Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11](O)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]2[C:19]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])([CH3:21])[CH3:20])=[C:4]([F:30])[CH:3]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>CCO.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[C:9]2[C:19]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])([CH3:20])[CH3:21])=[C:4]([F:30])[CH:3]=1
Reactant: CCOC(=O)C1(O)CN(c2ccc(Br)cc2F)C(C(C)(C)c2c(Cl)cccc2Cl)=N1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(Br)cc2F)c(C(C)(C)c2c(Cl)cccc2Cl)n1
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 87.6 %

Procedure:
To a mixture of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate (38 g, 73 mmol) in EtOH (200 mL) was added TFA (25.0 g, 220 mmol). The mixture was subsequently heated to 95° C. HPLC analysis after 2.5 hours showed <1% of alcohol intermediate remaining The mixture was diluted with 300 mL of CH2Cl2 and cooled to approximately 5° C. with an ice bath. The mixture was neutralized with 1N NaOH (120 mL) and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were concentrated on a rotary evaporator to give crude material. Recrystallization in EtOH (5 mL/1 g) provided 32 g of ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-1H-imidazole-4-carboxylate as an off-white solid (86% yield). 1H-NMR (DMSO-d6, 400 MHz) δ 7.92 (s, 1H), 7.16 (d, 1H, J=8.0 Hz), 7.22 (m, 3H), 7.11 (m, 1H), 7.04 (t, 1H, J=12.0 Hz), 4.25 (q, 2H, J=8.0 Hz), 1.94 (s, 6H), 1.27 (t, 3H, J=8.0 Hz); MS m/e 502.68 (M+H+); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 3.87 minutes.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15]O)[CH2:2][CH2:3][CH3:4].[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(NCCCO)c(=O)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCOc1c(NCCCS(C)(=O)=O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of 1-butoxy-2-(3-hydroxypropylamino)-1-cyclobutene-3,4-dione [prepared in Example 7] (1.0 g, 4.4 mmol) in 5 mL of pyridine was cooled to 0° C. and treated dropwise with 0.36 mL (4.6 mmol) of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 1 hour then poured into 80 mL of water and extracted with 20 mL of ethyl acetate. The organic phase was washed 4 times with water, dried and evaporated to give 0.84 g of title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[NH:11][C:12]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.[CH2:22]([O:24][C:25]([CH2:27][CH2:28][CH2:29]Br)=[O:26])[CH3:23].O>CN(C)C=O>[CH2:22]([O:24][C:25]([CH2:27][CH2:28][CH2:29][N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[N:11]=[C:10]1[CH2:9][O:8][C:7]1[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21
Temperature: 25 °C
Yield: 111.9 %

Procedure:
A sodium hydride solution (60% in oil, 325 mg, 8.1 mmol) was washed with hexanes (2×50 ml) and then diluted with N,N-dimethylformamide (100 ml). At room temperature, under a nitrogen atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (2.0 g, 7.3 mmol) was then added in one portion. The resulting mixture was then stirred at room temperature for thirty minutes, and then 3-(ethoxycarbonyl)propyl bromide (1.58 g, 8.1 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. Upon completion of this addition, the reaction mixture was stirred for about six hours at a temperature of 70-80° C. The reaction mixture was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl acetate (500 ml). The organic fraction was washed once with water (500 ml) and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 3.16 grams of a semi-solid material. The crude material was firther purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 1:1 methylene chloride:ethyl acetate. The fractions containing the desired title product were combined and concentrated in vacuo to yield 2.21 grams (78%) of a viscous yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][N:18]2[CH2:25][CH2:24][C:21]3([CH2:23][CH2:22]3)[C@H:20]([OH:26])[CH2:19]2)[CH2:14][O:13]C1(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:15]([CH2:14][OH:13])[CH2:16][CH2:17][N:18]1[CH2:25][CH2:24][C:21]2([CH2:23][CH2:22]2)[C@H:20]([OH:26])[CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CCN2CCC3(CC3)[C@H](O)C2)N1C(=O)OCc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(N[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1)OCc1ccccc1
Yield: 95 %

Procedure:
A solution of (S)-4-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid benzyl ester (5.00 g, 12.9 mmol) in methanol/water 9:1 (50 mL) was stirred at room temperature in the presence of Amberlite® IR-120 resin (15.8 g). After 16 h the resin was collected by filtration and washed with methanol. The filtrate was discarded, and the product was recovered by digesting the Amberlite® resin three times in 7 M methanolic ammonia solution (60 mL) at room temperature over 15 min. The ammonia solutions were combined and evaporated to afford the title compound (4.27 g, 95%). Colorless oil, MS (ISP)=349.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:23][C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CCO.O>[NH2:26][C:24](=[O:25])[CH2:23][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:27])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[CH3:22]
Reactant: COC(=O)COc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(CC(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1
Yield: 62.5 %

