Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[CH:7]=[N+:6]([O-])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:19][CH:12]1[C:13]2[C:8](=[CH:7][N:6]=[C:5]3[C:14]=2[CH:1]=[CH:2][CH:3]=[CH:4]3)[CH2:9][CH2:10][CH2:11]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cc2c(c3ccccc31)CCCC2
Product: CC(=O)OC1CCCc2cnc3ccccc3c21
Yield: 77 %

Procedure:
A solution of 7,8,9,10-tetrahydrophenanthridine N-oxide (Compound 4a) (1.23 g, 6.18 mmol) in acetic anhydride (50 mL) was heated to 100° C. for 20 hours, evaporated to dryness, dissolved in dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL). The aqueous layer was extracted with dichloromethane (2×50 mL), the combined organic layers were dried (Na2SO4), evaporated in vacuo, and the residue was purified by flash chromatography on silica eluting with Et2O to give pure Compound 5 (1.15 g, 77 percent) as a white crystalline solid: Rf =0.33 (ether); mp=128°-129° C. (from ether); IR (CDCl3) νmax 2970, 1728, 1241 cm-1 ; 1H NMR (500 MHz, CDCl3): δ 8.70 (s, 1 H, H-6), 8.08 (d, J=9.5 Hz, 1 H, H-4), 7.76 (d, J= 9.5 Hz, 1 H, H-1), 7.63 (t, J=7.2 Hz, 1 H, H-2 or H-3), 7.52 (t, J=7.2 Hz, 1 H, H-2 or H-3), 6.57 (bs, 1 H, CH-OAc), 3.02 (bd, J=17.5 Hz, 1 H, H-7), 2.88-2.80 (m, 1 H, H-7), 2.27 (bd, J=13.8 Hz, 1 H, H-9), 2.05 (s, 3 H, OAc), 2.01-1.88 (m, 3 H); 13C NMR (125 MHz, CDCl3): δ 170.2, 152.3, 147.5, 137.8, 131.8, 130.1, 127.9, 127.0, 126.8, 122.2, 64.5, 29.1, 27.8, 21.7, 18.4; MS (FAB+) m/e (relative intensity) 242 (M+H, 100), 182 (23); HRMS calcd. for C15H16NO2 (M+H) 242.1181, found 242.1181; Anal. calcd. for C15H15NO2 ; C, 74.67; H, 6.27; N, 5.80. Found: C, 74.59; H, 6.31; N, 5.82.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[NH:35][C:29]5=[N:30][C:31](Cl)=[CH:32][CH:33]=[C:28]5[N:27]=4)=[CH:21][CH:20]=3)[C:9]([C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.B(O)(O)[C:37]1[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[NH:35][C:29]5=[N:30][C:31]([C:37]6[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=6)=[CH:32][CH:33]=[C:28]5[N:27]=4)=[CH:21][CH:20]=3)[C:9]([C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Nc1ncnn2cc(C(=O)NCC(F)(F)F)c(-c3ccc(Nc4nc5ccc(Cl)nc5[nH]4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3nc(Nc4ccc(-c5c(C(=O)NCC(F)(F)F)cn6ncnc(N)c56)cc4)[nH]c3n2)cc1
Temperature: 150 °C
Yield: 10.6 %

