Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.[CH3:23][C:24]1([CH3:33])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26](=O)[CH2:25]1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[C:26]2[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29][C:24]([CH3:33])([CH3:23])[CH2:25]2)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCOCCO)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCCOCCO)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a stirred suspension of Zn (0.59 g, 9.00 mmol) in THF (10 mL) was added TiCl4 (0.50 mL, 4.50 mmol) dropwise. The mixture was refluxed under nitrogen for 2.5 h. After cooling to room temperature, a solution of 61 (0.34 g, 1.12 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.53 g, 3.37 mmol) in THF (15 mL) was added and the reaction mixture refluxed for an additional 2.5 h. Cooled to room temperature, the reaction was quenched with 10% K2CO3 (20 mL). The quenched reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel, the layers were separated, and the aqueous phase was extracted with EtOAc (50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give a pale yellow oil. The residue was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 55% EtOAc:hexanes to give 62 as a white solid (0.36 g, 75%). mp 122-124° C. 1H NMR (400 MHz, CD3OD): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.28 (s, 2H), 1.96 (s, 2H), 1.98 (s, 2H), 3.60-3.65 (m, 2H), 3.65-3.70 (m, 2H), 3.80-3.85 (m, 2H), 4.05-4.15 (m, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H). LRMS (APCI): m/z 425 (M+H)+, 423 (M−H)−. Anal. Calcd for C27H36O4: C, 76.38; H, 8.55; Found: C, 76.17; H, 8.65.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCOCC1>[CH2:30]([O:29][C:27](=[O:28])[CH3:26])[CH3:31].[CH2:12]([N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]1[NH2:1])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CBr
Agent: NC1c2ccccc2C(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(C)=O

Procedure:
To a solution of compound 24 (400 mg, 1.68 mmol) in dioxane (5 mL) was added potassium carbonate (695 mg, 5.04 mmol) and ethyl bromoacetate (0.56 mL, 5.04 mmol) and the resulting reaction mixture is allowed to stir at reflux for 18 hours. The reaction mixture is poured onto water and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography (SiO2, 40% EtOAc-Hexanes eluant) provided 300 mg of 25 as a yellow oil (546 mg theoretical, 55% yield).
Reaction SMILES: [OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7].[CH:48](=O)[CH2:49][CH:50]([CH3:52])[CH3:51].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7]
Reactant: CC(C)CC=O
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(CCC(C)C)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
A solution of Example 283A (50 mg, 0.075 mmol) in dichloroethane (1 mL) was treated with isovaleraldehyde (10 mg, 1.5 equivalents), acetic acid (5 μL, 2 equivalents), and sodium triacetoxy borohydride (32 mg, 2 equivalents), stirred at 25° C. for 16 hrs. The mixture was quenched with 10% NaHCO3 (2 mL) and CHCl3. The organic layer was separated, dried over sodium sulfate, and the solvents were evaporated. The residue was purified using 5% methanol/CHCl3 to give 49 mg (89%) of the title compound.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:12]([OH:19])(=O)[CH2:13][CH:14]=[CH:15][CH2:16][CH3:17].[C:20]1([C:26]#[C:27][C:28]2[CH:46]=[CH:45][C:31]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[S:41](=[O:44])(=[O:43])[NH2:42])=[O:33])=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:20]1([C:26]#[C:27][C:28]2[CH:46]=[CH:45][C:31]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[S:41]([NH:42][C:12](=[O:19])[CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH3:17])(=[O:43])=[O:44])=[O:33])=[CH:30][CH:29]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Reactant: CCC=CCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CC/C=C/CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 66.1 %

Procedure:
In a stream of nitrogen and at 0° C., 249 mg (1.30 mmol) of tosylic chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 149 mg (1.30 mmol) of 3-hexenoic acid and 532 mg (4.35 mmol ) of 4-dimethylaminopyridine, and the mixture was stirred for 1 hour. Next, this was mixed with 300 mg (0.80 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and stirred at room temperature for 1 hour, and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel chromatography to obtain 250 mg (yield: 65.0%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1.P([O-])(O)(O)=[O:24].[Na+].Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CC(=CC)C.C(O)(C)(C)C.O.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:24])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(CCCO)cc3)cc12
Agent: CC=C(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(CCCO)cc3)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 14 %

