Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:24]([NH2:42])=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=3)[CH2:19][CH2:18]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:29]2[CH:30]=[C:31]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([NH2:42])[C:23]([N:20]2[CH2:19][CH2:18][O:17][CH2:22][CH2:21]2)=[CH:32]3)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Ic1ccccc1-n1ncc2ccccc21
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc2ccc(-c3ccccc3-n3ncc4ccccc43)cc2cc1N1CCOCC1
Temperature: 140 °C

Procedure:
A mixture of 1-(2-iodophenyl)-1H-indazole (0.18 g, 0.563 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.10 g, 0.282 mmol, prepared as in Example 2, Step 1-2), potassium phosphate tribasic (0.12 mL, 1.408 mmol), Pd2(dba)3 (0.026 g, 0.028 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.027 g, 0.056 mmol) in dioxane/water (3/1.5 mL) was heated in mw for 12 min at 140° C. The mixture was concentrated and chromatographed on silica gel using 0-5% 2M NH3 MeOH/DCM to afford a light yellow oil which was repurified by HPLC to afford a white solid as 6-(2-(1H-indazol-1-yl)phenyl)-3-morpholinoquinolin-2-amine. MS (ESI, pos. ion) m/z: 422 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16](B(O)O)=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)(=O)C.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>[C:37]1([C:35]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([C:16]3[C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:26][CH:27]=2)(=[O:33])=[O:32])=[O:36])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: OB(O)c1ccccc1-c1ccccc1OCc1ccccc1
Reactant: O=C(NS(=O)(=O)c1ccc(Br)cc1)c1ccccc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NS(=O)(=O)c1ccc(-c2ccccc2-c2ccccc2OCc2ccccc2)cc1)c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of 2′-benzyloxy-biphenyl-2-boronic acid (100 mg, 0.33 mmol), 4-bromo-N-(1-phenyl-methanoyl)-benzenesulfonamide (95 mg, 0.28 mmol), potassium carbonate (309 mg, 2.24 mmol), and tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.033 mmol) in 1:1 toluene/ethanol (5 ml) was stirred and heated at 90° C. under nitrogen for 16 hours. After cooling the mixture was diluted with ethyl acetate and water. The organic phase was dried and evaporated. The residue was chromatographed eluting with ethyl acetate/iso-hexane (1:4-1:1) to give the title compound as a colourless solid. (40 mg 23%).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Fc1cnc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(F)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-fluoro-pyrimidine following a procedure analogous to that described in Example 19. LC (method 5): tR=2.14 min; Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:20]I>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N:8]([CH3:20])[C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Cc1ncccc1C(=O)Nc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ncccc1C(=O)N(C)c1cccnc1Cl
Reaction time: 0.33 h

Procedure:
To a stirred solution of N-(2-chloro-3-pyridinyl)-2-methylnicotinamide (1.48 g) in DMSO (20 mL) was added NaH (60% in oil, 0.26 g). After 20 minutes, methyl iodide (0.45 mL) was added, and stirring was continued for 30 minutes. The mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4), filtered, and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave N-(2-chloro-3-pyridinyl)-N-methyl-2-methylnicotinamide (1.51 g).
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:18]#[N:19]>>[Cl:23][C:22]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[S:8]([Cl:11])(=[O:10])=[O:9]
Reactant: N#Cc1ccc(Cl)c(N)c1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: N#Cc1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 3-amino-4-chloro-benzonitrile.
