Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.CN(C)[C:16](=[O:18])[CH3:17]>CCCCCC.C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:16](=[O:18])[CH3:17])=[N:8][CH:9]=1
Reactant: CC(=O)N(C)C
Reactant: Clc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(=O)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under cooling at −78° C., 1.56M n-butyllithium in hexane (27 mL) was added dropwise to 2-bromo-5-chloropyridine (6.8 g) in diethyl ether (45 mL), and then N,N-dimethylacetamide (5 mL) was added dropwise thereto, followed by stirring for 30 minutes. The reaction mixture was partitioned by use of saturated aqueous ammonium chloride and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give 1-(5-chloro-2-pyridyl)ethanone as a solid (3.26 g, 59%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C1(C)C=CC=CC=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>[C:1]1([CH2:7][CH:8]([NH:10][C:18](=[O:19])[CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: O=CCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC(Cc1ccccc1)NC(=O)Cc1ccccc1
Yield: 75.2 %

Procedure:
To a well stirred suspension of 2-phenylacetamide (540 mg, 4 mmol) in dry dichloromethane (2 mL) was added the 2-phenylacetaldehyde (240 mg, 2 mmol) and trimethylsilyltrifluoromethanesulfonate (22 mg, 0.1 mmol). The mixture was vigorously stirred for 12 h at room temperature, diluted with toluene (4 mL), and filtered. The precipitate was washed several times with toluene which was recrystallized with methanol and hexane to give the final product (560 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J=7.6 Hz, 2H), 7.14-7.28 (m, 15H), 5.55 (t, J=7.6 Hz, 1H), 3.39 (s, 4H), 2.93 (d, J=7.2 Hz, 2H). HPLC-MS (ESI): m/z 373.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[Se:20][C:21]([CH:24]=[CH2:25])=[CH:22][CH:23]=2)=[CH:15][CH:14]=1>C(OCC)(=O)C.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[Se:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=2)=[CH:15][CH:14]=1
Reactant: C=Cc1ccc(-c2ccc(-c3ccc(OCCC)c(F)c3F)cc2)[se]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCOc1ccc(-c2ccc(-c3ccc(CC)[se]3)cc2)c(F)c1F

Procedure:
3.0 g (5.0 mmol) of 2-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)-5-vinylselenophene are hydrogenated in 90 ml of ethyl acetate/toluene (2:1), in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:toluene=2:1). The further purification is carried out by recrystallisation from n-heptane. 2-(2′,3′-Difluoro-4′-propoxybiphenyl-4-yl)-5-ethylselenophene is obtained as a solid having an m.p. of 126° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[OH-].[K+].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:17][CH2:16][C:15]([F:19])([F:18])[F:14]
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Reactant: OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Br)c(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 25 mL round-bottomed flask, 5-bromo-6-chloropicolinic acid (433 mg, 1.83 mmol) and powdered potassium hydroxide (411 mg, 7.32 mmol) were combined with DMSO (1.9 ml) to give a colorless solution which was stirred at room temperature for 15 min. 2,2,2-trifluoroethanol (275 mg, 198 μl, 2.75 mmol, Eq: 1.5) was added. The reaction mixture was stirred for 24 h at ambient temperature. Since the reaction was complete, 0.75 extra equivalents of 2,2,2-trifluoroethanol was added and the reaction was stirred 48 h at ambient temperature. The reaction mixture was poured onto 1 M HCl/ice water (1×20 mL), extracted with iPrOAc (2×25 mL). The organic layers were dried over Na2SO4 and filtered, removed under reduced pressure to give the title compound as a white solid after recrystallization from CH2Cl2 and heptane (409 mg, 1.36 mmol, 74.4% yield), MS (EI): m/e=299.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([OH:14])=[O:13])=[C:4]([CH3:15])[CH:3]=1.OS(O)(=O)=O.[CH3:21][CH2:22]O>>[F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([O:14][CH2:21][CH3:22])=[O:13])=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1CC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 85 °C
Yield: 81 %

