Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.Cl.[C:15]([OH:18])(=[O:17])C.[CH3:19][NH:20]N.[C:22](O)(=O)C>>[C:7]1([C:6]2[N:20]([CH2:19][C:15]([O:18][CH3:22])=[O:17])[N:2]=[CH:4][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=NC(=O)c1ccccc1
Reactant: CC(=O)O
Reactant: CNN
Agent: Cl
Product: COC(=O)Cn1ncnc1-c1ccccc1
Yield: 96 %

Procedure:
N-[(Dimethylamino)methylene]benzamide (2.0 g, 0.011 mol) and methyl hydrazine acetate hydrochloride salt (1.9 g, 0.011 mol) were warmed in acetic acid at 90° C. for 11/2 hours. The acetic acid was evaporated under reduced pressure and the residue neutralised with saturated aqueous sodium bicarbonate, then extracted into chloroform (2×100 ml) washed with water, dried and evaporated under reduced pressure to give methyl [5-phenyl-1,2,4-triazol-1-yl]acetate as a clear oil (2.3 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:25]=[CH:24][C:13]2[C@:14]3([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=2[CH:11]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3.[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:3]4[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cc(F)c(F)cc3F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(F)c(F)cc4F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2,4,5-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (43 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (42 mg, 0.36 mmol). Methyl iodide (0.023 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 40 mg (89%) of the title compound as a foam. FDMS: m/e=359.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10]([OH:12])=O)[CH:7]=1.O=S(Cl)Cl.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:12])[CH:7]=1
Reactant: Cc1ccc(F)cc1C(C)(C)CC(=O)O
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 3-(5-fluoro-2-methylphenyl)-3-methylbutyric acid (3.80 g, 18.0 mmol) in 15 mL of dichloromethane was treated with SOCl2 (1.98 mL, 27.1 mmol) at 0° C. After 30 minutes, a mixture of morpholine (2.36 mL, 27.1 mmol) and pyridine (4.4 mL, 54.2 mmol) in 10 mL of dichloromethane was added to the reaction mixture at 0° C. After an additional 90 minutes, 60 mL of 2 M aqueous HCl solution was added, phases were separated and the aqueous layer was extracted with three 50 mL portions of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5.03 g of 3-(5-fluoro-2-methylphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one as an oil, which was used without further purification (quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([OH:15])=O)=[C:5]2[OH:16].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CC(N(C)C)=O.O>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:13]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[OH:16])=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=3)=[O:15])=[CH:32][CH:31]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2cc(F)c(F)cc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(F)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of 0.5 g of 6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid from preparation No. 15 and 0.435 g of carbonyldiimidazole in 8 mL of anhydrous dimethylacetamide is stirred 4 h at 65° C. The reaction mixture is cooled to 25° C. and 2 drops of distilled water is added. After an additional 10 min 0.34 mL of 4-chlorobenzylamine is added. The mixture is stirred 26 h at 25° C. and then diluted with 10 mL of distilled water. After standing for an additional 30 min the precipitate is collected by filtration and washed with three 10 mL portions of distilled water. The solid is dried in a stream of air and then at 20 torr/120° C./3 days. The yield is 0.51 g (70%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[F:13][C@H:14]1[CH2:16][C@H:15]1[C:17](O)=[O:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:17]([C@@H:15]3[CH2:16][C@@H:14]3[F:13])=[O:18])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc2ccc(Br)cc2cn1
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc2ccc(Br)cc2cn1)[C@@H]1C[C@@H]1F
Temperature: 50 °C
Reaction time: 18 h
Yield: 109.6 %

Procedure:
A mixture of 7-bromoisoquinolin-3-amine (4.531 g, 20.31 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (2.002 g, 19.24 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (12.148 g, 23.433 mmol), N,N-diisopropylethylamine (8.50 mL, 48.8 mmol), 4-dimethylaminopyridine (0.245 g, 2.00 mmol), and N,N-dimethylformamide (100 mL, 1000 mmol) was stirred at 50° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified via flash chromatography on silica gel (120 g silica, solvent gradient: 0-30% ethyl acetate in dichloromethane) to yield 6.5208 g of the title compound. LCMS (ESI): M+H=309.2.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:44][CH2:45]OC)CCC)(=[O:17])[CH3:16].O>CN(C)C=O>[ClH:27].[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[S:20][CH:19]1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:44]([CH3:45])[CH3:1])(=[O:17])[CH3:16]
Reactant: CCCN(CCCOc1ccc(OC)cc1C1Sc2cc(Cl)ccc2N1C(C)=O)CCOC
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CCCOc1ccc(OC)cc1C1Sc2cc(Cl)ccc2N1C(C)=O)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 180 %

