Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][OH:18])[C:10]2[C:5](=CC=CC=2)[CH:4]=[CH:3][CH:2]=1.[Mg].Br[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[C:24]1([C:27]2[C:11]([C:1]3[CH:10]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:12]([CH2:17][OH:18])[CH:13]=[CH:14][C:15]=2[CH3:16])[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(Br)cc1
Reactant: OCc1ccccc1-c1cccc2ccccc12
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Mg]
Product: Cc1ccc(CO)c(-c2ccccc2)c1-c1ccccc1

Procedure:
With the same method as for Compound 13, a Grignard reagent was prepared from magnesium (Wako Pure Chemical Industries, Ltd.) and p-bromotoluene (Wako Pure Chemical Industries, Ltd.), and benzophenone (Wako Pure Chemical Industries, Ltd.) was allowed to react with the reagent, to thereby obtain the title compound. m.p. 68-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.ClC1C=CC=CN=1.ClC1N=C(C2C=CC=CC=2)C(C(OCC)=O)=CC=1.N[C:57]1[N:62]=[C:61]([NH:63][CH2:64][CH2:65][NH:66][C:67]2[CH:72]=[CH:71]C(C3NC=CN=3)=C(C3C=CC(Cl)=CC=3Cl)[N:68]=2)[CH:60]=[CH:59][C:58]=1[N+:86]([O-:88])=[O:87]>CC#N.CCN(C(C)C)C(C)C.C1COCC1.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:71][CH:72]=[C:67]([NH:66][CH2:65][CH2:64][NH:63][C:61]2[CH:60]=[CH:59][C:58]([N+:86]([O-:88])=[O:87])=[CH:57][N:62]=2)[N:68]=1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Agent: CCOC(=O)c1ccc(Cl)nc1-c1ccccc1
Agent: Clc1ccccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl

Procedure:
Ethyl 2-(2,4-dichlorophenyl)-6-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyridine-3-carboxylate was prepared from ethyl 3-(2,4-dichlorophenyl)-3-oxopropanoate (ref. Wemple, J.; et. al. Synthesis 1993, 290-292.) as the starting material and THF/ethanol ratio of 3:1 as the solvent in the first step. The oxidation uses DDQ. The final product is achieved directly from the chloropyridine by reacting ethyl 6-chloro-2-phenylpyridine-3-carboxylate with 2-(2-aminoethylamine)-5-nitropyridine in CH3CN and Hünig's base at 120° C. for 18 hours. The procedures are analogous to the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:21]([CH3:23])[CH3:22])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:21]([CH3:23])[CH3:22])[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C(C(=O)OCc1ccccc1)c1ccc(N)cc1
Reaction time: 0.33 h

Procedure:
Iron powder, 55 g, was added in portions to a stirred mixture of 94.6 g of 2-(4-nitrophenyl)-3-methylbutanoic acid, benzyl ester, 400 ml of acetic acid, and 100 ml of water, while the temperature was kept at 90°-95° by occasional application of an ice bath. After an additional 20 minutes at 90°-95°, the hot mixture was filtered, and the filtrate was diluted with water, precipitating an oil. The oil was extracted into butyl chloride, and the butyl chloride solution washed with water (3 times) and saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to 85.7 g of orange oil, 2-(4-aminophenyl)-3-methylbutanoic acid, benzyl ester. Mass spectral analysis shows the expected molecular ion, m/e 283, of the product.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[CH2:31]([O:33][C:34]([C@@:36]1([NH2:41])[CH2:38][C@H:37]1[CH:39]=[CH2:40])=[O:35])[CH3:32]>CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:41][C@:36]1([C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH2:38][C@H:37]1[CH:39]=[CH2:40])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 22.5 °C
Reaction time: 1.12 h

Procedure:
To a suspension of 138.8 g (600 mmol) of Boc-(2S,4R)-hydroxyproline in 890 mL of EtOAc was added 63.7 g (630 mmol) of NMM at 20-30° C. To this mixture 72.3 g (600 mmol) of pivaloyl chloride was added at 15-22° C. within 10-20 min followed by 50 mL of EtOAc. The mixture was stirred at 20-25° C. for 60-75 min. Then the emulsion of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 6 was added at a temperature of 20-30° C. within 5-30 min. The dosing funnel was rinsed with 20 mL DMF and 100 mL EtOAc. The reaction mixture was stirred for 4 h at 20-25° C. After complete conversion 450 mL of aqueous HCl (IN) was added. Phases were separated and the aqueous layer was extracted with 600 mL of EtOAc. The organic phase was washed with 200 mL of water, 400 mL of aqueous NaOH (2M) and 200 mL of water. The combined organic phases were concentrated to 400 mL under reduced pressure. To the residue 1500 mL of toluene was added and the mixture was concentrated to 1000 mL under reduced pressure. To the residue 720 mL of toluene was added to yield the (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a 12-13 wt % solution in toluene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8]C)[C:5]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:4]([CH3:21])[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[OH-].[Na+]>CCOC(C)=O>[F:20][C:16]1[CH:15]=[C:14]([CH2:13][NH:12][C:10]([C:5]2[C:6]([OH:8])=[N:7][C:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:3][C:4]=2[CH3:21])=[O:11])[CH:19]=[CH:18][CH:17]=1
Reactant: C1COCCN1
Reactant: COc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOCC2)nc(O)c1C(=O)NCc1cccc(F)c1
Temperature: 120 °C
Yield: 45.5 %

