Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:55]([O:57][C:58](=[O:66])[CH2:59][C:60]1[N:61]=[C:62]([NH2:65])[S:63][CH:64]=1)[CH3:56]>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:55]([O:57][C:58](=[O:66])[CH2:59][C:60]1[N:61]=[C:62]([NH:65][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:16][CH:17]=2)=[O:22])[S:63][CH:64]=1)[CH3:56]
Reactant: Cc1cc(C)cc(S(=O)(=O)N2CCc3ccc(C(=O)O)cc32)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)cc(C)c2)CC3)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3,5-dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (0.20 g, 0.60 mmol) in dimethylformamide (1.00 mL) under argon was treated with N-methyl morpholine (0.31 g, 0.33 mL, 3.01 mmol), HATU (0.34 g, 0.90 mmol) and (2-amino-thiazol-4-yl)-acetic acid ethyl ester (0.17 g, 0.91 mmol). The mixture was stirred at room temperature for 30 min, then treated with 4-dimethylaminopyridine (0.07 g, 0.60 mmol). The mixture was warmed to 60° C. and stirred for 50 hours. After cooling to room temperature the mixture was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified via flash chromatography (heptane/ethyl acetate gradient) to yield (2-{[1-(3,5-dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester as an off-white solid, 0.10 g (35%), MS (ISP): m/e=500.4 (M+H).
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[O:25][CH2:24][CH:23]=[CH:22][C:17]4=3)[N:12]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:37]>C(O)C.[Pd]>[ClH:37].[O:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:12]1[C:13]2[C:18](=[C:17]3[CH2:22][CH2:23][CH2:24][O:25][C:16]3=[CH:15][CH:14]=2)[C:19]2[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]1=2)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C1=Cc2c(ccc3c2c2c(n3CCCCOc3ccccc3)CCN(Cc3ccccc3)CC2)OC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(OCCCCn2c3c(c4c5c(ccc42)OCCC5)CCNCC3)cc1
Yield: 97.6 %

Procedure:
A solution containing 10-benzyl-7-(4-phenoxybutyl)-7,8,9,10,11,12-hexahydro-3H-azepino[4,5-b]pyrano[3,2-e]indole (0.085 g., 0.18 mmol, Example 5) in ethanol (10.0 mL) was hydrogenated in the presence of palladium-on-carbon (0.04 g.) and 2 N hydrochloric acid (0.09 mL, 0.18 mmol) at 50 psi for 16 hours. After filtration through a pad of celite, the filtrate was concentrated in vacuo. The residue was recrystalized from EtOAc/MeOH to yield the title compound (0.075 g, 99%) as a light yellow solid. 1H NMR (300 MHz, MeOH-d4) δ 7.24-7.19, 7.03, 6.90-6.80, 6.57, 4.18-4.06, 3.85, 3.47-3.32, 3.28-3.17, 3.11, 2.04-1.95, 1.89-1.65, 1.40-1.25, 0.95-0.81; MS (ESI+) m/z 391 (M++H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([Cl:17])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC[C@H](C(O)=O)C1)(=O)C1C=CC=CC=1.S(Cl)(Cl)=O>ClCCl>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([Cl:17])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Agent: O=C(O)[C@H]1CCCN(C(=O)c2ccccc2)C1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)[C@H]1CCCN(C(=O)c2ccccc2)C1

Procedure:
The reaction was run in the same manner as 1-benzoyl-3-piperidinecarbonyl chloride, starting with (S)-1-benzoyl-3-piperidinecarboxylic acid (6.30 g; 27.0 mmols), thionyl chloride (16.06 g, 135 mmol), and dry dichloromethane (150 ml), giving (S)-1-benzoyl-3-piperidinecarbonyl chloride as a light yellow oil, which was used without further purification. MS (in CH3CN) m/z (positive ion) 503 (40), 485 (42), 467 (40), 254 (60), 252 (MH+; 100), 234 (68).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+].O>ClC1C=CC=CC=1Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([O:9][CH3:10])=[C:6]([N:7]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:8]=1
Reactant: COc1c(N)cc(Br)cc1C(C)(C)C
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Temperature: 200 °C
Reaction time: 22 h
Yield: 116.7 %