Procedure:
A solution of 100 mg (0.245 mmol) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester and 2 mL of 1N NaOH in 5 mL of EtOH was stirred for 2.0 hours, diluted with water and extracted with EtOAc. The aqueous layer was made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (MgSO4), and concentrated at reduced pressure. The residue was crystallized from MeOH to give 54 mg (57% yield) of 2-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid, mp, 225°-227° C.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[O:7][CH2:8][CH:9]1[CH2:13][O:12]C(C)(C)O1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C(OC)(OC)OC.C(Br)(C)=O.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[Br:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[O:7][CH2:8][CH:9]1[CH2:13][O:12]1
Reactant: CC1(C)OCC(COc2ncsc2Br)O1
Agent: CC(=O)Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: COC(OC)OC
Product: Brc1scnc1OCC1CO1

Procedure:
A soln. of 5-bromo-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)thiazole (18.80 g, 63.9 mmol) and PPTS (0.80 g, 3.19 mmol) in MeOH (256 mL) was stirred under reflux for 3 h. More PPTS (0.40 g, 1.60 mmol) was added and the mixture was stirred under reflux for additional 2 h. The mixture was conc. in vacuo, the residue was dissolved in MeOH (256 mL) and stirred under reflux for 2 h. The mixture was conc. in vacuo, the residue was dissolved in DCM (256 mL) and treated with trimethyl orthoformate (10.5 mL, 95.8 mmol). The mixture was stirred overnight at RT. Subsequently, additional trimethyl orthoformate (3.5 mL, 31.9 mmol) was added and the mixture was stirred at RT for 1 h. Then, the mixture was conc. in vacuo, the residue was dissolved in DCM (256 mL), treated with AcBr (5.73 mL, 76.7 mmol) and stirred at RT for 90 min. Subsequently, the mixture was conc. in vacuo, the residue was dissolved in MeOH (320 mL) and K2CO3 (17.66 g, 128 mmol) was added to the mixture. After the mixture was stirred at RT for 90 min, the mixture was filtrated and the filtrate was poured into cold aq. sat. NH4Cl. The mixture was extracted with EtOAc, the comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was purified by means of CC (2-40% EtOAc/Hept) to provide a yellow oil.
Reaction SMILES: ClCCl.Br[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:14]2[NH:15][CH:16]=[CH:17][CH:18]=2)[CH:20]=1
Reactant: Brc1ccc2[nH]nc(-c3ccc[nH]3)c2c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1cncc(-c2ccc3[nH]nc(-c4ccc[nH]4)c3c2)c1
Temperature: 25 °C
Yield: 42 %