Procedure:
Potassium carbonate (299 mg, 2.16 mmol) and ethyl bromoacetate (0.13 ml, 1.13 mmol) were added to a solution of 3-acetyl-6-chloro-2-[2-(3-(N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline (compound described in Example 3) (474 mg, 1.08 mmol) in anhydrous dimethylformamide at room temperature. The mixture was stirred at room temperature for 1.5 hours, water (30 ml) was added to the reaction mixture, and the whole was extracted with diethyl ether (50 ml). The organic layer was washed with water twice and saturated brine successively and dehydrated with anhydrous magnesium sulfate. Diethyl ether was evaporated under reduced pressure, and the obtained oily matter was purified by silica gel column chromatography (mobile phase:hexane/ethyl acetate=1/1). Methanol (2 ml) was added to the obtained oily matter, and a 10% solution (5 ml) of hydrogen chloride in methanol was added thereto with stirring under ice-cooling. The mixture was stirred at the temperature for five minutes, and the solvent was evaporatd under reduced pressure to give 542 mg (90%) of the target compound.
Reaction SMILES: [CH3:1][P:2]([CH3:4])[CH3:3].C([CH:7]([Br:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=C.O1CC[CH2:17][CH2:16]1>C(OCC)C>[Br-:14].[CH:16]([CH2:1][P+:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])[CH3:3])=[CH2:17]
Reactant: C=CC(Br)c1ccccc1
Reactant: C1CCOC1
Reactant: CP(C)C
Solvent: CCOCC
Product: C=CC[P+](C)(C)Cc1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
Trimethylphosphine (50.0 ml of a 1.0 molar solution in tetrahydrofuran, 5.00×10−2 mol) was added via addition funnel over about 2 minutes into a thoroughly nitrogen degassed dispersion of vinylbenzyl bromide (9.85 g, 5.00×10−2 mol) in diethyl ether (100 ml). A solid precipitate began to form almost immediately. The reaction was allowed to stir for 4 hours at room temperature, then was placed in a freezer overnight. The solid product was isolated by filtration, washed three times with 100 ml of diethyl ether, and dried under vacuum for 2 hours. Pure product (11.22 g) was recovered as a white powder (82.20% yield).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[N:21]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]4)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].[CH:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([CH3:41])[CH3:40].[CH3:48]C(N(C)C)=O>CN(C=O)C>[CH:39]([N:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:2][C:3]([NH:5][C:6]2[CH:7]=[C:8]([C:12]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]5)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:9]=[CH:10][CH:11]=2)=[O:4])[CH2:44][CH2:43]1)([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CCl)c4)nc4ccccc34)ccc21
Reactant: CC(=O)N(C)C
Reactant: CC(C)N1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)N1CCN(CCC(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A suspension of tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (112 mg, 0.223 mmol), 1-isopropylpiperazine (52 mg, 0.406 mmol), DMA (51 mg, 0.402 mmol) in DMF (2 mL) was stirred at 75° C. for 4 h. The reaction mixture was cooled to RT and the residue was poured into ice-water. The resulting white solid was filtered and dried for several hours under high vacuum. The crude product was purified by prep TLC using CH2Cl2:MeOH, (9:1) as the mobile phase to afford tert-butyl 5-(2-(3-(3-(4-isopropylpiperazin-1-yl)propanamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (60 mg, 0.094 mmol, 42%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]2[C:17]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]2[C:17]3[C:24]([Br:32])=[C:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)COC1CCCC(Nc2ncnc3oc(-c4ccccc4)cc23)C1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)COC1CCCC(Nc2ncnc3oc(-c4ccccc4)c(Br)c23)C1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
Suspend 1.65 g (3.9 mmol) of (+/−)-({3-[(6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-oxy)acetic acid tert-butyl ester in 4 ml of carbon tetrachloride and add 762 mg (4.3 mmol) of N-bromosuccinimide. Heat the reaction mixture under reflux for 1 h. After cooling to RT, add a further 350 mg of N-bromosuccinimide. Stir the reaction mixture under reflux again for 1 h, then cool and concentrate under reduced pressure. From the residue, after purification by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5:1), 0.99 g of the target product is isolated (50.6% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:12]([O:26]CC3C=CC(OC)=CC=3)=[N:11]2)=[CH:5][CH:4]=1.O1CCOCC1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:12](=[O:26])[NH:11]2)=[CH:5][CH:4]=1
Reactant: CCCCOC(=O)/C=C/c1cc(=O)n(Cc2ccc(OC)cc2)nc1OCc1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCOC(=O)CCc1cc(=O)n(Cc2ccc(OC)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of butyl (2E)-3-[1-{[4-(methyloxy)phenyl]methyl}-3-({[4-(methyloxy)phenyl]methyl}oxy)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-propenoate) (580 mg) in ethanol (15 ml)/1,4-dioxane (5 ml) was treated with 10% Pd/C (400 mg) and stirred under hydrogen at atmospheric pressure and rt for 2 h. The catalyst was filtered off using kieselguhr and the filtrate was evaporated and redissolved in 1,4-dioxane and the solution evaporated to dryness to give the product (0.43 g, 98%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].Cl.Cl.[CH2:23]([N:25]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1)[CH2:26][CH3:27])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].C>C(O)CC.Cl.Cl.C(N(CC1CCCCN1)CC)C.C(#N)C>[CH2:23]([N:25]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:26][CH3:27])[CH3:24]
Reactant: CCN(CC)CC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reaction time: 8 h
Yield: 65.1 %