Procedure:
To a mixture of 4-amino-5-{4-[(5-chloro-3H-imidazo[4,5-b]pyridin-2-yl)amino]phenyl}-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (50 mg, 0.1 mmol), p-tolylboronic acid (27 mg, 0.2 mmol), potassium carbonate (82 mg, 0.6 mmol), in DMF was added 1,1′-bis(diphenylphosphino)ferrocinepalladium (II) chloride (7.3 mg, 0.01 mmol). The mixture was then degassed using nitrogen for 10 min, and then heated (150° C.) in a microwave for 15 min. After cooling to room temperature, the mixture was diluted with methanol and concentrated under reduced pressure. The residue purified by silica gel chromatography using a 1 to 8% methanol/dichloromethane as the eluant to afford the desired product (5.9 mg, 11%). 1H-NMR (300 MHz, CD3OD) 7.86 (s, 1H), 7.81-7.87 (m, 4H), 7.73-7.79 (m, 2H), 7.63-7.69 (m, 1H), 7.53 (s, 1H), 7.40-7.49 (m, 2H), 7.22-7.28 (m, 2H), 3.92-3.99 (m, 2H), 2.38 (s, 3H); ES-MS m/z 558.3 (MH)+; HPLC RT (Method A) 2.64 min.
Reaction SMILES: [H-].[Na+].C([O:5][CH2:6][CH3:7])=O.[CH3:8][C:9]1(C)[CH2:26][C:13]2=[C:14]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[S:15][C:16]([S:17][CH3:18])=[C:12]2[C:11](=[O:27])[CH2:10]1>C1COCC1>[CH3:8][C:9]1([CH3:10])[CH2:26][C:13]2=[C:14]([C:19]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[O:20])[S:15][C:16]([S:17][CH3:18])=[C:12]2[C:11](=[O:27])[C:7]1=[CH:6][OH:5]
Reactant: CCOC=O
Reactant: CSc1sc(C(=O)N2CCCC2)c2c1C(=O)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1sc(C(=O)N2CCCC2)c2c1C(=O)C(=CO)C(C)(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a suspension of NaH (76 mg of a 60% dispension in oil, 1.9 mmol) in THF (5 ml,) was added ethyl formate (0.38 mL, 4.7 mmol) at 0° C. After stirring for 10 min a solution of 6,6-dimethyl-3-methylthio-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (305 mg, 0.94 mmol) in THF (7 mL) was added. The cooling bath was removed and the mixture stirred at room temperature for 18 h. After this time MeOH (0.5 mL) followed by water (0.5 mL) were added and the mixture stirred for 10 min. The solvents were removed in vacuo and the residue dissolved in water. The mixture was acidified to pH1 using 1 M HCl and the resultant solid collected by filtration. The solid was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with EtOAc: DCM (10:90), to give the title compound (173 mg, 52%) as a pale yellow oil. 1H NMR (250 MHz, CDCl3) δ1.18 (6H, s),1.93-1.99 (4H, m), 2.63 (3H, s), 2.82 (2H, s), 3.56-3.70 (4H, m), 7.56 (1H, d, J=10.4 Hz), 14.63 (1H, d J=10.4 Hz).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]1([CH3:27])[NH:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:9]1=[O:26]>O.O1CCCC1>[CH3:21][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:10]2[C:9](=[O:26])[C:8]([CH3:27])([CH3:7])[NH:12][C:11]2=[O:13])=[CH:15][C:16]=1[C:22]([F:25])([F:24])[F:23])=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(N2C(=O)NC(C)(C)C2=O)cc1C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1ccc(N2C(=O)NC(C)(C)C2=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
470 mg of sodium periodate were dissolved in 5 ml of water and admixed slowly with 640 mg of 114.1, dissolved in 10 ml of tetrahydrofuran, with ice bath cooling. The mixture was stirred at room temperature overnight. Another 210 mg of sodium periodate were added and the mixture was stirred for a further 8 h. Thereafter, the reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The chromatographic purification (silica gel; 96/4 dichloromethane/methanol) afforded 3-(4-methanesulfinyl-3-trifluoromethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (114.1a). Molecular weight 334.05 (C13H13F3N2O3S); retention time Rt=1.69 min. [B]; MS (ES−): 335.19 (M−H+).
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:12])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[O:23][Si:24]([CH3:30])([CH3:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH3:30][Si:24]([CH3:29])([C:25]([CH3:27])([CH3:26])[CH3:28])[O:23][C:22]1[CH:21]=[C:20]([CH2:19][CH2:12][C:10](=[O:11])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CCC(=O)CC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Sodium hydride (2.13 g of a 50% dispersion in mineral oil, 44 mmol) was washed twice with hexanes, covered with dry THF (150 mL) and 1-benzoylacetone (6.00 g, 37 mmol) added portionwise. The mixture was stirred at room temperature under an atmosphere of nitrogen for 10 minutes to give a slurry which was cooled to -20° C. n-Butyllithium (2.60 g, 40 mmol) in hexane (16.3 mL) was added dropwise to provide a solution which was stirred for 20 minutes prior to the dropwise addition of [3-(bromomethyl)phenoxy]dimethyl(1,1-dimethylethyl)silane (11.17 g, 37 mmol). After 15 minutes, the mixture was poured onto saturated ammonium chloride solution and extracted with CH2Cl2. The combined extracts were dried over sodium sulfate, concentrated in vacuo and the residual oil chromatographed on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (9:1) gave 5-[3-[dimethyl(1,1-dimethylethyl)siloxy]phenyl]-1-phenyl- 1,3-pentanedione (9.00 g, 63%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C(/N=N/C(N(C)C)=O)=O)C>C1COCC1>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)cc1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.7 %