Reaction SMILES: CO[CH2:3][N:4]([CH2:12][Si](C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([C:31](=[CH2:36])[C:32]([O:34][CH3:35])=[O:33])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:21][CH2:20][CH2:19][CH2:18]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([C:31]3([C:32]([O:34][CH3:35])=[O:33])[CH2:36][CH2:3][N:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:12]3)[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(C(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(c2ccc(OC)c(OC3CCCC3)c2)CCN(Cc2ccccc2)C1
Reaction time: 12 h
Yield: 97.7 %

Procedure:
To a solution of N-methoxymethyl-N-(phenylmethyl)trimethylsilylmethylamine (1.42 g, 6.0 mmol) and methyl 2-(3-cyclopentoxy-4-methoxyphenyl)prop-2-enoate (1.38 g, 5.0 mmol) in 10 mL of CH2Cl2 cooled to 0° C. was added a 0.7 mL of a 1M solution of trifluoroacetic acid. Stirring was continued for 12 hr, and the solution was partitioned between ether and sat. NaHCO3. The layers were separated and the aqueous layer was extracted ethyl acetate (2×). The combined organic layers were dried (K2CO3), filtered, and concentrated under reduced pressure to a pale yellow oil. Chromatography on silica gel (3:1, hexanes:ethyl acetate) provided 3-(3-cyclopentoxy-4-methoxyphenyl)-3-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (2.0 g, 99%) as a colorless oil. 1H-NMR (300 MHz): δ 2.75 (d, 1, J=9), 3.54 (d, 1, J=9), 3.67 (s, 3), 3.69 (s, 2), 3.81 (s, 3). Anal. Calcd for C25H31NO4 : C, 73.32; H, 7.63; N, 3.42. Found: C, 73.25; H, 7.65; N, 3.40.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.[OH-].[K+].C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C(C)=CC=CC=1.O>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:11][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: BrCCCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](OCCCOC3CCCCO3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
trans-4-(Dibenzylamino)cyclohexanol (200 mg), 2-(3-bromopropoxy)tetrahydro-2H-pyran (604 mg), powder potassium hydroxide (179 mg), and tetrabutylammonium bromide (44 mg) were suspended in xylene (2 mL), followed by stirring at room temperature for 2 hours. To the reaction mixture were added ethyl acetate and water, and the organic layer was extracted and washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to obtain trans-N,N-dibenzyl-4-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]cyclohexanamine (174 mg).
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([OH:15])=[O:14].[BH4-].[Na+].O>C(O)C>[OH:11][CH:10]1[CH2:9][CH2:8][C@H:7]([CH2:12][C:13]([OH:15])=[O:14])[C@H:6]1[CH2:5]/[CH:4]=[CH:3]\[CH2:2][CH3:1]
Reactant: CC/C=C\CC1C(=O)CCC1CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC/C=C\C[C@H]1C(O)CC[C@@H]1CC(=O)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
In a 50 ml three-necked flask equipped with a condenser, a thermometer and a magnetic stirrer, 1 g (4.8 mmol) of (+/−)-jasmonic acid was dissolved in 15 ml of absolute ethanol. 430 mg (11.4 mmol) of sodium borohydride, NaBH4, were added. The mixture was stirred at 50° C. for 4 hours. When the reaction was finished, 5 ml of water were added slowly. The precipitate formed was filtered off. The filtrate was acidified to pH=5 with hydrochloric acid and then extracted with ethyl acetate (3×30 ml). The organic phase was dried over sodium sulphate, filtered on filter paper, and then concentrated. The colourless oil obtained was purified by chromatography on silica gel (eluent: dichloro-methane/methanol). The colourless oil obtained was dried under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:13])=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.Cl[C:37](=O)[C:38]([O:40][CH3:41])=[O:39]>O>[CH3:41][O:40][C:38]([C:37]1[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]2[C:14]([C:12](=[O:13])[C:11]=1[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:28])=[CH:9][CH:8]=1)=[CH:19][CH:18]=[C:17]([Cl:20])[CH:16]=2)=[O:39]
Reactant: COC(=O)c1ccc(CCC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Reactant: COC(=O)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(Cc2c(C(=O)OC)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A 1 L round-bottomed flask equipped with a magnetic stir bar, a water cooled reflux condenser, a nitrogen bubbler and a thermometer was charged with 4-[3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propyl]-benzoic acid methyl ester (54 g, 137 mmol), toluene (2 L, 18.8 mol) and methyl 2-chloro-2-oxoacetate (200 mL, 2.17 mol). The resulting mixture was heated to reflux overnight. At this time, the reaction mixture was concentrated to a thick gum. This residue was dissolved in methanol (1 L), treated with potassium carbonate (31 g) and stirred overnight. At this time, the reaction was filtered to remove solids. The filtrate was treated with acetic acid (50 mL) and then concentrated in vacuo. The residue was absorbed onto silica gel. Flash chromatography (2″×6″ column; 50-66% ethyl acetate/hexanes) followed by concentration of the appropriate fractions produced a solid. This solid was slurried with 1:1 ethyl acetate/hexanes, collected by filtration and dried in vacuo to afford 7-chloro-3-(4-methoxycarbonyl-benzyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (34 g, 53.7%) as an off-white solid. This material was used without further purification.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[NH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1>>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([CH2:2][NH:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2
