Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Cl:47])C(=O)C1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:11]([Cl:47])=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Yield: 99 %

Procedure:
A suspension of 55.0 g (100 mmol) of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate in 320 mL of DMF was heated to 60° C. The resulting yellow solution was treated with 14.0 g (105 mmol) of NCS in one portion. The solution quickly darkened. After 5 minutes LCMS indicated complete conversion to the desired chloro compound. The solution was cooled to RT and diluted with 1 L of EtOAc. The resulting solution was washed with 5% aqueous NaCl (1×1 L), 5% aqueous sodium bisulfite (2×200 mL), saturated aqueous sodium bicarbonate (3×200 mL), and saturated aqueous brine (1×200 mL). The solution was dried over sodium sulfate and concentrated to dryness at reduced pressure to give 58.0 g (99%) of methyl 2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a brown solid. This material was taken forward to the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (q, J=4.42 Hz, 1H) 8.25 (s, 1H) 7.94-8.04 (m, 3H) 7.90 (d, J=2.63 Hz, 1H) 7.34-7.46 (m, 2H) 7.18 (s, 1H) 6.93 (br. s., 2H) 3.83 (s, 3H) 3.33 (s, 3H) 2.84 (d, J=4.59 Hz, 3H) 2.26-2.36 (m, 1H) 0.84-1.11 (m, 3H) 0.40 (br. s., 1H). LCMS (ESI): 586 (M+H+).
Reaction SMILES: [NH:1]1[C:10](=[S:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].Br[CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:3][C:2]1[N:4]=[C:5]2[C:9]([NH:8][CH:7]=[N:6]2)=[C:10]([S:11][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:1]=1
Reactant: Nc1nc2nc[nH]c2c(=S)[nH]1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SC(c2ccccc2)c2ccccc2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 48.1 %

Procedure:
A mixture of thioguanine (25 g), bromodiphenylmethane (37.1 g) and potassium carbonate (31.1 g) in N,N-dimethylformamide (250 cm3) was stirred at ambient temperature for 66 hour. The reaction mixture was filtered and the filtrate evaporated to give a cream solid. Recrystallisation from methanol gave 24 g (48%) of the title compound, m.p. 226°-227° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:20][C@H:14]2[C:13](=[O:32])[NH:12][C@:11]2([C:34]([NH:36][S:37]([CH:40]3[CH2:42][CH2:41]3)(=[O:39])=[O:38])=[O:35])[CH2:33][C@H:10]2[CH2:9][C:8]([F:44])([F:43])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.N1C=CC=CC=1.[CH3:52][C:53]1[O:57][N:56]=[C:55]([C:58](O)=[O:59])[CH:54]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH:40]1([S:37]([NH:36][C:34]([C@@:11]23[CH2:33][C@H:10]2[CH2:9][C:8]([F:43])([F:44])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:58]([C:55]2[CH:54]=[C:53]([CH3:52])[O:57][N:56]=2)=[O:59])[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]4[CH:31]=[N:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH2:20][C@H:14]2[C:13](=[O:32])[NH:12]3)=[O:35])(=[O:39])=[O:38])[CH2:42][CH2:41]1
Reactant: Cc1cc(C(=O)O)no1
Reactant: N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3cnc4ccccc4n3)CN2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@@H](Oc4cnc5ccccc5n4)CN3C2=O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS)-6-amino-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 2a, 8.05 mg, 0.012 mmol) in DMF (120 μl) was added pyridine (7 μl, 0.087 mmol) followed by 5-methylisoxazole-3-carboxylic acid (2.28 mg, 0.018 mmol) and then HATU (7.04 mg, 0.019 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, cooled to 0° C. and neutralized with HCl (4 N in dioxane, 22 μl; diluted with ethyl acetate). The mixture was concentrated and purified by prep-TLC (ethyl acetate) to provide the title compound N-((2R,6S,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide (7.65 mg, 10.29 μmol, 86% yield) MS (ESI): m/z=744.3 [M+H]. Example 2 provided an IC50 of >1.0 nM in a 1a enzyme assay; an IC50 of >1.0 nM in a 1b enzyme assay; a HLM stability value of <50 μl/min/mg; an EC50 of >5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of >5.0 nM in a replicon cell line assay in a 1b-con1 background.