26][C:17]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH:12]4[CH2:16][CH2:15][CH2:14][O:13]4)=[CH:8][C:7]=23)=[O:19])=[C:24]([CH3:27])[O:23][N:22]=1
Reactant: COc1ccc(C(=O)O)c2cc(C3CCCO3)oc12
Reactant: Cc1noc(C)c1N
Product: COc1ccc(C(=O)Nc2c(C)noc2C)c2cc(C3CCCO3)oc12
Yield: 66.8 %

Procedure:
Starting from 7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid (262 mg) and 3,5-dimethylisoxazol-4-ylamine (120 mg). Purification by column chromatography on silica eluting with 30% ethyl acetate in hexane afforded the title compound as an off-white solid (238 mg).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C([NH:32][CH:33]2[C:46](=[O:47])[N:35]3[CH:36]([C:41]4[NH:45][N:44]=[N:43][N:42]=4)[C:37]([CH3:40])([CH3:39])[S:38][C@H:34]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[C:50]1([CH2:56][C:57](Cl)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O.C(OC(C)C)(C)C.CC(C)=O>[C:50]1([CH2:56][C:57]([NH:32][CH:33]2[C:46](=[O:47])[N:35]3[CH:36]([C:41]4[NH:42][N:43]=[N:44][N:45]=4)[C:37]([CH3:39])([CH3:40])[S:38][C@H:34]23)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture of p-toluenesulfonic acid monohydrate (788 mg., 4.14 mmoles), acetone (35 ml.) and 6-triphenylmethylamino-2,2-dimethyl-3-(5-tetrazolyl)penam (2.0 g., 4.14 mmole) is stirred for twenty minutes at room temperature and is then diluted with water (100 ml.) and isopropylether (100 ml.). The biphasic mixture is stirred vigorously and adjusted to pH 7 with 2 N sodium hydroxide. Phenylacetyl chloride (700 mg., 4.55 mmole freshly distilled) is added and the reaction mixture maintained at pH 5.5-6.5 by addition of 2 N sodium hydroxide as necessary. Reaction is continued until the pH levels off at 6.5. The two phases are separated and the aqueous phase is washed with ether (2×50 ml.). Chloroform (100 ml.) is added and the pH is adjusted to 2 by addition of 6 N HCl. The mixture is stirred, the phases separated and the aqueous phase extracted with chloroform (2×50 ml.). The chloroform phases are combined, dried (Na2SO 4), and then concentrated under reduced pressure to about 50 ml. volume. A 1:1 solution of ether-hexane is added dropwise with vigorous stirring until precipitation of the product is complete. The white precipitate is filtered and air-dried. The yield is 850 mg. (57.4%), m.p. 168°-170°. NMR (DMSO-d6): 7.30 (s, 5H), 5.80-5.42 (m, 2H), 5.28 (s, 1H), 3.60 (s, 2H), 1.68 (s, 3H) and 1.10 ppm (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[C@H:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[CH2:13][C@@H:12]([SH:27])[CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].F[C:29](F)(F)[C:30]([O-])=[O:31].C(Cl)(=O)C>C([O-])(O)=O.[Na+].CCOC(C)=O.N1C=CC=CC=1>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[C@H:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[CH2:13][C@@H:12]([S:27][C:30](=[O:31])[CH3:29])[CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: O=C([O-])C(F)(F)F
Reactant: CCCc1cnc(N2C[C@H](S)C[C@H]2COCc2cc(F)c(F)cc2F)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CCCc1cnc(N2C[C@H](SC(C)=O)C[C@H]2COCc2cc(F)c(F)cc2F)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A solution of 397 mg (1 mmol) (3R,5S)-1-(5-Propyl-pyrimidin-2-yl)-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol (the trifluoro-acetate salt was extracted with aqueous saturated NaHCO3/EtOAc) in 6 ml pyridine were treated at 0° C. with 0.14 ml (2 mmol) acetyl chloride and stirred for 5 h at RT. The reaction was poured on ice water and extracted wit Et2O (3×). The organic phases were washed with aqueous 1 N HCl and 10% NaCl, dried (Na2SO4) and evaporated. Flash