Procedure:
A mixture of 1.37 g (4.4 mmol) 6-Chloro-N-[(3-Fluorophenyl)-methyl]-2-methoxy-4-methyl-pyridine-3-carboxylic acid amide and 2.9 ml (33.2 mmol) morpholine was heated in the microwave to 120° C. for 30 min. The RM was then diluted with EtOAc (50 ml) and a 1M aq. NaOH sol. (20 ml) was added. The precipitate formed was filtered off to give 715 mg (2.0 mmol, 47%) N-[(3-Fluorophenyl)-methyl]-2-hydroxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide. The organic layer was separated from the filtrate, washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:2) provided 397 mg (1.1 mmol, 25%) N-[(3-Fluorophenyl)-methyl]-2-methoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 19). [M+H]+ 360.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:26])[C:23](O)=[O:24])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1>C(OCC)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:23](=[O:24])[C:22]([N:19]2[CH2:18][CH2:17][CH:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=[O:26])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from 4-amino-benzonitrile and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) according to the method described in Example 1c. Melting Point: 167-169° C. (diethylether)
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:8][NH:9][C:10]([NH:12][NH2:13])=[O:11].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([S:4]([NH:8][NH:9][C:10]([NH:12][NH:13][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[O:11])(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)Cl
Reactant: NNC(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCS(=O)(=O)NNC(=O)NNS(=O)(=O)CCC
Temperature: 80 °C

Procedure:
Into a 1-liter reaction flask was charged 29.5 g (0.2 mole) n-propane sulfonyl chloride, 200 ml ethanol, 9 g (0.1 mole) carbohydrazide and 16.8 g (0.2 mole) sodium bicarbonate. The mix was stirred and heated gradually to 80° C over a one hour period and was then allowed to reflux for four hours. The separated sodium chloride was filtered off (hot). The filtrate was cooled whereupon the crystalline product separated (17 g) m.p. 191°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1OS(C(F)(F)F)(=O)=O)=[N:9][C:8]([O:20][CH3:21])=[CH:7][CH:6]=2.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>CN(C=O)C>[CH2:24]([C:11]1[C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[C:10]=1[N:9]=[C:8]([O:20][CH3:21])[CH:7]=[CH:6]2)[CH:23]=[CH2:22]
Reactant: COc1ccc2ncc(Cl)c(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=CCc1c(Cl)cnc2ccc(OC)nc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A flask charged with trifluoromethanesulfonic acid 3-chloro-6-methoxy-[1,5]naphthyridin-4-yl ester (1.50 g; prepared according to WO 2004/058144), allyltributylstannane (1.68 g) and DMF was degassed with N2. The reaction mixture was treated with LiCl (695 mg) and Pd(PPh3)4 (126 mg) and further stirred at 100° C. for 4 h. After cooling, the mixture was poured into 10% aq. NH4OH and EA, the aq. layer was extracted with EA and the combined org. layers were washed with water (2×) and brine, dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 4:1), affording a yellow oil (795 mg; 77% yield).
Reaction SMILES: CO[C:3](=[O:10])[CH2:4][CH2:5][NH:6][C:7](=[O:9])[CH3:8].[CH2:11]([CH2:13][NH2:14])[OH:12]>>[C:7]([NH:6][CH2:5][CH2:4][C:3]([NH:14][CH2:13][CH2:11][OH:12])=[O:10])(=[O:9])[CH3:8]
Reactant: NCCO
Reactant: COC(=O)CCNC(C)=O
Product: CC(=O)NCCC(=O)NCCO