Procedure:
To a mixture of 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile (185 mg, 0.99 mmol), 4-fluorobenzyl alcohol (188 mg, 1.49 mol), PPh3 (391 mg, 1.49 mmol) and THF (4 mL) cooled in an ice-water bath, TMAD (257 mg, 1.49 mmol) was added. The reaction mixture was stirred overnight at rt, filtered, and concentrated before purification by prep-HPLC to give the title compound (40 mg, 13%). 1H NMR (400 MHz, CDCl3): δ 5.14 (2H, s), 5.68 (1H, s), 7.00-7.05 (2H, m), 7.33-7.36 (3H, m), 7.52 (1H, s), 7.96 (1H, s), 8.64 (1H, s). [M+H] Calc'd for C16H11FN4O, 295; Found, 295.
Reaction SMILES: [CH2:1]([C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5][CH2:4]1)[CH3:2].C(O)C.[Cl-].[Ca+2].[Cl-]>[Fe].O>[NH3:6].[NH2:21][C:17]1[CH:16]=[C:15]([C:3]2([CH2:1][CH3:2])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5][CH2:4]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCCCCCN1CCC(CC)(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCCCCCN1CCC(CC)(c2cccc(N)c2)CC1
Product: N
Yield: 68 %

Procedure:
To a solution of 4-ethyl-N-hexyl-4-(3-nitrophenyl)piperidine (Preparation 63, 335 mg, 1.05 mmol) in 9:1 ethanol:water (41 ml) was added iron powder (530 mg, 9.45 mmol) followed by calcium chloride (58 mg, 0.53 mmol). The reaction mixture was heated under reflux for 2 h, then the mixture was allowed to cool. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (20 ml) and water (20 ml). The phases were separated and the organic extract was dried (MgSO4), filtered and concentrated in vacuo to give the crude product. This was purified by silica (10 g) column chromatography eluting with methanol:dichloromethane:0.880 ammonia (10:89:1) to give the title compound as a brown oil (103 mg, 34%).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]([NH:9]C(=O)OCC1C=CC=CC=1)([CH3:8])[CH3:7].[H][H].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)C.[Pd]>[CH3:7][C:6]([NH2:9])([C:2]1[O:1][CH:5]=[N:4][N:3]=1)[CH3:8]
Reactant: [H][H]
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1nnco1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CC(C)(N)c1nnco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzyl 2-(1,3,4-oxadiazol-2-yl)propan-2-ylcarbamate (1 g, 30% purity) and 10% Pd/C (0.06 g) in ethanol (30 mL) was charged with hydrogen balloon and stirred at room temperature overnight. After filtration, it was concentrated to give crude product which was directly used in the next reaction step without further purification but still contained OPPh3 and PPh3; MS: m/e 128.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([CH:15]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(C(Cl)Cn2ccnc2)c1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
144 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling, to a solution of 555 mg of methyl 4-mercaptobenzoate in 4 ml of dry dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 710 of 1-[2-chloro-2-(3-methoxyphenyl)ethyl]imidazole in 3 ml of dry dimethylformamide was added to this solution, and the reaction mixture was heated at 60°-70° C. for 5.5 hours. At the end of this time, the resulting mixture was treated and purified according to the same procedure as described in Example 1, to give 631 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13](=[O:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CC#N>[C:29]([O:28][C:26](=[O:27])[CH2:25][N:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:12][CH:11]=2)[C:7]([C:13](=[O:15])[CH3:14])=[CH:8]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)c1c[nH]c2ccc(OC(F)(F)F)cc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccc(OC(F)(F)F)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(5-trifluoromethoxy-1H-indol-3-yl)-ethanone (0.50 g, 2.06 mmol) in CH3CN (10 mL) was added K2CO3 (0.313 g, 2.26 mmol) and tert-butyl 2-bromoacetate (0.334 mL, 2.26 mmol). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was filtered, and the filtrate was diluted with CH2Cl2. The organics were washed with 1M aqueous HCl solution (5 mL) and saturated aqueous NaHCO3 solution (5 mL). The organic layer was dried (phase separator) and evaporated in vacuo to afford the title compound as a yellowish oil: MS: 358.0 [M+H]+; tR (HPLC conditions c): 5.66 min. The material thus obtained was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].N1C=NN=N1.C(N(CC)[P:17]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C.ClC1C=CC=C(C(OO)=[O:44])C=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.ClCCl>[P:17]([O:4][CH2:3][C:2]([CH3:8])([CH3:1])[CH2:5][CH2:6][OH:7])([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:44]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN(CC)P(OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(CO)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CCO)COP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 68 h
Yield: 17 %

