Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl>[F:15][C:16]([F:24])([F:25])[C:17]1[CH:18]=[CH:19][C:20]([NH:21][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])=[CH:22][CH:23]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.2 %

Procedure:
A suspension of 2.1 g of 5-chlorosulfonyl-2-oxindole, 1.6 g of 4-trifluoromethylaniline and 1.4 g of pyridine in 20 mL of dichloromethane was stirred at room temperature for 4 hours. The precipitate which formed was collected by vacuum filtration, washed twice with 5 mL of water and dried under vacuum at 40° C. overnight to give 2.4 g of crude product containing some impurities by thin layer chromatography. The crude product was chromatographed on silica gel eluting with ethyl acetate:hexane (1:2) to give 1.2 g (37% yield) of 5-(4-trifluoromethylphenylaminosulfonyl)-2-oxindole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)glycine (3.0 g, 17.1 mmol) in DMF (75 mL), N,N-diisopropylethylamine (14.9 mL, 85.5 mmol) was added, followed by EDC (3.6 g, 18.8 mmol) and HOBT (2.5 g, 18.8 mmol) at 0° C., under argon. The resulting mixture was stirred for 0.5 h after which time morpholine (3.0 mL, 34.2 mmol) was introduced in a dropwise manner. Upon complete addition, the reaction was warmed to ambient temperature, stirred overnight and concentrated. The resulting residue was diluted with EtOAc and saturated NaHCO3. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated to give 2.3 g (55%) of (2-morpholin-4-yl-2-oxo-ethyl)-carbamic acid tert-butyl ester which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][C@@H:4]1[CH3:19].[H][H]>CO.[Pd]>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[CH3:19]
Reactant: [H][H]
Reactant: CO[C@H]1CCN(C(=O)OCc2ccccc2)C[C@@H]1C
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1CCNC[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S,4S)-benzyl 4-methoxy-3-methylpiperidine-1-carboxylate (4.0 g, 15.19 mmol) in MeOH (150 mL) under an argon atmosphere was added wet Pd/C [(5% dry basis) (1.617 g, 0.759 mmol)] The atmosphere was replaced with hydrogen gas via a balloon. The heterogeneous mixture was stirred for 1 hour at room temperature, and then filtered through Celite®. The filter cake was washed with dichloromethane (150 mL) followed by 20% MeOH/DCM (150 mL). The eluent was concentrated to afford (3S,4S)-4-methoxy-3-methylpiperidine which was used without the need for further purification. 1H NMR (400 MHz, CD2Cl2) δ ppm 0.91 (d, J=6.6 Hz, 3 H) 1.20 (tdd, J=12.2, 12.2, 10.5, 4.3 Hz, 1 H) 1.37-1.55 (m, 1 H) 2.03 (ddt, J=12.6, 4.2, 3.0, 3.0 Hz, 1 H) 2.21 (dd, J=12.6, 10.6 Hz, 1 H) 2.53 (td, J=12.4, 2.8 Hz, 1 H) 2.70-2.81 (m, 1 H) 2.95 (ddd, J=12.5, 4.3, 1.6 Hz, 1 H) 3.01-3.11 (m, 1 H) 3.31 (s, 3 H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[C:18]([CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=2)[NH2:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:25]([O:29][C:30]([NH:32][C@H:33]([C:35](O)=[O:36])[CH3:34])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[C:18]([CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=2)[NH:19][C:35](=[O:36])[CH:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[CH3:34])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 77.2 %

Procedure:
3-(9-acridinylamino)-5-(hydroxymethyl)aniline and t-butoxycarbonyl-L-alanine were reacted with the same method to the example 38 to give the titled compound.
Reaction SMILES: [Na].[O:2]=O.[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:18])C(Cl)(Cl)Cl)=[CH:9][CH:8]=1)[CH3:5].Cl.[CH2:20](O)[CH3:21]>O.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[CH2:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:18][CH2:20][CH3:21])=[O:2])=[CH:11][CH:12]=1)[CH3:5]
Reactant: O=O
Reactant: CCOc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Reactant: CCO
Agent: Cl
Agent: [Na]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: CCOC(=O)c1ccc(OCC)cc1
Reaction time: 2 h
Yield: 66 %

