Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].[NH2:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(O)C>[C:30]([O:29][C:27]([CH2:26][O:25][N:24]=[C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)[CH3:2])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CON
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Solvent: CCO
Product: CC(=NOCC(=O)OC(C)(C)C)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Yield: 125.8 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g) and tert-butyl aminooxyacetate (0.71 g) in ethanol (5 ml) was refluxed for 13 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residual oil was suspended in ether and the insoluble material was filtered off. The filtrate was concentrated to give an cil of 4'-[1-(tertbutyloxycarbonylmethoxyimino)ethyl]-2'-(2,4-difluorophenoxy)methanesulfonanilide (2.6 g).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=[O:10].[Na+].[Na+].[O-][Mn](=O)(=O)=O.[K+]>CC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:10])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(Br)s1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
5-Bromo-2-thiophenecarboxaldehyde (1.0 g;5.24 mmol) was dissolved in acetone (4 ml) and treated with 20% Na2CO3 (aq) (0.53 ml). KMnO4 (0.827;5.24 mmol) was added portionwise and the solution stirred for 1 hour at RT. The reaction mixture was filtered through kieselguhr and the filtrate treated with H2O2 (0.8 ml of a 27% solution in water). When all effervesence had ceased, the aqueous was acidified with conc.HCl(aq) and a yellow solid precipitated. The suspension was extracted with EtOAc, the extracts combined and dried over Na2SO4, filtered, and the filtrate evaporated in vacuo to a yellow liquid. The liquid was diluted with hexane and cooled to -78° C. The solid that formed was collected by filtration and dried to yield the title compound as a pale yellow solid (0.3 g;28%).
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([NH:26][NH:27][C:28]([NH:30][CH3:31])=O)=O)[CH2:7]1)(=[O:4])=[O:3].O.N.[S:34](=O)(=O)(O)O>>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]2[S:34][C:28]([NH:30][CH3:31])=[N:27][N:26]=2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: CNC(=O)NNC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: O
Product: CNc1nnc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of (2S, 4R)-4-methanesulfonyloxy-2-(4-methylsemicarbazidocarbonyl)-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (2.00 g) in concentrated sulfuric acid (20 ml) was stirred at 0°-5° C. for 3 hours. The reaction mixture was poured into ice-water (200 ml), adjusted to pH 9 with concentrated ammonia water, extracted with dichloromethane (100 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99,V/V) to give (2S, 4R)-4-methanesulfonyloxy-2-{5-(methylamino)-1,3,4-thiadiazol-2-yl }-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.94 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:16])=[C:6]([Cl:15])[CH:7]=[C:8]([CH:12](Cl)[CH3:13])[C:9]=1[O:10][CH3:11].[CH3:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[N:24][C:25]=2[NH2:27])[NH:20][N:19]=1>CN(C)C=O.C(Cl)Cl>[Br:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([CH:12]([N:20]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:27])=[C:26]3[C:18]([CH3:17])=[N:19]2)[CH3:13])[CH:7]=[C:6]([Cl:15])[C:5]=1[CH3:16]
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (36 mg, 0.91 mmol) was added to a mixture of 3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (150 mg, 0.503 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.76 mmol) in N,N-dimethylformamide (8 mL) and the reaction was stirred at 30° C. overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 70% EtOAc in CH2Cl2 (103 mg, 50%). LCMS calculated for C16H18BrClN5O (M+H)+: m/z=410.0; Found: 410. The racemic products were applied on a Phenomenex Lux-Cellulose 1 column (21.1×250 mm, 5 micron particle size), eluting with 5% ethanol in hexanes at a flow rate of 18 mL/min, ˜13 mg/injection, to provide two enantiomers.