chromatography on silica gel (CH2Cl2/Et2O 100:0 to 95:5) gave 383 mg (87%) (3R,5S)-Thioacetic acid S-[1-(5-propyl-pyrimidin-2-yl)-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidin-3-yl]ester, MS: 440 (MH+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](Cl)=[N:17][N:16]=[C:15]3[Cl:23])=[O:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[O:28]1CCOCC1.Cl>O>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([OH:28])=[N:17][N:16]=[C:15]3[Cl:23])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCO1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(Cl)nnc(Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(O)nnc(Cl)c2c1
Temperature: 45 °C
Reaction time: 6 h

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.304 mg, 0.787 mmol), 2N NaOH (4 mL, 8.00 mmol) and dioxane (6 mL) was stirred at 45° C. for 6 h. The reaction mixture was diluted with water, acidified with conc. HCl to ˜pH 4 and extracted with EtOAc (×3). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated to afforded 4-chloro-1-hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.112 g) as a white solid, 1H NMR (600 MHz, CDCl3) δ: 7.33 (d, 1H), 7.43 (t, 1H), 8.03 (s, 1H), 8.06 (d, 1H), 8.36 (dd, 1H), 8.42 (d, 1H), 8.56 (s, 1H), 10.28 (s, 1H), 11.9 (s, 1H) ppm, 1H NMR (500 MHz, d6-DMSO) δ: 7.52 (d, 1H), 7.65 (t, 1H), 8.08 (d, 1H), 8.26 (s, 1H), 8.43 (d, 1H), 8.47 (dd, 1H), 8.52 (s, 1H), 11.02 (s, 1H), 13.02 (s, 1H) ppm. m/z 368.13; and 1-chloro-4-hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.083 g) as a white solid, 1H NMR (500 MHz, CDCl3) δ: 7.21 (d, 1H), 7.32 (t, 1H), 7.92 (d, 1H), 7.97 (d, 1H), 8.00 (s, 1H), 8.38 (d, 1H), 8.93 (s, 1H), 10.42 (s, 1H), 12.20 (s, 1H) ppm. m/z 368.13.
Reaction SMILES: [CH2:1]([C:4]1[CH:49]=[C:48]([Cl:50])[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:47]=[CH:46][C:15]([CH2:16][CH:17]([C:27]([N:29]([CH2:33][C:34]3[CH:39]=[C:38]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:37]=[CH:36][C:35]=3[Cl:45])[CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[C:6]([Cl:51])[CH:5]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:61].[Na+].OO>CCOC(C)=O.C1COCC1>[Cl:45][C:35]1[CH:36]=[CH:37][C:38]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:39][C:34]=1[CH2:33][N:29]([CH:30]1[CH2:32][CH2:31]1)[C:27](=[O:28])[CH:17]([CH2:16][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][O:8][C:7]2[C:6]([Cl:51])=[CH:5][C:4]([CH2:1][CH2:2][CH2:3][OH:61])=[CH:49][C:48]=2[Cl:50])=[CH:47][CH:46]=1)[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: [OH-]
Reactant: C=CCc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3cc(CCCOC)ccc3Cl)C3CC3)cc2)c(Cl)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCCc1ccc(Cl)c(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(CCCO)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a THF solution (0.04 M) of tert-butyl {2-{4-[2-(4-allyl-2,6-dichlorophenoxy)ethoxy]benzyl}-3-[[2-chloro-5-(3-methoxypropyl)benzyl](cyclopropyl)amino]-3-oxopropyl)carbamate from Example 122, Step 5 (1 eq.) was added 9-borabicyclo[3.3.1]nonane (0.5 M THF solution, 2.6 eq.) dropwise at 0° C. The resulting solution was warmed slowly to RT over 16 h. The reaction was quenched at 0° C. with the dropwise addition of ethanol. Then, NaOH (1 N aqueous solution, 4 eq.) and H2O2 (30% w/w aqueous solution, 12 eq.) were added. After 1 h of stirring at 0° C. and another 4 h of stirring at RT, the reaction mixture was diluted with EtOAc. The organic layer was separated, washed with water, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:1 (v/v) Hex:EtOAc→EtOAc), revealed the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:49]([CH:52]([CH3:54])[CH3:53])=[C:50]=[O:51]>>[CH:52]([NH:49][C:50](=[O:51])[O:39][C@H:36]1[CH2:37][CH2:38][C@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)O[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from (trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethyl-silyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol and 2-isocyanatopropane following a procedure analogous to that described for Intermediate 13. LC (method 5): tR=1.28 min.