Reactant: NCc1cccs1
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNCc1cccs1)C2
Temperature: 150 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
A mixture of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.942 g) and 2-aminomethylthiophene (4.528 g) was stirred in a hot bath at 150° C. in the stream of argon gas for 4 hours. The solvent was distilled off under reduced pressure. Chloroform was added to the residue, and washed with sodium bicarbonate water, and water in this order. After dried, the residue was crystallized from ethanol to obtain 2.712 g of a free base of the title compound as pale yellow prisms (mp.: 163°-165° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([C:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:16][CH:17]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:31][CH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CN(C1C=CN=CC=1)C.O>[Cl:31][CH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:12][C:10]2[S:11][C:7]3[C:6]([C:13]4[N:14]=[C:15]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)[S:16][CH:17]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: COc1ccc(-c2csc(N3CCOCC3)n2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2csc(N3CCOCC3)n2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.165 g of 4-methoxy-7-(2-morpholin-4-yl-thiazol-4-yl)-benzothiazol-2-ylamine (0.00047 Mol) were dissolved in dioxane (5 ml) and combined with 0.1 ml of triethylamine (0.0007 Mol), 0.006 g DMAP (0.000047 Mol) and a solution of 0.116 g of 4-(chlormethyl)benzoylchlorid (0.00062 Mol) in dioxane (1 ml). The reaction mixture was stirred for 6 hrs. at 70° C. After cooling down to room temperature, water (10 ml) and sat. NaHCO3 (10 ml) were added. A precipitation formed. It was filtered, washed with water and tried. This crude product was subjected to column chromatography (silicagel, CH2Cl2/MeOH 19:1). The title compound was obtained as a light yellow solid (65%); F.p.: 166-168° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]1[CH2:58][CH2:57][C@:56]([F:62])([C:59](O)=[O:60])[CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[F:62][C@:56]1([C:59](=[O:60])[NH:41][C@@H:40]([CH:42]([CH3:44])[CH3:43])[C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:46])=[O:45])[CH2:57][CH2:58][N:54]([C:52]([O:51][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:53])[CH2:55]1
Reactant: CC(C)(C)OC(=O)N1CC[C@](F)(C(=O)O)C1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
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: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(F)CCN(C(=O)OC(C)(C)C)C1)C(C)C
Yield: 40.5 %

Procedure:
According to the general procedure D, from #86 (300 mg, 0.45 mmol, 1 eq.), #168 (106 mg, 0.45 mmol, 1 eq.), dichloromethane (10 mL), HATU (194 mg, 0.54 mmol, 1.2 eq.) and diisopropylethylamine (117 mg, 0.9 mmol, 2 eq.) was synthesized the crude desired material, which was purified by reverse phase chromatography (Method P) to afford #191 (159 mg, 40%) as a white solid. HPLC (Protocol X): m/z 873.4 [M+H+], retention time=3.32 minutes (purity=99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.C(=O)(O)[O-].[Na+].[N+]([O-])(O)=O.CC1C=C(C)[N:34]([C:38](N)=[NH:39])N=1>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:38]([NH2:39])=[NH:34]
Reactant: Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Reactant: Cc1cc(C)n(C(=N)N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Yield: 50 %

Procedure:
A mixture of 5-amino-3-[(7-azaindol-3-yl)methylene]-2-oxindole (2.773 g, 10 mmol) and sodium bicarbonate (0.168 g, 2 mmol) in refluxing ethanol (100 ml) was treated with 3,5-dimethylpyrazole-1-carboxamidine nitrate (3.018 g, 15 mmol) for 20 h. The solvent was removed from the cooled solution, and the residue was chromatographed on silica gel with gradient elution (1 to 5% EtOH in CHCl3) to afford pure title compound in about 50% yield.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:20]([O:22]CC)=[O:21])=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(Cl)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(Cl)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
3.3 g (0.0087 mol) of ethyl 7,8-dichloro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 11.5 ml of acetic acid, 11.5 ml of water and 1.15 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, the product is isolated and washed with water.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([C:6]([C:8]#[C:9][C:10]([O:12]C)=[O:11])=[O:7])=[CH:4][C:3]=2[O:2]1.[OH-].[K+].O>O1CCCC1>[CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([C:6]([C:8]#[C:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)C#CC(=O)c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C#CC(=O)c1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
A solution of 5.9 g (25.4 mmol) of methyl 3-[3,4-(methylenedioxy)benzoyl]propiolate in 60 ml of tetrahydrofuran was treated slowly at 0° with 71 ml of 3% potassium hydroxide solution and stirred at 0° for a further 1 hour The reaction mixture was treated with water and extracted once with ether. The ether phase is discarded. The aqueous phase was adjusted to pH 1 with 1N hydrochloric acid and extracted twice with ether. The combined organic phases were dried over sodium sulphate and concentrated. Crystallization of the residue from methylene chloride/ ether/hexane yielded 3-[3,4-(methylenedioxy)-benzoyl]propiolic acid of melting point 122°-124°.