Procedure:
2-(4-Fluoro-2-methyl-5-nitrophenyl)acetic acid (18.43 g, 86.5 mmol) and conc. H2SO4 (4.00 mL) were combined in EtOH (300 mL) and heated at 85° C. for 2.5 h. The mixture was cooled to RT, concentrated, the residue dissolved in MTBE and washed with H2O (2×), then brine (2×), dried (MgSO4), and evaporated to afford ethyl 2-(4-fluoro-2-methyl-5-nitrophenyl)acetate (16.79 g, 81% yield) as a dark orange oil which was used without further purification. MS (ESI) m/z: 242.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[CH:20][N:21]=4)[CH:18]=3)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:21]1[CH:20]=[CH:19][N:17]2[CH:18]=[C:13]([CH:11]([C:8]3[N:6]4[N:7]=[C:2]([C:24]5[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[CH3:12])[CH:14]=[CH:15][C:16]=12
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2ccc3ncc(C(C)c4ccc5nccn5c4)n3n2)c1
Temperature: 150 °C

Procedure:
(rac)-6-Chloro-3-(1-imidazo[1,2-a]pyridin-6-yl-ethyl)-imidazo[1,2-b]pyridazine (Example 292, 200 mg, 0.672 mmol) was dissolved in DME (3.36 mL) with 3-tolylboronic acid (91 mg, 0.672 mmol), 2 M Na2CO3 solution (1.21 mL, 2.418 mmol) and tetrakis(triphenylphosphine)palladium (38.8 mg, 0.034 mmol). The RM was heated at 150° C. 5 min under microwave irradiations. It was taken up with EtOAc and washed with 10% Na2CO3 solution and brine. Then it was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated. The white solid obtained was a repurified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound as a white solid (tR 0.9 min (conditions 2), MH+=354).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25](O)=[O:26])(=[O:3])[NH2:2].[CH3:28][O:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32]>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:32][CH2:31][C:30]([O:29][CH3:28])([CH3:34])[CH3:33])=[O:26])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: COC(C)(C)CN
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Product: COC(C)(C)CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with (2-methoxy-2-methylpropyl)amine similar to as described in Example 2 to afford 14.8 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(2-methoxy-2-methyl-propyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 459 (M)+. 1H NMR (400 MHz, DMSO) δ 11.24 (t, 1H), 8.60 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 7.87 (s, 1H), 7.02 (d, J=10.6 Hz, 1H), 5.48 (s, 1H), 5.10-4.90 (m, 2H), 4.63-4.45 (m, 2H), 3.34 (d, J=5.6 Hz, 2H), 3.14 (s, 3H), 1.49 (s, 7H), 1.15 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>N1C=CC=CC=1>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1ccc2c(O)n[nH]c2c1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
Methyl 3-hydroxy-1H-indazole-6-carboxylate (1.6 g, 8.3 mmol) was suspended in pyridine (10 mL). Ethyl chloroformate (1.0 mL, 10 mmol) was added slowly and the reaction was allowed to stir at room temperature for 2 hours. The reaction was poured into water (65 mL) and cooled in a refrigerator for 4 hours. The resulting brown precipitate was collected by filtration, rinsed with water, and dried under vacuum to give the title compound (1.35 g, 61%) as a beige solid. +ESI (M+H) 265.0; 1H NMR (400 MHz, CDCl3, δ): 8.80 (d, J=6.0 Hz, 1H), 8.01 (dd, J=8.2, 1.2 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 4.60 (q, J=7.0 Hz, 2H), 3.98 (s, 3H), 1.57 (t, J=7.1 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].Cl.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:17]1([CH2:16][C@H:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:34]3[CH2:35][CH2:36][CH:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:32][CH2:33]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:13]([OH:15])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Na]
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-3-phenyl-propionic acid, sodium salt and 4-phenyl-piperidine hydrochloride were condensed to give the title compound, mp=167-169° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1.N1C=CC=CC=1>C(O)C>[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[N:2][OH:3])[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1
Reactant: CCCC(=O)c1ccc(OCOC)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCC(=NO)c1ccc(OCOC)cc1
Yield: 77.3 %