Procedure:
A suspension of 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (276 g, 0.959 mol), and 2-[(diethylamino)methyl]piperidine dihydrochloride (244.95 g, 100.7 mol), of sodium carbonate (223.9 g, 2.112 mol) and acetonitrile (1.92 liters) are stirred for 6 hours at a reaction temperature of 70° C. After this time, the 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one has 95-97% reacted (TLC). The mixture is left to stand overnight at ambient temperature, then suction filtered. The contents of the filter are washed three times, each time with acetonitrile (60 ml). The dark colored filtrates are discarded. The remaining solid is stirred for a further 2 hours with water (1.5 liters), suction filtered again and washed with another water (300 ml) and finally dried at 40° C. in a circulating air drier. The crude product thus obtained (390 g) is transferred into a 10 liter flask, taken up in 1-propanol (5.14 liters) and, after the addition of 2-[(diethylamino)methyl]piperidine dihydrochloride (13.5 g, 0.0555 mol) and anhydrous sodium carbonate (11.8 g, 0.1113 mol), refluxed for 16 hours. After the addition of activated charcoal (39 g) the mixture is heated to boiling for a further 30 minutes and the boiling hot mixture is then forced through a SEITZ filter. Clarification is repeated twice more in the same way using activated charcoal (20 g). The filtrate is left to stand for 12 hours at ambient temperature, the precipitated crystals are suction filtered and washed twice, each time with 1-propanol (50 ml). The product is again stirred with cold 1-propanol (0.5 liters), suction filtered and again washed twice, each time with 1-propanol (50 ml). It is then dried in a circulating air drier at 40° C. and almost colorless crystals (263 g) are obtained, mp. 226°-227° C.
Reaction SMILES: [O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[C:28](O)(=[O:33])[CH2:29][C:30](O)=[O:31].P(Cl)(Cl)(Cl)=O>>[O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[OH:33][C:28]1[C:27]2[C:19](=[CH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[CH:26]=2)[NH:18][C:30](=[O:31])[CH:29]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(O)CC(=O)O
Agent: c1ccc(Oc2ccnc3ccccc23)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(O)c1ccc2[nH]c(=O)cc(O)c2c1

Procedure:
The 4-phenoxyquinoline core structure was synthesized according to a published procedure (42). The synthesis of compound 3 is described in FIG. 13. The synthesis began with stirring p-aminobenzoic acid with malonic acid and phosphorus oxychloride to yield 4-hydroxy-6-carboxy-2-(1H)-quinolinone. Reacting the quinolinone with dichloroiodobenzene is followed by refluxing with butanol produced 3-Iodo-4-phenoxyl-6-carboxyl-2-(1H)-quinolinone. Diodination of the 3-iodo quinolinone yielded compound 3.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[C:22]([C:24]#[N:25])[N:23]=2)=[O:18])=[C:12]([C:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=2)[CH:11]=1)[CH2:6][N:7]=[N+]=[N-])=[N+]=[N-].O.CO.[NH4+].[Cl-]>C1COCC1.[Zn]>[NH2:7][CH2:6][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[CH:21]=[C:22]([C:24]#[N:25])[N:23]=2)=[O:18])=[C:12]([C:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=2)[CH:11]=1)[CH2:4][NH2:1]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CN=[N+]=[N-])CN=[N+]=[N-])cc1C1=CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CN)CN)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(2-azido-1-azidomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared above, 546 mg, 1.00 mmol) was dissolved in THF (1 mL), water (2 mL) and MeOH (10 mL). To this solution NH4Cl (534 mg, 25.0 mmol) and Zn powder (653 mg, 10.0 mmol) were added with cooling. The resulting mixture was stirred at RT for 30 min and filtered through a thin pad of Celite. The filter cake was washed with MeOH (2×10 mL). The filtrate was concentrated, dissolved in 5% i-PrOH/DCM and washed with satd aq NaHCO3 (20 mL). The organic layer was dried (Na2SO4) and concentrated to obtain the title compound (207 mg, 42%): Mass spectrum (ESI, m/z): Calcd. for C26H38N6O2Si, 495.3 (M+H), found 495.2.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[C:15]([OH:16])=[CH:14][C:13]([O:17][CH2:18][CH2:19][OH:20])=[C:12]([N+:21]([O-])=O)[CH:11]=1.[OH-].[Na+]>O>[ClH:9].[NH2:21][C:12]1[CH:11]=[C:10]([Cl:9])[C:15]([OH:16])=[CH:14][C:13]=1[O:17][CH2:18][CH2:19][OH:20]
Reactant: O=[N+]([O-])c1cc(Cl)c(O)cc1OCCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cl
Product: Nc1cc(Cl)c(O)cc1OCCO