Procedure:
To a solution of the product from Example 9A (0.80 g, 6.8 mmol) and 1H-tetrazole (0.190 g) in THF (7.0 mL) at 0° C. was added dibenzyl diethylphosphoramidite (0.96 mL), and the solution was allowed to warm to room temperature and was stirred for 68 hours. To this solution was added dichloromethane (7.0 mL) and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (1.3 g). The mixture was stirred at −45° C. for 1 hour and at room temperature for 1 hour. 10% Na2CO3 was added and the reaction was extracted twice with chloroform. The combined organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient of 50-100% ethyl acetate in chloroform, to give the title compound (0.396 g, 17%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][C:18]=1[CH3:26].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:41])([F:40])[F:39])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:25][N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][C:38]([F:39])([F:40])[F:41])[N:28]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(-c3nc(-c4ccccc4OC(F)(F)F)no3)cc2C)c(OC)c1

Procedure:
Oxalyl chloride (112 μL; 1.32 mmol; 3 eq.), Intermediate 28 (120 mg; 0.44 mmol; 1 eq.), Intermediate 2 (97 mg; 0.44 mmol, 1 eq.) and DIEA (228 μL; 1.32 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:6](=[O:17])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reaction time: 4 h
Yield: 101.1 %

Procedure:
To 0.314 g (1.31 mmol) of the above nitro compound in THF-MeOH (16 mL, 1:1) was added 0.460 g of 10% Pd/C and the mixture was stirred under hydrogen (40 in/Hg) for 4 hrs. The reaction mixture was filtered through celite, washed with MeOH and concentrated to give 0.277 g (99% yield) of tert-butyl 5-aminopyridin-2-yl-carbamate as a white powder: 1H NMR (DMSO-d6) δ 9.00 (br s, 1H), 7.62 (dd, J=2.7, 0.4 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 6.94 (dd, J=8.7, 2.8 Hz, 1H), 4.92 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16](OCC)=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:24])[CH3:23])=[N:10]2)=[C:4]([F:25])[CH:3]=1.OC1C(C(C)C)=NNC(=O)[C:28]=1[C:37]([O:39]CC)=[O:38].[H-].[Na+].BrC1C=CC(CBr)=C(F)C=1.C[N:55](C)C=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:55][CH2:28][C:37]([OH:39])=[O:38])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:23])[CH3:24])=[N:10]2)=[C:4]([F:25])[CH:3]=1
Reactant: CCOC(=O)c1c(O)c(C(C)C)nn(Cc2ccc(Br)cc2F)c1=O
Reactant: CCOC(=O)c1c(O)c(C(C)C)n[nH]c1=O
Reactant: CN(C)C=O
Agent: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyl 2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. To a solution of ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (9.5 g, 42.0 mmol) in N,N-Dimethylformamide (DMF) (250 ml) at 0° C. was added sodium hydride (60% in oil, 2.52 g, 63.0 mmol) in portions. The reaction mixture was stirred at room temperature for 45 minutes and then cooled back to 0° C. and 4-bromo-2-fluorobenzyl bromide (12.38 g, 46.2 mmol) was added portionwise. The mixture was stirred at ambient temperature for 2.5 hours then quenched with 1N HCl (10 ml) and diluted with water (30 ml). The aqueous solution was extracted with ethyl acetate (2×100 ml), the organic layers combined and washed with water (100 ml) and brine (100 ml), dried over Magnesium sulfate, filtered and solvents removed with rotary evaporation. The crude oil was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to provide the crude product (8 g, ˜75% pure, 35% yield) as a pale yellow solid. The material