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH2:16][C:17]([O:20][Si](C(C)(C)C)(C)C)([CH3:19])[CH3:18])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH:38]2[CH2:43][C:42]([CH3:45])([CH3:44])[NH:41][C:40]([CH3:47])([CH3:46])[CH2:39]2)[N:32]=1>N1C=CC=CC=1>[CH3:19][C:17]([OH:20])([CH2:16][CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:35]3[CH:36]=[CH:31][N:32]=[C:33]([NH:37][CH:38]4[CH2:43][C:42]([CH3:45])([CH3:44])[NH:41][C:40]([CH3:47])([CH3:46])[CH2:39]4)[N:34]=3)=[CH:7][NH:6]2)=[CH:10][CH:11]=1)[CH3:18]
Reactant: CC(C)(CCc1ccc2ccn([Si](C)(C)C(C)(C)C)c2c1)O[Si](C)(C)C(C)(C)C
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Solvent: c1ccncc1
Product: CC(C)(O)CCc1ccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c2c1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-6-[3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-butyl]-1H-indole (prepared by Raney-Nickel hydrogenation of (E)-3-(1H-Indol-6-yl)-acrylic acid methyl ester, followed by reaction with MeMgBr (Step A of Method A) and TBDMS protection according to standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the TBDMS protecting groups with HF in pyridine. Yield: 57 mg (17%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:15][CH:16]([C:22]1([CH3:27])OCC[O:23]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]2=[O:28])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:15][CH:16]([C:22](=[O:23])[CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]2=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O)C(C)=O

Procedure:
Ethyl 2-(5-t-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (126 mg, 28%) in the same manner as described in the above example 6 (20) from ethyl 3-(5-t-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.52 g, 1.33 mmol) and p-toluenesulfonic acid monohydrate (50 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]([C:18]2[C:19]([C:27]([NH:29][C:30]([CH3:34])([CH2:32][OH:33])[CH3:31])=O)=[CH:20][CH:21]=[C:22]3[O:26][CH2:25][O:24][C:23]=23)=[C:11]2[O:17][CH2:16][O:15][C:12]2=[CH:13][CH:14]=1)=[O:8])([CH3:5])[CH3:4]>S(Cl)(Cl)=O>[CH2:25]1[O:24][C:23]2[C:18]([C:10]3[C:11]4[O:17][CH2:16][O:15][C:12]=4[CH:13]=[CH:14][C:9]=3[C:7]3[O:8][CH2:2][C:3]([CH3:5])([CH3:4])[N:6]=3)=[C:19]([C:27]3[O:33][CH2:32][C:30]([CH3:31])([CH3:34])[N:29]=3)[CH:20]=[CH:21][C:22]=2[O:26]1
Reactant: CC(C)(CO)NC(=O)c1ccc2c(c1-c1c(C(=O)NC(C)(C)CO)ccc3c1OCO3)OCO2
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc3c(c2-c2c(C4=NC(C)(C)CO4)ccc4c2OCO4)OCO3)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
N,N'-Bis(3-hydroxy-2-methylpropan-2-yl)-5,6-methylenedioxy-5',6'-methylenedioxy-2,2'-biphenyldicarboxamide (3 g) is added to thionyl chloride (20 ml), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is distilled under reduced pressure to remove thionyl chloride, and the residue is dissolved in ethyl acetate. The solution is washed, dried and distilled to remove the solvent, and the residue is crystallized from diisopropyl ether to give 5,6-methylenedioxy-5',6'-methylenedioxy-2,2'-bis(4,4-dimethyl-4,5-dihydro-2-oxazolyl)biphenyl (2 g) as colorless crystal. M.p. 152°-154° C.