Procedure:
70 g of sodium hydrosulphite are added portionwise and with stirring to a solution of 32 g of 6-chloro-3-(β-hydroxyethoxy)-4-nitrophenol phenate and 75 ml of 10 N NaOH in 250 ml of water, the temperature being maintained in the region of 60°-65° C. After the mixture is cooled, the product is precipitated by neutralizing the reaction medium with acetic acid. The hydrochloride is obtained by dissolution in hydrochloric acid in the heated state and precipitation on cooling.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>CC#N>[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C(O)CCCl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To 3-Chloro-1-propanol (5.02 mL, 60 mmol) was added CH3CN (200 mL), p-toluenesulfonyl chloride (17 g, 90 mmol) and pyridine (7.3 mL, 90 mmol). The reaction mixture was stirred at room temperature for 12 hours under an atmosphere of argon. Saturated NaHCO3 (200 mL, aq) was added and stirring was continued for 15 minutes. The mixture was then poured into a separatory funnel and extracted several times with CH2Cl2. The CH2Cl2 extracts were combined and dried over Na2SO4. The CH2Cl2 layer was filtered and concentrated in vacuo to give 12.35 g (83.8%) of the title compound. TLC (Rf: 0.5; 20% EtOAc/Hexane). 1H NMR (CDCl3) δ 2.1 (m, 2H, CH2), 2.5 (s, 3H, CH3), 3.6 (t, 2H, CH2), 4.2 (t, 2H, CH2), 7.6 (d & d, 4H, Ar). 13C NMR (CDCl3) δ 21.4 (CH3), 31.5 (CH2), 40.2 (CH2), 66.7 (CH2), 127.8 (Ar), 129.8 (Ar), 132.5 (Ar), 144.9 (Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](SC)[N:6]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:12]=2)[CH:4]=1.OO[S:31]([O-:33])=[O:32].[K+].[C:35](OCC)(=O)C>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([S:31]([CH3:35])(=[O:33])=[O:32])[N:6]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:12]=2)[CH:4]=1
Reactant: O=S([O-])OO
Reactant: CCOC(C)=O
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(SC)n1
Agent: [K+]
Product: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(S(C)(=O)=O)n1

Procedure:
A mixture of EXAMPLE 1A (6.2 g, 15.0 mmol) and OXONE® (92 g, 150 mmol) in ethyl acetate (350 mL) was stirred at 77° C. for 2 days. The mixture was filtered and the solids were washed with dichloromethane and concentrated to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][CH2:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C=O)C>[Cl-:1].[CH3:30][N+:31]([CH3:38])([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][CH2:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)[CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CN(C)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCC3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+](C)(C)C4CCOCC4)cc2)CCC3)cc1
Product: [Cl-]
Reaction time: 23 h
Yield: 85.7 %

Procedure:
To a solution of N-(4-chloromethylphenyl)-2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (9.38 g, 23.3 mmol) in DMF (50 ml) was dropwise added a solution of N,N-dimethyl-N-tetrahydropyran-4-ylamine (4.5 g, 35.0 mmol) in DMF (50 ml). Under nitrogen atmosphere, the mixture was stirred for 23 hours. The solvent was evaporated to give powder, which was washed with acetone and dried. The resulting colorless powder was recrystallized from ethanol to give N,N-dimethyl-N-(4-(((2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl)carbonyl)amino)benzyl)-N-(4-tetrahydropyranyl)ammonium chloride (Compound 1) (10.6 g, 86%) as colorless powder.