Procedure:
5-Bromo-3-(tert-butyl)-2-methoxyaniline (311 g) and bis(2-chloroethyl)amine hydrogenchloride (251 g) were suspended in 4 L of 1,2-dichlorobenzene, and the mixture was vigorously stirred for 22 hours at an external temperature of 200° C. The mixture was cooled to room temperature, and then potassium carbonate (620 g) and water were added and extraction was performed with methylene chloride (6 L). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to yield a black oil (460 g). Purification was performed by NH-silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (161 g) as blackish purple solid (41%).
Reaction SMILES: [NH:1]([C:3]1[NH:8][C:7](=[O:9])[N:6]([CH3:10])[C:5](=[O:11])[CH:4]=1)[NH2:2].[C:12]1([CH:22]=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH3:10][N:6]1[C:5](=[O:11])[CH:4]=[C:3]([NH:1][N:2]=[CH:22][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[NH:8][C:7]1=[O:9]
Reactant: O=Cc1cccc2ccccc12
Reactant: Cn1c(=O)cc(NN)[nH]c1=O
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(NN=Cc2cccc3ccccc23)[nH]c1=O
Temperature: 25 °C

Procedure:
A solution of 84 mg (0.54 mmol) 6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione and 84 mg (0.54 mmol) 1-naphthaldehyde in 3 mL DMF was heated to 70° C. for 30 min before cooling to room temperature affording a solution of 1-naphthaldehyde (1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone. Isonicotinaldehyde (110 mg, 1.0 mmol) and piperidine (50 μL, 0.6 mmol) were added, and the mixture was heated at 70° C. for 20 h. 1,1,1-trifluoro-2-iodoethane (130 μL, 1.3 mmol) and DBU (200 μL, 1.3 mmol) were added, and the mixture was heated at 90° C. for 20 h. Solvent was removed and the residue was purified by preparative reverse phase HPLC (30%-60% gradient of CH3CN-water with 0.1% TFA) to afford the title compound as the trifluoroacetate salt.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: COc1ccccc1O
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: COc1ccccc1Oc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methoxy-phenol to give [1-(2-methoxy-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 333(MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[N:19][C:18]=3[C:17]([O:33][CH3:34])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35].CO>>[ClH:35].[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([NH:23][C:20]2[S:21][C:22]3[C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=[C:17]([O:33][CH3:34])[C:18]=3[N:19]=2)=[O:32])=[CH:30][CH:29]=1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCNCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Yield: 70 %

Procedure:
0.90 g (0.185 mMol) 4-[2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazol-7-yl]-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 3 ml 2.5 M HCl/MeOH and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo and taken up in 4 ml isopropanol. The suspension formed was filtered and the material on the filter was washed with diethyl ether and dried in vacuo. One obtained 55 mg (70%) 4-fluoro-N-[4-methoxy-7-piperidine-4-yl-benzothiazol-2-yl]-benzamide hydrochloride (1:1) as a white solid. F.p.: 310-312° C.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+].[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C@H:44]2[CH2:49][CH2:48][C@H:47]([CH:50]=O)[CH2:46][CH2:45]2)=[CH:40][CH:39]=1)#[N:37]>O>[F:2][CH2:3][CH2:4][CH:5]=[CH:50][C@H:47]1[CH2:48][CH2:49][C@H:44]([C:41]2[CH:42]=[CH:43][C:38]([C:36]#[N:37])=[CH:39][CH:40]=2)[CH2:45][CH2:46]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc([C@H]2CC[C@H](C=CCCF)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (10.0 g, 24.8 millimols) with THF (50 ml) was cooled down to -20° C., followed adding t-BuOK (3.1 g, 27.3 millimols) to the mixture, stirring the resulting mixture for 30 minutes, dropwise adding to the mixture, a THF (60 ml) solution of trans-4-(4-cyanophenyl)cyclohexanecarbaldehyde (5.8 g, 27.3 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, adding water (50 ml) to the reaction product after completion of the reaction, extracting the product with ethyl acetate (300 ml), three times washing the resulting organic layer with water, drying it over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and subjecting the residue to silica gel column chromatography (eluent: toluene), to obtain raw 4-(trans-4-(4-fluorobutenyl)cyclohexyl)benzonitrile (5.0 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:8]1[C:6]2=[N:7][C:2]([Br:1])=[CH:3][C:4]([CH3:13])=[C:5]2[N:10]=[C:9]1[CH2:11][CH3:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCc1nc2nc(Br)cc(C)c2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(Br)nc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
To a solution of 10 g (39 mmol) of the product of Step C in DMF (70 mL) at rt was added NaH (1.3 g of an 80% oil dispersion, 43 mmol). After 20 minutes benzyl bromide (5.15 mL, 43 mmol) was added and the reaction was stirred for 16 hours. The mixture was poured onto 500 g of ice and the solid residue was filtered, washed with water and air dried to give 13 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=[CH:14]2>CC(C)=O.[OH-].[Na+]>[NH2:1][C:2]1[N:7]=[C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=[CH:14]3)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Nc1nc(Cl)cc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Temperature: 62 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6.56 g (40 mMol) 2-amino-4,6-dichloropyrimidine and 7.52 g (40 mMol) 6-hydroxy-1-naphthoic acid in 160 ml acetone and 80 ml 1 N aqueous NaOH is heated to 62° C. for 36 h. The mixture is cooled to rt, partially concentrated in vacuo and the residue poured into 1.6 l icewater. Under vigorous stirring, 20 ml 2 N HCl are added dropwise (pH≈4). After stirring the suspension for 30 min, the title compound is filtered off and washed with water; HPLC: tRet=12.8.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:13][C:14]([F:41])([F:40])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1.S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O>[F:13][C:14]([F:40])([F:41])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[O:36])=[CH:33][CH:32]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A solution of 31.4 g. of benzenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise, with stirring and cooling, to a suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide during 30 minutes at room temperature. Stirring is continued for 30 minutes. In the meantime, a mixture of 36.2 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid in 100 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated and to the resulting oil residue is added, in one portion, the previously prepared mixture of sodium benzenesulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes, without cooling, and then filtered. The filtrate is poured into 2 liters of water and 250 ml. of saturated sodium chloride solution. The product is collected by filtration and then dissolved in methylene chloride, the mixture is filtered through diatomaceous earth, and brine is added to break the emulsion. The layers are separated, the organic phase is dried and evaporated. The residue is crystallized from toluene to yield the product as a white solid.
Reaction SMILES: N1C=CN=C1.[NH2:6][C@H:7]([C:11]([OH:13])=[O:12])[CH2:8][CH2:9][OH:10].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C=O)C>[NH2:6][CH:7]([CH2:8][CH2:9][O:10][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](CCO)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC(N)C(=O)O
Reaction time: 0.25 h