Procedure:
Cupric chloride dihydrate (0.125 g; 0.733 m. moles) and 1,10-phenanthroline hydrate (0.375 g; 1.9 m. moles) were added to a solution of sodium (1.15 g; 50 m. moles) in ethanol (75 ml). A stream of dry oxygen was passed through the mixture, 1-(4-ethoxyphenyl)-2,2,2-trichloroethanol (11.72 g; 43.6 m. moles) added and the mixture stirred at 30°-35° C. for 11/2 hours. A solution of sodium (0.575 g; 25 m. moles) in ethanol (10 ml) was then added and the reaction was allowed to continue for a further 1 hour. The reaction mixture was diluted with water (250 ml), acidified with hydrochloric acid and extracted with ether (3×50 ml). The combined ether extracts were washed once with water and twice with dilute aqueous sodium carbonate, dried (MgSO4) and evaporated. The residue was distilled to give ethyl 4-ethoxybenzoate (5.3 g; yield 66%), b.p. 148°-150° C./12 mm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([O:11][CH3:12])(=O)[CH2:8][OH:9].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[C:35]3[C:30](=[CH:31]C(F)=[CH:33][CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[C:35]3[C:30](=[CH:31][C:12]([O:11][CH2:7][C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:9])=[CH:33][CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: C1COCCN1
Reactant: COC(=O)CO
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCC(=O)N4CCOCC4)ccc23)CC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 24.1 %

Procedure:
A mixture of morpholine (107.4 mg, 1.23 mmol) and methyl glycolate (77.5 mg, 860 μmol) was stirred at 150° C. for 3 hr. The resulting homogeneous clear amber oil was taken up in toluene (2×2 mL) with repeated rotary evaporation to remove methanol. The residue was taken up in dry THF (860 μL) and KOtBu was added (113 mg, 1.01 mmol). The mixture was stirred at 100° C. for 5-10 min until a brown slurry formed with no visible chunks. The mixture was then allowed to cool to rt, 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (302 mg, 912 μmol), as prepared in Example 65b, was added, and the resulting nearly homogeneous reddish-brown solution was stirred at rt for 1 hr, at which point the reaction solidified into a paste. The reaction was taken up in DCM (4 mL) and washed with 1M NaHCO3 (1×2 mL) and 1M NaH2PO4 (1×2 mL), and the organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica flash chromatography (9:1 DCM/acetone→8:2→8:2 DCM/acetone/3% DMEA eluent) to provide the title compound as a pale yellow oil (94.8 mg, 24% over two steps). LC/MS (ESI): calcd mass 456.2, found 457.3 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:25]3[CH2:27][CH2:26]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:28]([CH2:30][NH2:31])[OH:29].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([NH:31][CH2:30][CH2:28][OH:29])=[O:24])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:25]3[CH2:26][CH2:27]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=C(O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1)NCCO
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To a stirred suspension of 2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)acetic acid (0.185 g, 0.48 mmol) in dimethylformaminde (7 mL) at 0° C. was added ethanolamine (0.044 mL, 0.72 mmol, 1.5 eq.) followed by diisopropylethylamine (0.34 mL, 1.94 mmol, 4.0 eq.) and HATU (0.221 g, 0.58 mmol). After stirring for 2 h, the reaction mixture was diluted with water (100 mL) and the resulting white solid isolated by filtration. The solid was purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford 2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)acetamide (67 mg, 33%) as a white solid. M.p. 131-133° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.10 (s, 1H), 8.31-8.29 (m, 1H), 8.27 (dt, J=7.0, 1.5 Hz, 1H), 8.19 (d, J=1.5 Hz, 1H), 8.08 (t, J=5.5 Hz, 1H), 7.74-7.69 (m, 1H), 7.67 (dd, J=8.5, 2.0 Hz, 1H), 7.60 (br s, 1H), 7.58-7.52 (m, 2H), 4.68 (t, J=5.5 Hz, 1H), 3.44-3.39 (m, 4H), 3.13 (q, J=6.0 Hz, 2H), 2.07 (septet, J=4.5 Hz, 1H), 1.14-1.09 (m, 2H), 1.06-1.00 (m, 2H); APCI MS m/z 424 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:10][CH:11]=1
Reactant: NCCO
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NCCO)cn1
Yield: 90 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (80 mg, 0.26 mmol) was converted, using ethanolamine instead of 4-aminotetrahydropyran, to the title compound (82 mg, 90%) which was obtained as an off white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:22]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:20]1>CN(C=O)C>[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:3])=[O:15])=[CH:12][C:11]=1[C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:22]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:20]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Reaction time: 3 h
Yield: 84.9 %

Procedure:
Methyl iodide (0.17 ml) and potassium carbonate (0.4 g) were added to a solution of 4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-tetrahydro-2H-pyran-2-yl]benzoic acid (1.5 g) in DMF (10 ml) at room temperature and the mixture was stirred for three hours. The insoluble matter was separated by filtration and the filtrate was diluted with ethyl acetate. The diluted solution was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain methyl 4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-tetrahydro-2H-pyran-2-yl]benzoate (1.3 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)C1C=CC=CC=1>C(O)C.O.[Pd]>[F:29][C:26]([F:27])([F:28])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=1)[CH2:15][O:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][C@@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2OCCN(Cc3ccccc3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cc(CO[C@H]2OCCN[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Reaction time: 36 h
Yield: 69.6 %