Procedure:
[1,1′-Bis(diphenylphosphino)-ferrocene)dichloropalladium(II) 1:1 complex with dichloromethane (40.8 mg, 0.05 mmol) was added to a mixture containing 5-bromo-3-(1H-pyrrol-2-yl)-1H-indazole (Preparation #16c, 105 mg, 0.40 mmol), aqueous pyridine-3-boronic acid (1M, 1.0 mL), and Cs2CO3 (391 mg, 1.20 mmol) in DMF (2.0 mL) under a nitrogen atmosphere was added and the mixture was purged with N2 again, then heated at reflux for about 3 days. The reaction was cooled to ambient temperature and the organic layer was filtered through silica gel and concentrated under reduced pressure. The residue was further purified by preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 20 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min). Product fractions were combined and concentrated to remove organic solvents and the lyophilized to yield 5-pyridin-3-yl-3-(1H-pyrrol-2-yl)-1H-indazole (44 mg, 42%) as an off-white powder. RP HPLC (Table 1, Method e) Rt=2.23; m/z: (MH)+ 261.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:47]([C:49]1[S:53][CH:52]=[C:51]([C:54](O)=[O:55])[CH:50]=1)[CH3:48].C(N(CC)CC)C>CN(C=O)C>[CH2:47]([C:49]1[S:53][CH:52]=[C:51]([C:54]([N:28]2[CH2:29][C:30]3([CH2:35][CH2:34][N:33]([CH2:36][C:37]4[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=4)[CH2:32][CH2:31]3)[O:25][CH2:26][CH2:27]2)=[O:55])[CH:50]=1)[CH3:48]
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Reactant: CCc1cc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (0.449 g) was added in one portion to a solution at 0° C. of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.28 g) and 5-ethylthiophene-3-carboxylic acid (0.142 g) and triethylamine (0.506 mL) in DMF (10 mL). The mixture was then stirred at 20° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.21 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](=[N:7]/[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:10][CH:9]=1)/[CH3:6])[CH3:2].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH2:1]([O:3][C:4]([C:5]1[NH:7][C:8]2[C:9]([CH:6]=1)=[CH:10][C:11]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[CH:12][CH:13]=2)=[O:19])[CH3:2]
Reactant: CCOC(=O)/C(C)=N/c1ccc(-n2ccnc2)cc1
Agent: CS(=O)(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)c1cc2cc(-n3ccnc3)ccc2[nH]1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-[(E)-4-Imidazol-1-yl-phenylimino]-propionic acid ethyl ester (842 mg) was added to an Eaton's reagent (4 ml), and this was stirred at 100° C. for one hour. After adjusting the pH of the reaction mixture to 11 using an aqueous solution (about 10 ml) of 20% potassium phosphate, the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with an aqueous solution saturated with sodium chloride (20 ml), and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol). Thus, 5-imidazol-1-yl-1H-indole-2-carboxylic acid ethyl ester was obtained as a yellow amorphous material (370 mg, 47%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])/[C:12](O)=[O:13])=[CH:7][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:12](=[O:13])/[C:11](/[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:26][CH:27]=1
Reactant: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Reactant: Nc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC/C(=C(\C(=O)Nc1ccc(O)cc1)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a mixture of 3 (60 mg, 0.192 mmol), 4-aminophenol (23.0 mg, 0.211 mmol), 4-Dimethylaminopyridine (1.2 mg, 0.00982 mmol) and N,N-Diisopropylethylamine (37.2 mg, 0.287 mmol) in CH2Cl2 (2 ml) was added O-Benzotriazoyl-N,N,N′,N′-tetramethyluronium Hexafluorophosphate (76.5 mg, 0.202 mmol) under ice cooling, and the mixture was stirred at 0° C. for 5 min, and at room temperature for 15 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with CHCl3, the organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 3:1 to 2:1) gave 6a (68%). 6a: colorless powder; 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.5 Hz), 2.77 (2H, t, J=7.5 Hz), 3.43 (3H, s), 5.09 (2H, s), 6.79 (4H, m), 7.00 (2H, d, J=8.8 Hz), 7.00 (1H, brs), 7.07 (2H, m), 7.15-7.22 (3H, m), 7.37 (2H, d, J=8.8 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:17]COCC.[N+](=C)=[N-].C(O)(=O)C>C(OCC)(=O)C>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:17])=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(=O)c1ccc(OCCCC(=O)O)cc1
Agent: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)CCCOc1ccc(C(C)=O)cc1

Procedure:
4-(p-Acetylphenoxy)butyric acid (4.1 g.) was suspended in ethyl acetate (80 ml.), and to the suspension was added dropwise an ether solution of diazomethane with stirring under ice-cooling until a color of the diazomethane was appeared. After the stirring was continued at the same temperature for additional half an hour, a small amount of acetic acid was added to the reaction mixture, and then the solution was stirred for a while. This solution was evaporated to dryness under reduced pressure and the residue was treated with a mixture of isopropyl ether and n-hexane (1:1 by volume) to give methyl 4-(p-acetylphenoxy)butyrate (3.83 g.).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3F)[C:11](=[O:26])[C:10]([C:27]([OH:29])=[O:28])=[CH:9]2)[CH2:7][CH2:6]1>C(O)C>[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:25])=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3[O:2][CH3:1])[C:11](=[O:26])[C:10]([C:27]([OH:29])=[O:28])=[CH:9]2)[CH2:6][CH2:7]1
Reactant: C[O-]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: COc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
To the solution of sodium methoxide prepared from sodium (0.2 g) and absolute ethanol (9 ml) was added 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (0.5 g) and the mixture in sealed tube was heated for 72.5 hours at 140° to 150° C. After cooling, the reaction mixture was concentrated, water (4 ml) was added to the residue, and the solution was adjusted to pH 7 with acetic acid. The insoluble materials were filtered off and the filtrate was allowed to stand in a refrigeretor. The resulting precipitate was collected by filtration and recrystallized from dichloromethane-methanol (2:1; 6 ml) to give the title compound (0.12 g) as colorless prisms, mp 185°-187.5° C. (decompd.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[N:4][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)=[CH:6][N:7]=1.BrC1N=C(NCC2C=C[C:40]([O:43]C)=CC=2)C(N)=NC=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.C(=O)([O-])[O-].[K+].[K+]>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.CN(C)C=O.O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:18]2[C:3]3=[N:4][C:5]([C:8]4[CH:17]=[CH:16][CH:15]=[C:14]5[C:9]=4[CH:10]=[CH:11][CH:12]=[N:13]5)=[CH:6][N:7]=[C:2]3[NH:1][C:40]2=[O:43])=[CH:21][CH:22]=1
Reactant: COc1ccc(CNc2nc(-c3cccc4ncccc34)cnc2N)cc1
Reactant: COc1ccc(CNc2nc(Br)cnc2N)cc1
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: OB(O)c1cccc2ncccc12
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)[nH]c3ncc(-c4cccc5ncccc45)nc32)cc1
Yield: 15 %