Procedure:
According to scheme V, N-acetyl-β-alanine methyl ester 5 is reacted with ethanolamine neat at 85° C., giving 3-(acetylamino)-N-(2-hydroxyethyl)propanamide 16 which is reacted with oleoyl chloride 1, giving the ester isostere product 2-[[3-(acetylamino)-1-oxopropyl]amino]ethyl-9(Z)-octadecenoate 17. ##STR13##
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C[O:54][C:55](=O)[CH2:56][CH:57]([CH:67]1[CH2:70][CH2:69][CH2:68]1)[NH:58][CH2:59][C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=1.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH:67]1([CH:57]2[N:58]([CH2:59][C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)[C:19](=[O:21])[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)=[C:55]([OH:54])[CH2:56]2)[CH2:70][CH2:69][CH2:68]1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)CC(NCc1ccc(F)cc1)C1CCC1
Agent: CC[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(C1=C(O)CC(C3CCC3)N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 22 h
Yield: 33.1 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.119 g, 0.337 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.140 g, 0.368 mmol) and 4-methylmorpholine (0.074 mL, 0.673 mmol) were added sequentially to a solution of rac-3-cyclobutyl-3-(4-fluoro-benzylamino)-propionic acid methyl ester (0.089 g, 0.335 mmol) in N,N-dimethylformamide (5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 22 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (5 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.46 mL, 1.42 mmol) was added and the reaction mixture was heated to 60° C. for 4 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 60-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[6-cyclobutyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.063 g, 0.111 mmol, 31%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.64-1.94 (4H, m), 2.36 (1H, d, J=17.2 Hz), 2.64-2.71 (1H, m), 2.95 (3H, s), 3.03 (1H, dd, J1=6.5 Hz, J2=17.7 Hz), 3.53-3.57 (1H, m), 4.15 (1H, d, J=14.8 Hz), 4.24 (2H, d, J=6.2 Hz), 5.10 (1H, d, J=15.1 Hz), 7.12-7.16 (2H, m), 7.24 (1H, s), 7.34-7.38 (2H, m), 7.64 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C23H25FN4O6S3 568.09. found 569.2 [M+H+].
Reaction SMILES: [CH:1]([N:14]([CH3:19])[CH2:15][CH2:16][NH:17][CH3:18])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH:1]([N:14]([CH3:19])[CH2:15][CH2:16][N:17]([CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]1=[O:35])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCN(C)C(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCCN1C(=O)c2ccccc2C1=O)CCN(C)C(c1ccccc1)c1ccccc1

Procedure:
13.9 g (54,7 mmol) N1-benzhydryl-N1,N2-dimethyl-ethan-1,2-diamine, 15.4 g (54.7 mmol) N-(4-bromobutyl)-phthalimide, 15.1 g (109.5 mmol) potassium carbonate and 1.6 g (10.6 mmol) sodium iodide are stirred for four hours in DMF at 70° C. After cooling, the mixture is concentrated under vacuum and the residue is distributed between chloroform and water. The organic phase is dried over sodium sulfate and evaporated under vacuum until dry. The purification occurs by chromatography on silica gel with CHCl3/CH3OH (100/0 to 99/1): Yield 20.8 g (83%).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9](=[O:11])[O:8][C:7](=O)[C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.C([NH2:16])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:16][C:7]2=[O:8]
Reactant: NC=O
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Product: O=C1NC(=O)c2c(F)ccc(F)c21
Temperature: 0 °C

Procedure:
Under argon, 2.15 g (11.68 mmol) of 4,7-difluoro-2-benzofuran-1,3-dione were stirred in 15 ml of formamide at 130° C. for 5 h. The cooled reaction mixture was then added to ice-water. A solid precipitated out. This solid was filtered off with suction and washed with water. The product was dried under high vacuum. This gave 0.45 g (21% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:16]=3)[C:11](=[O:24])[C:10]([C:25]([NH2:27])=[O:26])=[CH:9]2)=[CH:4][CH:3]=1.[Cl-].[CH2:29]=[N+:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN(C=O)C.C(=O)(O)[O-].[Na+]>O>[N:30]1([CH2:29][NH:27][C:25]([C:10]2[C:11](=[O:24])[C:12]3[C:17](=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:26])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Reactant: C=[N+]1CCOCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCN1CCOCC1)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A mixture of 1.08 g 1-(4-fluorophenyl)-1,4-di -hydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (Example 1 h), 0.45 g N-methylenemorpholinium chloride and 10 ml DMF was heated at 100° C. for 15 min. The reaction mixture was cooled, poured into 100 ml water and the pH adjusted to 8 with saturated sodium bicarbonate solution. The solid precipitate was collected, dried and recrystallized from an acetonitrile -chloroform mixture to give 0.90 g N-(4-morpholinylmethyl)-1-(4-fluorophenyl)1,4 -dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide, m.p. 258-260° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([OH:18])[C:12]([O:19]C)=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.B(Br)(Br)Br>ClCCl>[OH:19][C:12]1[C:13]([OH:18])=[C:14]([N+:15]([O-:17])=[O:16])[C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2cc(OC)c(O)c([N+](=O)[O-])c2o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1cc2cc(O)c(O)c([N+](=O)[O-])c2o1
Temperature: -5 °C
Reaction time: 24 h