Procedure:
Imidazole (20.4 g, 300 mmol) is added to a solution of homoserine (11.9 g, 100 mmol) in DMF (100 mL) and the solution is stirred 15 minutes then cooled to 0° C. tert-Butyldimethylsilyl chloride (13.7 g, 91 mmol) added and the mixture is stirred for ten minutes at 0° C. the for 4 hours at room temperature. The reaction mixture is poured into water (3 L) and the resulting solid is collected by filtration. The isolated product is dried and used without further purification.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]([NH:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)(=[O:22])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.1 %

Procedure:
Into a DCM solution (50 mL) of tert-butylamine (5.9 mL, 56.5 mmol) and triethylamine (7.16 mL, 51.3 mmol) at 0° C. was slowly added a DCM solution (20 mL) of 4-fluoro-benzenesulfonyl chloride (10 g, 51.3 mmol), and the reaction stirred at RT for 19 h. The reaction was concentrated and the resulting solid recrystalized from ether/hexanes to get the product (9.5 g, 80%)as white crystals. MS: APCI (AP+): 230.1 (M)+.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])([O-:7])=[O:6].[CH3:18]O>>[N+:5]([C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:18])=[O:11])([O-:7])=[O:6]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
Thionylchloride (253 mL) was added dropwise to 3 1 methanol at 0°-10° C. Toward end of the addition, the temperature was allowed to rise to 20° C. Solid 2-nitro-3-methylbenzoic acid (500 g) was charged in one portion and the reaction mixture was heated to reflux overnight. It was distilled until pot reached 73° C. After cooling to 60° C., 685 mL water was introduced dropwise and the reaction mixture was cooled to 20° C. Upon adding 26 mL water and 125 mL 80% NaOH, the pH was adjusted to 7. The product was collected by filtration and washed with 3×100 mL water and air dried overnight. Yield of methyl 2-nitro-3-methylbenzoate was 503.5 g (93.5%), mp 72° C.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]1=[O:16])([CH3:3])[CH3:2].[F:17][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[F:17][C:8]1[CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5](=[O:16])[N:4]([CH:1]([CH3:2])[CH3:3])[C:9]=1[CH3:10]
Reactant: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(C)n(C(C)C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
A mixture of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in Example 1(5) (2.23 g, 10.0 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (3.76 g, 10.6 mmol) in acetonitrile (80 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (300 mL), and extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with water (100 mL×6), brine (100 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=2/1˜1/1) to give 572 mg (24%) of the title compound as a yellow solid.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[S:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[S:13]1[CH:17]=[CH:16][C:15]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:14]1
Reactant: O=Cc1cccnc1Br
Reactant: OB(O)c1ccsc1
Agent: OBO
Product: O=Cc1cccnc1-c1ccsc1