Procedure:
(3-Amino-6-(5-quinolyl)pyrazin-2-yl)[(4-methoxyphenyl)methyl]amine. 6-Bromo-N2-(4-methoxybenzyl)pyrazine-2,3-diamine (0.928 g, 3.00 mmol), quinoline-5-boronic acid (0.675 g, 3.9 mmol), tetrakis(triphenylphosphine)palladium (0.306 g, 0.265 mmol), potassium carbonate (1.10 g, 7.95 mmol), water (7 ml) and dimethylformamide (35 mL) were reacted according to General Procedure B. The crude material was purified via Biotage silica gel chromatography (0-10% methanol in dichloromethane) followed by triturating with water/methanol to afford the title compound (0.165 g, 15% yield). MS (ESI) m/z 358.3 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:27]=[C:28]([CH2:30][OH:31])[N:29]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>O1CCOCC1.CCOC(C)=O.O>[OH:31][CH2:30][C:28]1[N:29]=[C:3]2[C:2]([C:40]3[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=3)=[N:7][CH:6]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]4)=[N:12][CH:13]=3)[N:4]2[CH:27]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(Cl)c4nc(CO)cn34)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(-c4ccncc4)c4nc(CO)cn34)cn2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a mixture of compound 87c (95.0 mg, 0.214 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (48.2 mg, 0.235 mmol), Cs2CO3 (174 mg, 0.534 mmol), and Pd(dppf)2.CH2Cl2 (17.5 mg, 0.0214 mmol) in 1,4-dioxane (3 mL) was added 1.5 mL of water. The resulting mixture was stirred at 90° C. for 4 h. After cooling to rt, the mixture was treated with EtOAc (30 mL) and washed with H2O (2×10 mL) and brine (10 mL). Removal of the solvent gave a residue, which was purified by flash column chromatography on silica gel (0-6% MeOH/DCM) to give compound 87d as a bright yellow-green solid. 1H-NMR (CDCl3; 400 MHz) δ 8.84 (br. s., 2H), 8.65 (d, J=4.9 Hz, 2H), 8.51 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 4.96 (s, 2H), 3.66-3.75 (m, 4H), 3.55-3.66 (m, 4H), 3.00 (br. s., 1H), 1.51 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calcd. for C26H29N2O3, 488.2 (M+H). found 488.2.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C([O:9][CH2:10][CH2:11][N:12]1[C:16]([SH:17])=[N:15][N:14]=[N:13]1)(C)(C)C.Cl.C(OCC)(=O)C>C1(OC)C=CC=CC=1.ClCCl>[OH:9][CH2:10][CH2:11][N:12]1[C:16]([SH:17])=[N:15][N:14]=[N:13]1
Reactant: CC(C)(C)OCCn1nnnc1S
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COc1ccccc1
Product: OCCn1nnnc1S
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of aluminum chloride (0.2 g) in anisole (1 ml) cooled at 0° C. is added a solution of 1-(2-t-butoxyethyl)-1H-tetrazole-5-thiol (0.202 g) in dichloromethane (2 ml), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into a mixture of 3N-hydrochloric acid (10 ml) and ethyl acetate (20 ml), shaken and the resulting organic layer is taken up. The layer is extracted with aqueous 5% sodium hydroxide. The extract is acidified with hydrochloric acid and extracted again with ethyl acetate. The extract is concentrated under reduced pressure to give 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol. mp. 135°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)O)=[O:4].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:31])=[C:28]([NH2:30])[CH:29]=1.C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.NC1C(=O)N(C)C=C(Cl)C=1>>[Br:10][C:8]1[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]([CH:14]([NH:30][C:28]2[CH:29]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=2[CH3:31])[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cn1
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cn1cc(Cl)cc(N)c1=O
Product: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1cc(Cl)ccc1C)c1ccc(Cl)cn1

Procedure:
The title compound was prepared in analogy to the procedure described for Step L3 but 5-bromo-2-[(5-chloro-pyridin-2-yl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step BK2) and 5-chloro-2-methyl-phenylamine were used instead of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-amino-5-chloro-1-methyl-1H-pyridin-2-one respectively. The title compound was obtained as a yellow-brown solid. ESI-MS: tR=1.59 min, [M+H]+ 510/512/514 (LC-MS 1).