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:17]2[C@@H:13]([N:14]([CH:18]([CH2:21][OH:22])[CH2:19][OH:20])[O:15][CH2:16]2)[C@H:12]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:11]1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)C1C=CC=CC=1.CO[C:41](OC)([CH3:43])[CH3:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].C[O-].[Na+].[Cl-].[NH4+]>CC(C)=O>[CH2:32]([O:31][C@@H:11]1[C@@H:12]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:13]2[N:14]([CH:18]3[CH2:21][O:22][C:41]([CH3:43])([CH3:42])[O:20][CH2:19]3)[O:15][CH2:16][C@@H:17]2[C@H:10]1[OH:9])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O[C@@H]1[C@H]2CON(C(CO)CO)[C@H]2[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccccc1
Reactant: COC(C)(C)OC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(N2OC[C@@H]3[C@@H](O)[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]32)CO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
The compound (1.20 g, 2.31 mmol) synthesized in Example 16 (16a) was dissolved in acetone (30 mL) and 2,2-dimethoxy propane (2.27 mL, 18.5 mmol) and p-toluenesulfonic acid monohydrate (660 mg, 3.47 mmol) were added thereto, followed by stirring of the mixture at room temperature for 15 minutes. After saturated aqueous sodium hydrogencarbonate (50 mL) was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate (50 mL), the organic layer was washed with saturated brine (50 mL). The solvent was distilled off under reduced pressure and the residue was dissolved in methanol. Sodium methoxide (0.4 mL, 1.96 mmol) was added thereto and the mixture was stirred at room temperature for 20 minutes. After saturated aqueous ammonium chloride (50 mL) was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate (50 mL), the organic layer was washed with saturated brine (50 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 1:1, V/V) to obtain the desired title compound (840 mg, yield 80%) as a colorless solid.
Reaction SMILES: [F:1][CH:2]1[C:11](=[O:12])[N:5]2[C:6]([CH3:10])([CH3:9])[O:7][CH2:8][C@H:4]2[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1([F:33])[C:11](=[O:12])[N:5]2[C:6]([CH3:10])([CH3:9])[O:7][CH2:8][C@H:4]2[CH2:3]1
Reactant: CC1(C)OC[C@H]2CC(F)C(=O)N21
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@H]2CC(F)(F)C(=O)N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution consisting of (7aR)-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (8.0 g, 46.2 mmol, mixture of diastereomers of 5.1) in dry THF (300 mL) at −75° C. was added lithium bis(trimethylsilyl)amide (50.8 mL, 50.8 mmol, LiHMDS 1 M in THF) dropwise over ten minutes, then stirred for one hour. The reaction mixture was then treated with a solution consisting of N-fluorobenzenesulfonimide (17.5 g, 55.4 mmol) in THF (100 mL) with steady addition over ten minutes. The resulting mixture was stirred for 30 minutes. Lithium bis(trimethylsilyl)amide (10.0 mL, 10 mmol) was added, and the reaction stirred for 16 hours, warming to room temperature. To the reaction mixture was added a 50% aqueous solution of ammonium chloride. The organic material was extracted with ethyl acetate-heptane (5:1). The organic layer was washed sequentially with a 50% aqueous solution of sodium chloride, water, and a saturated solution of sodium chloride, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography. Elution with ethyl acetate-hexanes (1:5 v/v) afforded the title compounds as a tan solid (7.39 g; 79%); TLC Rf 0.70 (solvent system: 50:50 v/v ethyl acetate-hexanes); 1H-NMR (CDCl3) δ 4.3 (dd, 1H), 4.2-4.0 (m, 1H), 3.5 (t, 1H), 2.9-2.7 (m, 1H), 2.2-2.0 (m, 1H), 1.7 (s, 3H), 1.5 (s, 3H).