Procedure:
2-(thiophen-3-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and thiophen-3-ylboronic acid (60 mg, 101.8 mg theoretical, 58.9%). LC-MS m/z 190.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.CN(C)C=O>O>[CH:7]([C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:16]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:5]=1)=[O:8]
Reactant: COC(=O)c1cccnc1F
Reactant: Cc1n[nH]cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccnc1-n1cc(C=O)c(C)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
A mixture of 3-methyl-1H-pyrazole-4-carbaldehyde (300 mg, 2.72 mmol), potassium carbonate (565 mg, 4.08 mmol), methyl 2-fluoropyridine-3-carboxylate (507 mg, 3.27 mmol) and dimethylformamide (2 mL) is stirred at 60° C. for 16 h. Water is added and the compound is extracted in ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and solvent is evaporated. The crude mixture is purified by normal phase Isco chromatography using hexane:ethyl acetate, 2:1 as eluent to yield 422 mg of the title compound. MS (m/z): 246 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[C:4]=1[CH3:12])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[F:11][C:5]1[C:4]([CH3:12])=[C:3]([CH:1]2[CH2:2][O:21]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C=Cc1ccc(C#N)c(F)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C2CO2)ccc(C#N)c1F
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-ethenyl-2-fluoro-3-methylbenzonitrile (4.60 g, 28.5 mmol) and mCPBA (85%, 12.3 g, 71.4 mmol) in 300 mL of DCM was stirred at room temperature for 120 hours. The reaction mixture was cooled to 0° C. and was washed subsequently with saturated NaHCO3 (50 mL), saturated Na2SO3 (50 mL), 5% NaOH (2×50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (petrol ether:EtOAc=20:1) to afford the title compound: 1H-NMR (400 MHz, CDCl3) δ ppm 7.36-7.39 (m, 1H), 7.04-7.06 (m, 1H), 3.92-3.94 (m, 1H), 3.15-3.17 (m, 1H), 2.57-2.59 (m, 1H), 2.30 (d, J=2.0 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:16][CH:17]=[CH:18][C:5]=3[C:4](=[O:19])[N:3]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][NH2:29])[CH:8]=[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]1=2.[C:30]1([C:47](O)=[O:48])[C:43]2[C:34](=[CH:35][C:36]3[C:41]([C:42]=2[C:44](O)=[O:45])=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:16][CH:17]=[CH:18][C:5]=3[C:4](=[O:19])[N:3]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][N:29]1[C:47](=[O:48])[C:30]3[CH:31]=[CH:32][CH:33]=[C:34]4[C:43]=3[C:42](=[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]3=[CH:35]4)[C:44]1=[O:45])[CH:8]=[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]1=2
Reactant: O=C(O)c1cccc2cc3ccccc3c(C(=O)O)c12
Reactant: NCCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Solvent: Cc1ccccc1
Product: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A mixture of 1.0 g (2,5 mmol) of N-[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-N'-(2-aminoethyl)-1,3-propanediamine in 50 ml of toluene was treated with 0.62 g (2,5 mmol) of anthracene-1,9-dicarboxylic acid anhyride in 10 ml of toluene, refluxed for 6 hours, and cooled to room temperature. The solid was collected, dried in vacuo, and crystallized from toluene to give 0.8 g 48% of N,N'-Bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine. M.p. 191° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:12]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[OH:11])[C:5]([OH:7])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1ccc(O)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(O)c(-c2ccccc2)c1
Temperature: 45 °C
Yield: 67 %

Procedure:
3-Bromo-4-hydroxybenzoic acid (500 mg, 2.30 mmol, 1 eq.), phenylboronic acid (281 mg, 2.30 mmol, 1 eq.), palladium(II)acetate (16 mg, 0.069 mmol, 0.03 eq.) and 1.5M cesium carbonate (aqueous) (4.61 mL) were dissolved in DMF (10 mL) at room temperature under nitrogen then heated at 45° C. for 20 hours. Worked up by adding water (10 mL) then adjusting to pH=3 with 1N HCl. Extracted the acidic aqueous 3 times with ethyl acetate. The ethyl acetate layers were combined and rinsed 3 times with water (10 mL). The ethyl acetate layer was then dried over sodium sulfate and stripped to an oil. The oil was purified over silica gel in 1:1 hexanes/ethyl acetate. Obtained 3-phenyl-4-hydroxybenzoic acid (330 mg) as an oil which eventually solidified. Yield=67%. LCMS detects (M+H)+=257.23.