Procedure:
6-Hydroxy-5-methoxy-7-nitro-benzofuran-2-carboxylic acid ethyl ester (0.25 g) was dissolved to dichloromethane and cooled to −5° C. 1 M boron tribromide solution in dichloromethane (4.5 ml) was added and the mixture stirred at 0° C. for 24 hours. The mixture was poured in ice water and the dichloromethane layer separated. The water phase was extracted with ethyl acetate. The combined organic phases were dried with Na2SO4 and evaporated to dryness. The product was purified by reverse phase column chromatography using methanol (1%) in dichloromethane as an eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](S(C1C=CC(C)=CC=1)(=O)=O)[CH:13]=[C:12]2[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30]([NH:36][C@@H:37]2[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]2)[N:29]=1.[OH-].[Na+]>O1CCOCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30]([NH:36][C@@H:37]2[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]2)[N:29]=1
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4c(F)cccc4F)cc23)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(-c2c[nH]c3ccc(-c4c(F)cccc4F)cc23)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Yield: 77.2 %

Procedure:
To a solution of (R)-tert-butyl 3-((4-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)amino)piperidine-1-carboxylate (500 mg, 0.726 mmol) in dioxane (7 mL) was added 7M aq.NaOH (7 mL) and the mixture was heated at 90° C. for 6 h. The reaction was quenched with water and the suspension was filtered. The resulting solid was washed with water and dried. The crude product was purified with silica gel chromatography (eluting with 50% EtOAc in Hexanes) to give (R)-tert-butyl 3-((4-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)amino)piperidine-1-carboxylate (300 mg, 77%). MS (ESI, pos. ion) m/z: 536.0 (M+1); 1H-NMR (400 MHz CDCl3): δ ppm: 8.63 (s, 1H), 8.41 (brs, 1H), 7.90 (s, 1H), 7.65-7.77 (m, 1H), 7.48-7.57 (m, 2H), 7.30-7.35 (m, 1H), 6.99-7.03 (m, 2H), 6.43 (s, 1H), 5.00 (s, 1H), 4.09-4.13 (m, 1H), 3.92 (s, 3H), 3.33-3.73 (m, 4H), 2.05 (s, 1H), 1.63-1.72 (m, 1H), 1.38 (s, 9H), 0.86-0.90 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:8][S:16]([CH3:15])(=[O:18])=[O:17])[CH:5]=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)Oc1cncc(Br)c1
Reaction time: 2 h

Procedure:
A flask is charged with 5-bromo-pyridin-3-ol (0.200 g, 1.126 mmol), potassium carbonate (0.212 g, 1.487 mmol) and acetone (3 mL). Methanesulfonyl chloride (0.143 g, 1.239 mmol) is then added dropwise. After 2 h, an other portion of methanesulfonyl chloride (0.071 g, 0.61 mmol) is added. After overnight stirring, the suspension is concentrated, diluted with ethyl acetate and filtered through a pad of silica gel. The filtrate is concentrated in vacuo to give a residue, which is purified by silica gel flash chromatography (heptane-ethyl acetate, 4:1 to 7:3) to give a mixture of product and starting material. The fractions are combined, washed three times with saturated aqueous sodium bicarbonate and dried over MgSO4. Concentration in vacuo gives methanesulfonic acid 5-bromo-pyridin-3-yl ester as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.25 (s, 3H), 7.86 (m, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])[C@H:10]([N:14]([CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32](C(OC(C)(C)C)=O)[CH:31]=[CH:30]2)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:43])[C@H:10]([N:14]([CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C(=O)OC(C)(C)C)c2)[C@@H](C(=O)OCc2ccccc2)C(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(Cc2ccc3[nH]ccc3c2)[C@@H](C(=O)OCc2ccccc2)C(C)C)cc1
Yield: 75.4 %

Procedure:
A solution of 2(R)-[(N-tert-butoxycarbonylindol-5-ylmethyl)-(4-methoxybenzene-sulfonyl)amino]-3-methylbutyric acid benzyl ester (2.7 g. 4.45 mmol) and trifluoroacetic acid (5 mL) in methylene chloride (15 mL) was stirred for 2 h at room temperature. The organics were removed under vacuum and the residue was dissolved in ethyl acetate (80 mL) and the ethyl acetate layer was washed with 5% sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated to give a white foamy solid which was chromatographed on a silica gel column eluting with (5-100%) ethyl acetate/hexanes. This procedure gave 2(R)-[(1H-indol-5-yl-methyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (1.7 g) as a white foamy semi-solid, which was converted to 2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyric acid by following the procedure described in Example 1, Step 6 above.