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])=[N:37][CH:38]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:59]C(N1CCCC1C(O)=O)=O)(C)(C)C>>[OH:59][C@@H:42]1[CH2:41][N:40]([C:44](=[O:54])[C@@H:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:47])[CH3:48])[C@H:39]([C:36]2[NH:37][CH:38]=[C:34]([C:31]3[CH:30]=[CH:29][C:28]([C:23]4[CH:24]=[C:25]5[C:20](=[CH:21][CH:22]=4)[CH:19]=[C:18]([C:15]4[NH:14][C:13]([C@@H:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:17][CH:16]=4)[CH:27]=[CH:26]5)=[CH:33][CH:32]=3)[N:35]=2)[CH2:43]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1nc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)c[nH]1)C(C)C

Procedure:
(S)-tert-butyl 2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate was prepared following the procedure for 2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (Example EQ), substituting 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:25]=[C:26]([N:30]([CH3:38])[C:31]([N:35]([CH3:37])[CH3:36])=[N:32][C:33]#[N:34])[CH:27]=[C:28]([CH3:29])[C:5]=2[N:4]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:25]=[C:26]([N:30]([CH3:38])[C:31]([N:35]([CH3:37])[CH3:36])=[N:32][C:33]#[N:34])[CH:27]=[C:28]([CH3:29])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(N(C)C(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc2c(C)cc(N(C)C(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1d from methyl 4'-[[2-ethyl-4-methyl-6-(3,3-dimethyl-2-cyano-1-methyl-guanidino) -1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:17]3[CH2:18][CH2:13][CH2:14][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 g, 0.0077 mol), (R)-tert-butyl 3-hydroxy-1-piperidinecarboxylate (2.3 g, 0.012 mol), and triphenylphosphine (3 g, 0.012 mol) in tetrahydrofuran (70 mL), diethyl azodicarboxylate (2 g, 0.012 mol) was added at 0° C. The mixture was stirred at room temperature under an atmosphere of nitrogen for 2 days. In order to complete the reaction, additional (R)-tert-butyl 3-hydroxy-1-piperidinecarboxylate (0.62 g, 0.003 mol), and triphenylphosphine (0.81 g, 0.012 mol), and diethyl azodicarboxylate (0.6 g, 0.003 mol) were added to the mixture. The mixture was stirred at room temperature under an atmosphere of nitrogen for additional 18 hours. The solvent was removed under the reduced pressure to yield crude (S)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate, which was used crude for the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:16])[CH2:14]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1OCCC1.CC(C)([O-])C.[Na+].C1COCC1.N1C=CN=C1.O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:14][O:16]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)CO)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CC1CCCO1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H]2CO2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
(S)-3-((S)-1,2-Dihydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (230 g, 990 mmol, 1.0 eq.) was combined with MeTHF (4.9 kg, 57 mol) and cooled to 0° C. 2.0 M Sodium t-butoxide in THF (994 mL, 2.0 eq.) was added drop wise over 20 minutes. The mixture was stirred at −1° C. for 15 minutes, then cooled to −7° C. p-Tolylsulfonyl)imidazole (243 g, 1.1 mol, 1.1 eq.) was added and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was quenched with cold H2O (5.7 kg, 320 mol). Hexanes (1.8 kg, 21 mol) was added and the mixture was warmed to 23° C. and stirred for about 30 minutes. The layers were allowed to settle, the phases were separated, and the reaction vessel was rinsed with MeTHF (100 mL). The organic layer (˜8 L) was removed and stored at 5° C. overnight, then filtered through Na2SO4 and concentrated at 60 torr to 30 torr with a water bath at 25° C. to yield the title compound (220 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[CH3:13].C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][C:12]=1[CH3:13])[C:6](=[O:7])[O:8][CH:9]2[OH:10]
Reactant: Cc1cc2c(cc1C)C(=O)OC2=O