Procedure:
To 6-chloro-5-[4-(3-hydroxypropyl)phenyl]-1H-indole-3-carbaldehyde (40 mg, 0.13 mmol) in 2-methyl-2-butene/t-butanol/water (v/v/v=1/1/1, 6 mL) was added sodium dihydrogen phosphate (30.5 mg, 0.254 mmol) and sodium chlorite (23 mg, 0.25 mmol) at room temperature. The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was added sodium sulfite (0.254 mmol), diluted with water, extracted with EtOAc, then concentrated in vacuo and purified via preparative HPLC to give the title compound (6.0 mg, 14% yield).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:2]1[NH:15][N:16]=[N:17][C:1]=1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OCC#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2nn[nH]n2)cc1

Procedure:
A mixture of methyl 4-cyanomethyloxybenzoate (53.5 g, 0.20 mol), sodium azide (16.9 g, 0.26 mol) and ammonium chloride (13.9 g, 0.26 mol) in DMF 1000 (mL) was refluxed overnight under N2. After cooling, the mixture was concentrated in vacuo. The residue was suspended in cold water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo, to afford methyl 4-(2H-tetrazol-5-ylmethoxy)benzoate. This compound was used as such in the following step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:29]=1)[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.CN(C)C(C1C=CC(C2C=CC3=C(C=2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCC)=C3)=CC=1)=O.C([O-])([O-])=O.[Na+].[Na+].O.[K].[K].C1(P(C2C=CC(S(O)(=O)=O)=CC=2)C2C=CC(S(O)(=O)=O)=CC=2)C=CC=CC=1.N#N.CN(C)C(C1C=CC(B(O)O)=CC=1)=O>CCO.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH2:14]([N:13]([CH2:17][CH2:18][CH3:19])[C:12]([C:10]1=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:34]3[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=3)=[CH:29][C:6]=2[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9]1)=[O:20])[CH2:15][CH3:16]
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: OB(O)c1ccc(O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: O
Solvent: CCO
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(O)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by these procedures using tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and 4-hydroxyphenylboronic acid. Preparation of tert-butyl (1E,4E)-8-(4-(dimethylcarbamoyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate: To Na2CO3 (129 mg, 1.214 mmol) in a 50 mL round-bottom flask was added water (3.7 mL) was bubbled with N2 for 10 min. To this mixture was added tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate (200 mg, 0.40 mmol) in EtOH (4.9 mL) at room temperature. The resulting mixture was bubbled with N2 for 10 min. Pd(OAc)2 (9.3 mg, 0.040 mmol) and 4,4′-(phenylphosphinidene)bisbenzenesulfonic acid dipotassium hydrate (45 mg, 0.081 mmol) were added. The resulting mixture was warmed to 65° C. with N2 bubbling. To this mixture was added a solution of 4-(dimethylcarbamoyl)phenylboronic acid (97 mg, 0.49 mmol) in EtOH (0.6 mL). The resulting mixture was stirred at 65° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material that was diluted with water (5 mL) and EtOAc (10 mL). The mixture was filtered through GF/F filter. The aqueous layer was separated and extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that was purified by silica gel flash column chromatography (CH2Cl2 to 2% MeOH in CH2Cl2). MS APCI (+) m/z 478 (M+1) detected.
Reaction SMILES: O=[C:2]1[NH:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:5][C:4]2[N:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O1CCOCC1>[S:31]=[C:2]1[NH:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:5][C:4]2[N:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CCOC(=O)N1CCC2(CC1)NC(=O)c1cccnc1N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)N1CCC2(CC1)NC(=S)c1cccnc1N2
Yield: 152.3 %