Procedure:
A solution of 3.6 g (7.27 mmol) of 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine in 100 mL of ethanol and 5 mL of water, containing 0.72 g of 10% Pd/C was hydrogenated on a Parr apparatus for 36 h. The catalyst was filtered and thoroughly washed with EtOAc. The filtrate was concentrated and the residue was partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using a gradient of 10-60% EtOAc/hexane to isolate 2.05 g (70%) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.6 M n-Butyllithium in hexanes (9.6 mL, 15 mmol) was added to a solution of N,N-diisopropylamine (2.3 mL, 16 mmol) in THF (43 mL) at −78° C. Upon complete addition, the reaction was warmed to 0° C. for 30 minutes and then was re-cooled to −78° C. A solution of 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (3.00 g, 10.2 mmol, from Example 2, Step 1) in THF (8 mL) was added dropwise. After stirring for one hour at −78° C., ethyl chloroformate (1.4 mL, 14 mmol, Alfa Aesar) was added and the reaction was stirred at −78° C. for 2 hours, after which time it was allowed to warm to room temperature. The reaction was poured into dilute HCl and the product was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted, and the solvent removed in vacuo. Flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes afforded product as a yellow solid (2.15 g, 57%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(=[O:35])[O:34][C:32](=[O:33])[CH2:31][O:30][CH2:29]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([C:32](=[O:33])[CH2:31][O:30][CH2:29][C:28]([OH:35])=[O:34])[CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(=O)O1
Reactant: O=C(NCCNCCNC(=O)OCc1ccccc1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)COCC(=O)N(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
37.14 g (100 mmol) of the bis(benzyloxycarbonylaminoethyl)-amine described in Example 1a is dissolved in DMF, mixed in an ice bath with 17.4 g (150 mmol) of diglycolic anhydride (Janssen Chimica) and 21 ml (150 mmol) of triethylamine and then stirred overnight at room temperature. The solution is concentrated by evaporation in a vacuum, the residue is taken up in ethyl acetate and shaken out with diluted hydrochloric acid. The organic phase is dried with sodium sulfate and after filtration from drying agent, it is crystallized by adding hexane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[O:12])=[CH:5][CH:4]=1)#[N:2].[Al](Br)(Br)Br.[Cl:23][C:24]([Cl:28])([Cl:27])[C:25]#[N:26].[ClH:29]>>[Cl:23][C:24]([Cl:28])([Cl:27])[C:25]1[N:26]=[C:25]([C:24]([Cl:27])([Cl:23])[Cl:29])[N:26]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[O:12])=[CH:7][CH:8]=2)[N:2]=1
Reactant: Cl
Reactant: CCOCCOC(=O)CSc1ccc(C#N)cc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: Br[Al](Br)Br
Product: CCOCCOC(=O)CSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1

Procedure:
The mixed solution of 10 g of 2-ethoxyethyl 2-(4-cyanophenylthio)acetate (37.7 mmol), 0.8 g of AlBr3, and 50 g of trichloroacetonitrile was bubbled with dry HCl at room temperature.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]=[C:26]=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:3]=1[NH:4][C:26]([NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:27]
Reactant: Nc1ccc(C(F)(F)F)cc1O
Reactant: O=C=Nc1ccccc1-c1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1O)Nc1ccccc1-c1ccccc1
Yield: 64 %