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)C(O)OC2=O
Reaction time: 1 h

Procedure:
To a solution of 4,5-dimethylphthalic anhydride (1.5 g, 8.5 mmol) in anhydrous tetrahydrofuran (25 ml) was added a 1.0 mol/L solution of tri-tert-butoxy aluminohydride in anhydrous tetrahydrofuran (8.5 ml) under ice cooling and argon atmosphere, and stirred for 1 hr under ice cooling. To the reaction solution was added ice-cold water, and the insoluble materials was filtered off. The filtrate was concentrated under reduced pressure to give crude 5,6-dimethyl-3-hydroxyphthalide. To this was added methyl iodide (12 g, 85 mmol) and K2CO3 (9.4 g, 68 mmol), and heated under reflux in acetone solvent for 5 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform) to give 0.64 g of methyl 4,5-dimethyl-2-formylbenzoate.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26](=[O:28])N)[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:29].[Na+].C(OCCOCCO)C>O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=[O:29])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCOCCOCCO
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reaction time: 16 h

Procedure:
A mixture of 37.3 g of 3-[4-(4-phenyl-1,2,3,6tetrahydropyridyl)-butyl]-5-carbamoylindole, 27.1 g of NaOH, 525 ml of water and 450 ml of diethylene glycol monoethyl ether is boiled with stirring for 16 hours. The mixture is cooled, worked up in the customary manner and acidified to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylic acid, m.p. 284°-285°.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](Br)[N:34]=1>>[NH2:32][C:33]1[N:34]=[C:35]([C:9]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=4)[C:11]=3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:31])[CH3:30])[C:8]=2[CH3:29])[CH:36]=[CH:37][CH:38]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: Nc1cccc(Br)n1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N)n1)OCC2c1ccc(C(C)C)cc1
Yield: 68 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-amino-6-bromopyridine, the title compound was obtained in the same manner as in Example 107. Yield: 68%. Melting point: 237-239° C. (ethyl acetate-hexane).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]([CH3:30])[C:27]([OH:29])=O)=[CH:23][C:22]=4[F:33])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:7]=[CH:6][C:5]=12.O1C2C=CC(OC3C(C(NCC4C=CC(O[C@H](C)C(O)=O)=CC=4F)=O)=CC=C[N:45]=3)=CC=2OC1>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][C@@H:26]([C:27](=[O:29])[NH2:45])[CH3:30])=[CH:23][C:22]=3[F:33])=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)c(F)c1)C(=O)O
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)c(F)c1)C(N)=O

Procedure:
The compound of Formula (5.5.16) was prepared in a manner analogous to that described in Example 14, substituting (R)-2-[4-({[2-(benzo[2,1,3]thiadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid for the corresponding (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid material.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=2)[C:13](/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH3:36])=[N:12][C:11]=1[Cl:37])(C(C)(C)C)(C)C.[F-]>CCCCCC.C(OCC)(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]2[C:10]([CH2:9][OH:8])=[C:11]([Cl:37])[N:12]=[C:13]2/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH3:36])=[CH:17][CH:18]=1)([O:30][CH3:31])=[O:29]
Reactant: CCC/C=C\c1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC/C=C\c1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
5-t-Butyldimethylsilyloxymethyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-2-(cis-pent-1-en-1-yl)imidazole (100 mg) was desilylated with fluoride by procedures familiar to one skilled in the art. Flash chromatography in 1:1 hexane/ethyl acetate yielded 65 mg of a viscous, colorless oil. NMR (200 MHz, CDCl3) δ 7.85 (d, 1H), 7.55 (t, 1H), 7.42 (t, 1H), 7.28 (m, 3H), 7.05 (d, 2H), 6.11 (d, 1H), 5.92 (d of t, 1H), 5.30 (s, 2H), 4.57 (d, 2H), 3.64 (s, 3H), 2.69 (quart., 2H), 1.62 (t, 1H), 1.47 (sext., 2H), 0.92 (t, 1H).