Procedure:
Hydroxylamine hydrochloride (2.7 g, 39.4 mmol) was added to a stirred solution of 1-(4-(methoxymethoxy)-phenyl)butan-1-one (4.1 g, 19.7 mmol) and pyridine (94.67 g, 59.1 mmol) in ethanol (30 mL), and the mixture heated to reflux for 1.5 hours then allowed to cool. Most of the ethanol was removed by concentration under reduced pressure, and the residue was partitioned between water and dichloromethane. The layers were separated and the aq phase extracted 2× with dichloromethane. The combined extracts were washed twice with water, then with saturated brine and dried over magnesium sulfate. The solvent was removed in vacuo, leaving 5.1 g of slightly cloudy, colorless syrup, which was flash chromatographed on a column (50×70 mm) of silica gel eluting with Hxa/EtOAc/acetone 8:1:1 to afford 3.4 g (77%) of snow-white crystalline solid; mp 74-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:26])([CH3:25])[C:17](=[O:24])[N:18]2[CH:21]2[CH2:23][CH2:22]2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:26])([CH3:25])[C:17](=[O:24])[N:18]2[CH:21]2[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)=[O:6]
Reactant: O=C(O)c1ccncc1Cl
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ccc21
Product: CC1(C)C(=O)N(C2CC2)c2cc(NC(=O)c3ccncc3Cl)ccc21

Procedure:
Prepared in analogy to example 26 from 3-chloroisonicotinic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one (example 14c). The title compound was obtained as white foam.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[CH2:19]([N:6]1[C:5]2[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=[C:2]1[Cl:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1cc2nc(Cl)n(Cc3ccccc3)c2cc1Cl
Reaction time: 48 h
Yield: 96.3 %

Procedure:
2,5,6-trichlorobenzimidazole (5, 50 mg, 0.0002 moles) was dissolved in 15 ml of CH3CN, and K2CO3 (33 mg, 0.0002 moles) was added. The mixture was stirred at room temperature for one hour, at which time benzyl bromide (0.024 ml, 0.0002 moles) was added. The mixture was then stirred for two days. TLC analysis showed the formation of a new compound with a higher Rf than staffing material. The mixture was then concentrated and a liquid-liquid extraction was done using CHCl3, and H2O. The CHCl3 layer was kept, dried with MgSO4, filtered, and then concentrated. Column chromotograpy was then performed using 2% MeOH/CHCl3 to elute the compounds. The fractions were collected and those containing the compound were concentrated. The compound was recrystallized from MeOH, giving 60 mg of 1-benzyl-2,5,6-trichlorobenzimidazole (181) (96.2%). 1H NMR (CDCl3): d 3.49 ppm (s, 3H), 7.13 (m, 2H), 7.32 (m, 4H), 7.78 (s, 1H). 13C NMR (CDCl3): d 43.20 ppm, 106.25, 115.78, 121.62, 122.24, 122.66, 123.50, 124.15, 129.05, 129.16, 135.97, 137.68. GC-MS: m/e 310, 273, 239, 221,197, 170, 158, 138, 120, 100, 91, 77, 65, 51, 39. m.p: 175°-176° C. Elemental Analysts: (C14H9Cl3N2): Calculated: C, 53.85; H, 2.88; N, 8.97. Found: C, 53.92; H, 2.85; N, 8.89. UV imax nm (e×104): (pH 7) 263 (0.080), 290 (0.102), 299 (0.154); (pH 1) 224 (0.412), 258 (0.157), 290 (0.155), 299 (0.166).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1.C(O)(=O)C.Cl>CO>[CH3:21][C:20]([OH:22])([CH3:23])[CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([N:1]2[CH:26]=[CH:30][CH:29]=[CH:28]2)=[CH:10][CH:9]=3)=[O:12])[CH2:14][CH2:15]1
Reactant: CC(C)(O)CC1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(O)CC1CCN(C(=O)c2cc3cc(-n4cccc4)ccc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 127 mg of 1-{1-[(5-amino-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol in 3 mL of methanol were added 90 μl, of 2,5-dimethoxytetrahydrofuran and 1 mL of acetic acid, followed by stirring at 60° C. for 1 day. 1M hydrochloric acid was added to the reaction liquid which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then solidified from ethyl acetate-hexane to obtain 30 mg of 2-methyl-1-(1-{[5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}piperidin-4-yl)propan-2-ol as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:4]2[CH:3]=[CH:2][C:11]3[C:6](=[CH:7][C:8]([NH:22][CH2:21][CH2:20][C:17]4[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=4)=[CH:9][CH:10]=3)[N:5]=2)=[CH:16][CH:15]=1
Reactant: Fc1ccc2c(Cl)ccnc2c1
Reactant: NCCc1ccc(Cl)cc1
Product: Clc1ccc(CCNc2ccc3ccc(NCCc4ccc(Cl)cc4)nc3c2)cc1