Procedure:
The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171 g, 1 mmol)) and 2-phenyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.24 g, 64%). EI-MS m/z 373(M+H)+
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C:15]1[CH:20]=[CH:19][C:18](OS(C(F)(F)F)(=O)=O)=[CH:17][C:16]=1[O:29][CH3:30])[NH:4][C:5]([C@H:7]1[CH2:9][C@@H:8]1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:6].[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.O.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>[OH:1][CH2:2][C@H:3]([NH:4][C:5]([C@H:7]1[CH2:9][C@@H:8]1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[C:15]1[CH:20]=[CH:19][C:18]([C:34]2[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=2)=[CH:17][C:16]=1[O:29][CH3:30]
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1[C@H](CO)NC(=O)[C@H]1C[C@@H]1c1cccs1
Reactant: Cc1ccccc1B(O)O
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(-c2ccc(C)cc2)ccc1[C@H](CO)NC(=O)[C@H]1C[C@@H]1c1cccs1
Temperature: 80 °C
Yield: 21.3 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 4-{(R)-2-hydroxy-1-[((1S,2S)-2-thiophen-2-yl-cyclopropanecarbonyl)amino]-ethyl}-3-methoxy-phenyl ester (66 mg, 0.142 mmol), tolylboronic acid (38.1 mg, 0.284 mmol), Pd(PPh3)4 (16.4 mg, 0.014 mmol) and Na2CO3 (45.2 mg, 0.426 mmol) in DME/H2O (1.2/0.4 mL) was heated at 80° C. for 3 h. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to preparative HPLC to give the titled compound (12.3 mg). 1H NMR (400 MHz, MeOD) δ ppm 7.7 (d, J=8.3 Hz, 2H), 7.6 (d, J=8.3 Hz, 1H), 7.5 (d, J=7.8 Hz, 2H), 7.4 (t, J=5.4 Hz, 2H), 7.1-7.2 (m, 1H), 7.1 (d, J=3.5 Hz, 1H), 5.6 (dd, J=7.8, 4.5 Hz, 1H), 4.8 (s, 1H), 4.2 (s, 3H), 4.0 (dd, J=11.1, 4.5 Hz, 1H), 3.9 (dd, J=11.4, 7.8 Hz, 1H), 2.8 (dd, J=6.3, 2.5 Hz, 1H), 2.6 (s, 3H), 2.3 (dd, J=8.0, 4.7 Hz, 1H), 1.8 (ddd, J=9.2, 4.8, 4.7 Hz, 1H), 1.5 (ddd, 1H). LRMS (ESI)=408, [(M+1)+ calcd for C24H26NO3S 407.5].
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:6]([C:11]2[CH:12]=[C:13]([Cl:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)[C:7](=[O:10])[C:8]=1O)(=O)[CH3:2].[CH3:27][NH:28][NH2:29]>CC(O)=O.CCOCC.C(Cl)Cl>[Cl:19][C:13]1[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=[C:11]([N:6]2[CH:5]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:4]3[C:1]([CH3:2])=[N:29][N:28]([CH3:27])[C:8]=3[C:7]2=[O:10])[CH:12]=1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Reactant: CNN
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 19.5 %

Procedure:
To a stirred solution of 5-(3-acetyl-2-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-chloro-1-methylpyridin-2(1H)-one (Step 57.1) (300 mg, 0.763 mmol) in AcOH (5 mL) was added methyl hydrazine (0.201 mL, 3.81 mmol) and the reaction mixture was stirred for 18 hr at 100° C. The reaction mixture was concentrated under reduced pressure, quenched with a saturated aq. NaHCO3 solution and extracted with CH2Cl2). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAc. Trituration in Et2O/CH2Cl2 (9:1) afforded the title product (60 mg, 0.149 mmol, 20% yield) as white solid. tR: 4.05 min (HPLC 1); tR: 0.95 min (LC-MS 2); ESI-MS: 403/405 [M+H]+ (LC-MS 2); Rf=0.24 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.89 (s, 3H) 3.41 (s, 3H) 3.89 (s, 3H) 6.07 (s, 1H) 7.26 (d, J=8.2 Hz, 2H) 7.35 (d, J=8.2 Hz, 2H) 7.86 (d, J=2.0 Hz, 1H) 7.90 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2]S([O-])(=O)=O.[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:21]=1[N:20]=[C:19]1[C:14](C=[CH:16][CH:17]=[CH:18]1)=[NH+:13]2.[OH-].[Na+]>O>[O:2]=[C:1]1[C:14]2[C:19](=[N:20][C:21]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:7])[CH:18]=[CH:17][CH2:16]1
Reactant: COS(=O)(=O)[O-]
Reactant: Cc1cccc2[nH+]c3ccccc3nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc2nc3c(nc12)C=CCC3=O
Reaction time: 5 h
Yield: 58 %

Procedure:
Further steps of the process are conducted as described in Example 1 hereinbefore. The solution of 9-methylphenazinium methylsulphate in distilled water is first irradiated for 3 hours and the reaction mixture is brought to the pH of 8.5 by using a 0.1N solution of sodium hydroxide, whereafter the irradiation is continued for additional 5 hours to give 0.79 g (58%) of 4-keto-9-methylphenazine in the form of blue crystals with the melting point of 133°-135° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[F:40]>>[F:33][C:34]1[CH:35]=[C:36]([C:12]2[N:11]=[CH:10][C:9]3[O:8][C:5]4[C:4]([C@:15]5([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:26]2[CH:27]=[N:28][CH:29]=[C:24]([F:23])[CH:25]=2)=[CH:7][CH:6]=4)[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cncc(F)c1
Product: NC1=N[C@@]2(COC1)c1cc(-c3cncc(F)c3)ccc1Oc1cnc(-c3ccc(F)c(F)c3)cc12

Procedure:
The title compound was synthesized by steps analogous to those described in Method A1, but using Intermediate 10B, 5-fluoropyridin-3-ylboronic acid, and 3,4-difluorophenylboronic acid.