Procedure:
A solution of ethyl 3′,4′-dihydro-4′-oxospiro[piperidine-4,2′-[1′H]-(pyrido[2,3-d]-pyrimidine)]-1-carboxylate (0.74 g, 2.55 mmol) and Lawesson's reagent (0.62 g, 1.5 mmol) in dioxane (15 ml) was heated at reflux for 2 h. The mixture was absorbed onto silica gel and purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (50:1) to afford the product as a white solid (0.7 g). MS (+CI) m/Z 307 [M+H]+; 1H NMR (d6-DMSO) 10.37 (1H, dd), 8.34 (1H, dd), 8.24 (1H, dd), 8.10 (H, s), 6.76 (1H, dd), 4.04 (2H, q), 3.6-3.78 (2H, m), 3.3-3.5 (2H, m), 1.75-1.90 (4H, m), 1.21 (3H, t).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=O)=[CH:22][CH:21]=2)=[O:19])[CH2:14][CH2:13]1.[NH2:30][C:31]1[N:35](C(OC(C)(C)C)=O)[N:34]=[C:33]([CH2:43][CH2:44][C:45]2[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([O:53][CH3:54])[CH:46]=2)[CH:32]=1.[NH4+].[Cl-]>C1COCC1>[CH3:52][O:51][C:49]1[CH:50]=[C:45]([CH2:44][CH2:43][C:33]2[NH:34][N:35]=[C:31]([NH:30][C:24](=[O:26])[C:23]3[CH:22]=[CH:21][C:20]([C:18]([N:15]4[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]4)=[O:19])=[CH:29][CH:28]=3)[CH:32]=2)[CH:46]=[C:47]([O:53][CH3:54])[CH:48]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(C)CC2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(C(=O)N4CCN(C)CC4)cc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.6 %

Procedure:
A solution of NaHMDS (1M in THF) (2.86 mL, 2.86 mmol) was added dropwise to a stirred solution of methyl 4-(4-methylpiperazine-1-carbonyl)benzoate (0.250 g, 0.95 mmol) and tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (0.397 g, 1.14 mmol) in THF (2 mL), over a period of 10 mins under nitrogen. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was poured into saturated NH4Cl (25 mL), extracted with EtOAc (2×25 mL), washed with saturated brine and dried over MgSO4, filtered and evaporated to afford the crude product (0.501 g) as a yellow gum. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% ammonium hydroxide) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.257 g, 56.5%) as a yellow solid; 1H NMR (399.9 MHz, DMSO-d6) δ 2.21 (3H, s), 2.25-2.40 (4H, m), 2.89 (4H, s), 3.16-3.20 (1H, d), 3.32 (4H, s), 3.72 (6H, d), 6.33 (1H, m), 6.42-6.44 (2H, d), 7.46-7.50 (2H, d), 8.02-8.06 (2H, d)
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH2:29][CH2:28][CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:29][CH2:28][CH2:27]2
Reactant: Fc1ccc2c(c1)CCCN2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCN3CCCc4cc(F)ccc43)cn2)c1
Yield: 13 %

Procedure:
The title compound was prepared in 13% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 6-fluoro-1,2,3,4-tetrahydroquinoline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 1.75 (2H, t, J=5.5 Hz), 2.64 (2H, t, J=6.2 Hz), 3.06 (2H, t, J=5.4 Hz), 3.60 (2H, t, J=6.2 Hz), 4.19 (2H, t, J=6.3 Hz), 6.60 (1H, m), 6.74 (1H, s), 6.76 (1H, d, J=8.5 Hz), 7.53 (1H, d, J=4.6 Hz), 7.72 (1H, s), 7.85 (1H, s), 8.25 (1H, s), 8.55 (1H, d). [M+H] Calc'd for C20H19FN4O2, 367. Found, 367.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([NH:6][C:7]1[C:12]2[N:13]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].[OH-].[Na+].C1COCC1>CO>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][N:13]1[C:12]2[C:7]([NH:6][C:4](=[O:5])[C:3]([OH:29])=[O:2])=[CH:8][CH:9]=[CH:10][C:11]=2[O:16][CH2:15][C:14]1=[O:17]
Reactant: COC(=O)C(=O)Nc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)Nc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-oxalamic acid methyl ester, K-67 (95 mg,) in methanol (2.0 mL), 1.0 M NaOH (0.5 mL) was added followed by THF (2.0 mL) resulting in a clear solution. Reaction was stirred at room temperature for 30 minutes and then concentrated to remove the solvents. The residue was taken in water (2.0 mL), acidified with 1.0 M HCl and extracted with ethyl acetate (5.0 mL×4). Combined extracts were washed with water (5.0 mL), dried (brine, Na2SO4) and concentrated to afford N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo [1,4]oxazin-5-yl)-oxalamic acid, A51 (69 mg). 1H NMR (CDCl3) 4.66 (s, 2H), 5.21 (s, 2H), 7.02 (m, 2H), 7.07 (d, J=8.5 Hz, 1H), 7.14 (br s, 1H), 7.33 (br s, 2H), 7.50 (s, 1H), 7.65 (m, 3H), 8.69 (s, 1H). MS (ESI−) Calcd. for: 376.4; Found: 375.5 (M−H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]([C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:30](F)[CH:29]=4)[C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)#[N:8]>CS(C)=O.O>[C:7]([C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:30]([NH:20][C@H:19]5[CH2:27][CH2:26][C@H:1]([OH:4])[CH2:17][CH2:18]5)[CH:29]=4)[C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)#[N:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1N[C@H]1CC[C@H](O)CC1
Temperature: 90 °C