was purified by reverse phase HPLC (C18, 75-90% acetonitrile/0.3 M aqueous ammonium formate) to give the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6.82 Hz, 6H) 1.26 (t, J=7.20 Hz, 3H) 3.09-3.17 (m, 1H) 4.26 (q, J=7.07 Hz, 2H) 5.16 (s, 2H) 7.21 (t, J=8.08 Hz, 1H) 7.40 (dd, J=8.34, 1.77 Hz, 1H) 7.57 (dd, J=9.73, 1.89 Hz, 1H) 12.31 (s, 1H). MS (ES+) m/e 413 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]([C:22]([OH:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2.Cl[C:29]1[C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]([C:22]([OH:24])=[O:23])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:29]3[C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:19][CH:20]=1)[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Reactant: O=C(O)c1cc2cc(Br)ccc2nc1NC(Cc1ccc(O)cc1)C(=O)O
Product: O=C(O)c1cc2cc(Br)ccc2nc1NC(Cc1ccc(Oc2nc3ccccc3cc2C(=O)O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 96, 6-bromo-2-[1-carboxy-2-(4-hydroxy-phenyl)-ethylamino]-quinoline-3-carboxylic acid is reacted with 2-chloro-quinoline-3-carboxylic acid to provide the title compound in good yield.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:6][CH2:5][C@@H:4]1[C:7]([O:9][CH3:10])=[O:8].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=O)C.CC1(C)N([O])C(C)(C)CCC1.O>C(Cl)Cl>[CH:2]([C@@H:3]1[CH2:6][CH2:5][C@H:4]1[C:7]([O:9][CH3:10])=[O:8])=[O:1]
Reactant: COC(=O)[C@H]1CC[C@H]1CO
Agent: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H]1C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.7 %

Procedure:
To a stirred solution of (1S,2R)-methyl 2-(hydroxymethyl)cyclobutanecarboxylate (100 mg, 0.694 mmol) in DCM (5 mL) was added bis(acetoxy)iodobenzene (335 mg, 1.040 mmol) and TEMPO (10.84 mg, 0.069 mmol) at 0° C. The temperature of the reaction was allowed to slowly warm to RT and stirred for 6 h. Water was added to reaction mass and the compound was extracted with DCM (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate evaporated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 40% EtOAc in petroleum ether). Fractions containing the product were combined and evaporated to afford Intermediate 238A as yellow oil (50 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1H) 3.71 (s, 3H), 3.69-3.36 (m, 2H), 2.31-2.16 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:15][CH2:14]1)([O-:3])=[O:2].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:17][CH2:18]1)([O-:3])=[O:2]
Reactant: COc1ccccc1N1CCN(CCNc2ccccc2[N+](=O)[O-])CC1
Reactant: Brc1ccccn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1N1CCN(CCN(c2ccccn2)c2ccccc2[N+](=O)[O-])CC1
Temperature: 160 °C
Yield: 48 %

Procedure:
A mixture of 0.43 g of 1-[N-(2-nitrophenyl)-2-aminoethyl]-4-(2-methoxyphenyl)piperazine (prepared as described in U.S. Pat. No. 3,472,854), 0.19 g of 2-bromopyridine, 0.17 g of anhydrous potassium carbonate and 0.01 g of powdered copper was heated to 100° C., and maintained at that temperature for 3 h, followed by the addition of another 0.138 g of 2-bromopyridine, and the heating of the mixture to 160° C. for 24 h. After cooling the mixture to room temperature and extraction with ethyl acetate (2×20 mL), the combined organic phases were then washed with water, dried on sodium sulphate, and evaporated to dryness in vacuo. The obtained crude was next purified by flash chromatography (ethyl acetate-petroleum ether 7:3). The recovered fractions, after evaporation to dryness, afforded 0.25 g of the compound of Example 11 (52%).