Procedure:
A mixture of 2.0 g of 4-chloro-7-fluoroquinoline and 3.5 g of 2-(4-chlorophenyl)ethyl amine was heated neat until fuming began. The mixture was then cooled. The product was extracted into a CHCl3 /ammonium hydroxide solution, which was then washed with water. Solvent was removed by reducing pressure. The residue was placed on a silica gel column with acetone, then flushed with ethanol. Solvent was removed by reducing pressure, giving the title product as a yellow-brown foam. Yield 1.1 g. M.P. 55°-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH2:26]([O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1)[CH3:27]>CN(C=O)C>[CH2:26]([O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:32][CH:31]=1)[CH3:27]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A solution of 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (800 mg) in DMF (10 mL) was added to a suspension of NaH (60% in mineral oil, 204 mg) in DMF (8 mL) over a period of 20 minutes. Stirring was continued for 30 minutes at r.t. The mixture was cooled to 0° C. and ethyl-4-(bromomethyl)-benzoate (591 mg, [CAS Reg. No. 26496-94-6]) dissolved in DMF (7 mL) was added dropwise over a period of 15 minutes. Stirring was continued for 1 hour at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (625 mg, 53%). MS (m/e)=508.0 [MH+].
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:14])[C@@H:5]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]([CH3:8])[CH3:7].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:45])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:36][C:37]([C:39]3[N:40]=[N:41][N:42]([OH:44])[CH:43]=3)=[O:38])[CH2:30][C@@H:31]([OH:35])[C:32]([OH:34])=[O:33])=[CH:24][CH:23]=2)[CH:21]=1.CC(C)=O.CCN(CC)CC>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:45])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:36][C:37]([C:39]3[N:40]=[N:41][N:42]([O:44][CH2:2][O:3][C:4](=[O:14])[C@@H:5]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]([CH3:8])[CH3:7])[CH:43]=3)=[O:38])[CH2:30][C@@H:31]([OH:35])[C:32]([OH:34])=[O:33])=[CH:24][CH:23]=2)[CH:21]=1
Reactant: COC(=O)N[C@H](C(=O)OCCl)C(C)C
Reactant: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)N[C@H](C(=O)OCOn1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)nn1)C(C)C
Temperature: 65 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
(S)-2-Methoxycarbonylamino-3-methylbutyric acid chloromethyl ester (37.4 mg, 167 μmol) was added to a solution of (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (30.0 mg, 66.8 mol) in acetone (0.5 mL, 6.8 mmol). Et3N (18.6 μL, 134 μmol) was added and the resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (8.2 mg). MS m/z [M+H]+ calc'd for C28H31ClFN5O9, 636.18. found 636.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15]N(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]CC.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:28]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(N)c1ccccc1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(-c3ccccc3)ncc2C1
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step B, 509 mg, 2.0 mmol), benzamidine hydrochloride hydrate (470 mg, 3.0 mmol), and sodium ethoxide (1 M in ethanol, 6.0 mL, 6.0 mmol) in absolute ethanol (4 mL) was heated to reflux for about 3 d, cooled to room temperature, and concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (Biotage Flash 40S™, 10→15% ethyl acetate/hexanes) to give 304 mg (49%) of the title compound of Example 101, Step C as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.40-8.38 (c, 2H), 7.50-7.44 (c, 3H), 4.62 (s, 2H), 3.78 (t, 2H) 3.02 (t, 2H), 1.50 (s, 9H); MS (APCI) 312 (MH+).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C(O[C@@H:13]1[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C.[Sn](Cl)(Cl)(Cl)Cl.C(#N)C>ClCCCl>[C:16]([O:15][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:30][C@H:13]1[N:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3])(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1cc[nH]c(=O)n1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Solvent: ClCCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Cytosine is silylated by the general method of Wittenberg. It is reacted with 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose in 1,2 dichloroethane followed by tin tetrachloride in 1,2-dichloroethane (or acetonitrile) according to the method of Vorbruggen and Niedballa to provide the 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)cytosine 33.1b (Xi=β-cytidin-1-yl). Following methanolysis with sodium methoxide in methanol the 1-(β-D-glucopyranosyl)cytosine is obtained. Following protection of the heterocyclic amine this is converted into the morpholino subunit 32.2b (Xi=β-N4-benzoylcytidin-1-yl) by the general procedure.