Reaction SMILES: S(=O)(=O)(O)O.CO[C@@H:8]1[O:30][C:29]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:19]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:9]1[O:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:51]([OH:54])(=[O:53])[CH3:52]>C(OC(=O)C)(=O)C.C(OCC)(=O)C.O>[C:51]([O:54][C@@H:8]1[O:30][C:29]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:19]([O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:9]1[O:10][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:53])[CH3:52]
Reactant: CO[C@@H]1OC(COC(=O)c2ccccc2)(COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@@H]1OC(COC(=O)c2ccccc2)(COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sulfuric acid (97%, 75 mL) was added to a solution of 1-O-methyl-2,3,5-tri-O-benzoyl-4-C-(benzoyloxymethyl)-β-D-ribofuranose (1.7 g, 2.8 mmoles) in a mixture of acetic acid (6.7 mL) and acetic anhydride (0.67 mL) at 0° C. The reaction mixture was stirred at 25° C. for 15 h and diluted with ethyl acetate (50 mL) and water (10 mL). This solution was washed with brine (3 times), with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was subjected to silica gel chromatography [ethanol (0–2%) in dichloromethane] to give 1.4 g of the titled compound as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:33]=[C:9]2[N:10]=[C:11]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:12]=[C:13]([N:14]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]2[N:7]=1)=[O:5].[CH2:35]([Mg]Br)[CH3:36].[Cl-].[NH4+]>O1CCCC1>[C:4]([C:6]1[CH:33]=[C:9]2[N:10]=[C:11]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:12]=[C:13]([N:14]([CH:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]2[N:7]=1)(=[O:5])[CH2:35][CH3:36]
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1cc2nc(N3CCCC3)cc(N(C(=O)OC(C)(C)C)C3CCOCC3)n2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)c1cc2nc(N3CCCC3)cc(N(C(=O)OC(C)(C)C)C3CCOCC3)n2n1
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl (2-{[methoxy(methyl)amino]carbonyl}-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ylcarbamate (2.22 g, 4.68 mmol) in tetrahydrofuran (50 mL) was added ethylmagnesium bromide solution (1M in tetrahydrofuran, 14.0 mL, 14.0 mmol) at 0° C. After being stirred for 20 min at same temperature, the reaction mixture was poured into saturated ammonium chloride. The mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:ethyl acetate=3:2) to give tert-butyl (2-propionyl-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ylcarbamate. MS (APCI): m/z 444 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]#[N:26])=[CH:22][CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:33][C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:40][C:38]1[CH:37]=[CH:36][C:35]([CH3:41])=[C:34]([CH:39]=1)[O:33][C:17]1[N:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(C#N)cc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCNCC2)c2ccc(C#N)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
The compound of step 3 (20 mg, 36 μmol) was dissolved in DCM (6 ml), TFA (2 ml) was added, and the mixture was stirred at room temperature for 1 h. The solvents were evaporated. The residue was dissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight. 11 mg of the title compound were obtained in the form of the 2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carbonitrile hydrochloride.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH:5]1[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)(=[O:3])[CH3:2].[Li+].[BH4-]>CO>[CH2:9]([N:7]1[CH2:8][CH:4]([CH:1]([OH:3])[CH3:2])[CH:5]([C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[CH2:6]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-((3SR,4RS)-4-acetyl-1-benzyl-pyrrolidin-3-yl)-benzonitrile (IV-5) (IV-5) (6.30 g, 20.7 mmol) in MeOH (300 mL) at RT were added portion wise LiBH4 (9.49 g, 0.43 mol). Stirring was continued for overnight, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield 4-[(3SR,4RS)-1-benzyl-4-((RS)-1-hydroxy-ethyl)-pyrrolidin-3-yl]-benzonitrile (V-B-5) 1.35 g (21%) as a colorless oil ES-MS m/e: 307.2 (M+H+) and 4-[(3SR,4RS)-1-benzyl-4-((SR)-1-hydroxy-ethyl)-pyrrolidin-3-yl]-benzonitrile (V-A-5) 1.30 g (20%) as a colorless oil ES-MS m/e: 307.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCc1cc(OC)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCc1cc(O)ccc1F
Temperature: -15 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
To a solution of ethyl 3-(2-fluoro-5-methoxyphenyl)propanoate (100 mg) in dichloromethane (3.0 mL) was added dropwise a 1.0 M solution of boron tribromide in dichloromethane (0.15 mL) at −15° C., and the mixture was stirred at −15° C. for 5 hr. Water (20 ml) was added dropwise to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (60 mg) as a colorless oil. This compound was used for the next step without further purification.