Procedure:
0.3 g of potassium carbonate and 1.68 g of 4-trans-aminocyclohexanol are successively added to a solution of 0.34 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate in 6 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 2 hours in a microwave, and then diluted with distilled water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (75/25 by volume), so as to give 0.15 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzoate in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[K+].C([Li])(C)(C)C.C([O:23][B:24](OCCCC)[O:25]CCCC)CCC.P(=O)(O)(O)O>CCOCC>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][CH:5]=[CH:4][C:3]=2[C:2]=1[B:24]([OH:25])[OH:23]
Reactant: Cc1ccc2[nH]ccc2c1Br
Reactant: CCCCOB(OCCCC)OCCCC
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1ccc2[nH]ccc2c1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
A solution of 4-bromo-5-methylindole (800 mg, 3.8 mmol) in anhydrous ether (8 mL) is added with stirring to a suspension of potassium hydride (560 mg, 4.2 mmol, 30% dispersion in mineral oil) in anhydrous ether at 0° C. under argon. The resulting mixture is cooled to −78° C. and tert-butyllithium (4.9 mL of 1.7 M in pentane, 8.4 mmol) is slowly added. The resulting cream-colored mixture is stirred at −78° C. for 1 hour. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reaction mixture is stirred for 1 hour at −78° C. before being allowed to slowly warm to room temperature. More anhydrous ether is added to facilitate stirring. After stirring for 24 hours, the resulting sticky mixture is diluted with ether and transferred in portions with stirring to a precooled solution of 1 M phosphoric acid (50 mL). After stirring for 30 minutes, the acidic mixture is extracted with diethyl ether (75 mL×3) and the combined extracts are extracted with 1 N sodium hydroxide (20 mL×4). The combined base extracts are cooled with an ice bath, acidified with 1 M phosphoric acid and extracted with ethyl acetate (20 mL×3). The combined extracts are washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a beige residue. The residue is triturated with hexane to obtain the desired 5-methylindole-4-boronic acid as a beige gum (230 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.NC(C(O)=O)CCSC>CS(O)(=O)=O.O>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccc(C(=O)O)c2)c1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Solvent: O
Product: O=C(O)c1cccc(-c2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 93.3 %

Procedure:
A suspension of 3'-methoxy-3-biphenylcarboxylic acid (4.1 g) and DL-methionine (26.7 g) in methanesulfonic acid (116 ml) was stirred at room temperature for 22 hours, diluted with water, and extracted three times with diethyl ether. The extracts were combined, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from n-hexane to afford 3'-hydroxy-3-biphenylcarboxylic acid (3.59 g) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:24])[C:4]=2[CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(C(C)C)CC)(C)C.CCOCC>N1C=CC=CC=1>[C:25]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:24])[C:4]=2[CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)c(=O)c1ccccc1n2CCCCCC(=O)O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2c(c1)c(=O)c1ccccc1n2CCCCCC(=O)O
Reaction time: 3 h
Yield: 86 %

Procedure:
6-(2-Amino-9-oxo-9H-acridin-10-yl)hexanoic acid (370 mg: 1.14 mmol) was dissolved in anhydrous pyridine (10 ml) and acetic anhydride (100 μl) followed by diisopropylethylamine (350 μl). The mixture was stirred for 3 hours. The solution was evaporated to dryness under vacuum and the gummy residue dissolved in dichloromethane. The solution was washed with 1.0M hydrochloric acid and then brine. The organic phase was dried with anhydrous magnesium sulphate, filtered and the solvent removed by rotary evaporation to leave a sticky solid. Trituration with ether gave a solid which was dried under vacuum to give 360 mg (86%) of 6-(2-acetamido-9-oxo-9H-acridin-10-yl)hexanoic acid.