Reaction SMILES: CCCCCC.[O-:7][CH2:8][CH3:9].[Na+].Cl[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1>C(O)C>[CH2:8]([O:7][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH3:9]
Reactant: CC[O-]
Reactant: Clc1nc2ccccc2s1
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: CCOc1nc2ccccc2s1
Temperature: 25 °C

Procedure:
Exactly 5.8 g of hexane-wet sodium spheres (0.02 mole) was carefully dissolved in 100 ml of anhydrous ethanol. To the resulting cooled sodium ethoxide solution, stirring at 25° C. under nitrogen, was added a solution of 33.8 g (0.2 mole) of 2-chlorobenzothiazole in 100 ml of ethanol over a seven minute interval. There was a strong exotherm during this addition. The reaction mixture was heated to a reflux over 15 min and held at reflux for one hour. The apparatus was then fitted for downward distillation and the ethanol distilled from the reaction mixture at atmospheric pressure over a period of one hour. The cooled oily residue was dissolved in 50 ml of methylene chloride and rapidly stirred for 10 min with 400 ml of water. The organic layer was separated, dried over anhydrous potassium carbonate and stripped of solvent under vacuum. The crude product was distilled under reduced pressure to give 33.15 g (93%) of analytically pure 2-ethoxybenzothiazole, b.p. 78°-80° C., 0.11mm. (lit b.p. 80°-81°, 0.2 mm.) : UV (MeOH):λmax 218 nm (ε=31,100),λmax 245 nm (ε=7,800),λmax 277 nm (ε=1,100),λmax 287 nm (ε=1,060).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:41])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:42]([NH:52][C@H:53]([C:61](O)=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].N>ClCCl.CO>[C:42]([NH:52][C@H:53]([C:61]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:41])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 53 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-L-phenylalanine. Yield 53%. Rf 0.29 (dichloromethane/methanol/conc. ammonia 15:1:0.1).
Reaction SMILES: Cl.C(OCC)(=O)C.C(OCC)(=O)C.C(OC(=O)[NH:20][C@@H:21]([CH2:36][O:37]CC1C=CC=CC=1)[CH2:22][O:23][CH2:24][C:25](=O)[C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)(C)(C)C>[H][H]>[F:34][C:28]1[CH:27]=[C:26]([C@H:25]2[NH:20][C@@H:21]([CH2:36][OH:37])[CH2:22][O:23][CH2:24]2)[CH:31]=[C:30]([F:32])[C:29]=1[F:33]
Reactant: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1cc(F)c(F)c(F)c1)COCc1ccccc1
Reactant: [H][H]
Agent: Cl
Solvent: CCOC(C)=O
Product: OC[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A 4 N hydrochloric acid-ethyl acetate solution (30 mL) was added to an ethyl acetate solution (30 mL) of {(S)-1-benzyloxymethyl-2-[2-oxo-2-(3,4,5-trifluorophenyl)ethoxy]ethyl}carbamic acid tert-butyl ester (3.55 g) at room temperature. The resulting reaction solution was stirred at room temperature for 1 hr and then concentrated under reduced pressure. To a methanol solution (50 mL) of the obtained residue, 10% palladium-carbon (containing 50% water, 167 mg) was added. The resulting reaction solution was stirred in hydrogen atmosphere at room temperature for 18 hr, and the palladium carbon in the reaction solution was removed by filtration. The filtrate was concentrated under reduced pressure, and a saturated sodium hydrogencarbonate aqueous solution and ethyl acetate were added thereto. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) to give 1.52 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([NH:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[N:8][C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:5]=2[CH2:4][NH:3]1.[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>>[F:35][C:10]1[C:5]2[CH2:4][NH:3][C:2](=[O:1])[C:6]=2[C:7]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[N:8][C:9]=1[NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)NC3)c1
Yield: 46 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (94 mg, 0.208 mmol) and SELECTFLUOR® (73.7 mg, 0.208 mmol) was stirred at 0° C. for 5 h and at RT for 1 h. The mixture was filtered and the filtrate was purified by preparative HPLC. The fractions were collected and concentrated. The residue was washed with saturated aq NaHCO3 solution, extracted with EtOAc, washed with brine, dried over MgSO4, and evaporated to give the title compound as yellow solid (45 mg, 46.0%). [M+H] calc'd for C25H32FN5O3, 470. found, 470.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH:38]1[CH2:42][CH2:41][CH2:40][O:39]1>CN(C)C=O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:37][CH:38]1[CH2:42][CH2:41][CH2:40][O:39]1)[C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]2
Reactant: CCOC(=O)c1cc2cc(OCCc3nc(-c4ccccc4)sc3C)ccc2[nH]1
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCc3nc(-c4ccccc4)sc3C)ccc2n1CC1CCCO1
Reaction time: 16 h
Yield: 40.4 %

Procedure:
A solution of ethyl 5-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]-1H-indole-2-carboxylate 220 (40.7 mg, 0.100 mmol) in N,N-dimethylformamide (0.9 mL) was added to a stirred mixture of cesium carbonate (325 mg, 1.00 mmol) and 2-(bromomethyl)tetrahydrofuran (19.8 mg, 0.120 mmol) in N,N-dimethylformamide (2.4 mL). The reaction was stirred for 16 h and then the mixture was filtered though a plug (500 mg) of silica gel using ethyl acetate to rinse. The filtrate was concentrated in vacuo and then reverse phase preparative HPLC chromatography gave 19.8 mg of product (retention time=2.4 min.). This material was taken to the next reaction without further purification or analysis.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(O)C>[CH3:4][O:3][C:1](=[O:2])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:18][C:17]2[CH:19]=[CH:20][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: COC(=O)c1ccc(C=Nc2ccc(Cl)cc2)cc1
Temperature: -10 °C

Procedure:
165 g (1 mole) of 4-carbomethoxybenzaldehyde and 128 g (1 mole) of 4-chloroaniline were stirred in 2500 ml of ethanol for 3 hours on a weak reflux, when cooled to -10°C, filtered with suction and washed with ethanol having a temperature of -10° C. After drying, 227 g (83% of the theory) of 4-(p-chlorophenylimino-methyl)-benzoicacid methyl ester of the following formula were obtained ##STR42##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:40]1([S:50](Cl)(=[O:52])=[O:51])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14]([S:50]([C:40]1[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=[CH:42][CH:41]=1)(=[O:52])=[O:51])[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc2ccccc12)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.015 g, 0.04 mmol) and Et3N (0.01 ml, 0.07 mmol) in anhydrous THF (0.35 ml) was added to a solution of 1-naphthalenesulfonyl chloride (0.04 mmol) in anhydrous THF (0.4 ml) at rt in a sealed reaction vessel. The resulting suspension was stirred at rt for 20 hr, then evaporated to dryness. The product was suspended in a mixture of H2O(0.4 ml) and saturated NaHCO3 solution (0.4 ml), then extracted with CH2Cl2 (3×0.75 ml). The combined extracts were evaporated to dryness to give the crude product. Purification by reverse-phase HPLC on a Primesphere C-18HC (50.0 mm×10.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN 1% TFA/H2O (85:10:5), increasing to H2O:CH3CN:1% TFA/H2O (5:90:5) at 8 min., detected on a Micromass Platform 2 mass spectrometer (DAD 190-600 nM) gave material which, after evaporation to dryness, was purified by reverse-phase HPLC on a Primesphere C-18HC (3.0 mm×2.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:TFA (99.9:0:0.1), increasing to H2O:CH3CN:TFA (0:99.9:0.1) at 4 min., detected with a UV detector (300 nM +/−90 nM and 254 nM +/−25 nM), gave an eluent that was evaporated to dryness to give the named product. MS m/e 583 (M++1).
Reaction SMILES: [C:1]([O:7][CH:8]([C:13]([Br:16])([Br:15])[Br:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].S([N:27]=[N+:28]=[N-])(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C>C(#N)C>[N+:27](=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH:8]([C:13]([Br:14])([Br:15])[Br:16])[CH:9]=[C:10]([CH3:11])[CH3:12])=[O:6])=[N-:28]
Reactant: CC(=O)CC(=O)OC(C=C(C)C)C(Br)(Br)Br
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)=CC(OC(=O)CC(=O)C=[N+]=[N-])C(Br)(Br)Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methyl-1-tribromomethyl-2-butenyl acetoacetate (8.32 g, 0.0198 mole) and tosyl azide (3.9 g, 0.0198 mole) in 40 ml of acetonitrile was added dropwise over a period of 35 minutes a solution of triethylamine (2.0 g, 0.020 mole) in 10 ml of acetonitrile. The resulting mixture was stirred at room temperature for 21/2 hours to give 3-methyl-1-tribromomethyl-2-butenyl diazoacetoacetate. Then 60 ml of 1 N aqueous sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then diluted with ether, the organic phase was separated, the aqueous phase was extracted with ether, and the organic phases were combined. The ethereal solution was washed with three successive portions of 3% aqueous potassium hydroxide containing sodium chloride, then three times with saturated aqueous sodium chloride. The washed ethereal solution was dried over magnesium sulfate and treated with active charcoal. Evaporation of the ether afforded an oily residue. 3-Methyl-1-tribromomethyl-2-butenyl diazoacetate (5.78 g, 71% yield) was isolated therefrom by column chromatography.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12](OC)=[O:13])[C:3]=1[C:16]([O:18]C)=O.O.[NH2:21][NH2:22]>C(O)C>[OH:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12](=[O:13])[NH:21][NH:22][C:16](=[O:18])[C:3]=12
Reactant: COC(=O)c1nc2ccccc2c(O)c1C(=O)OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c(=O)c2c(O)c3ccccc3nc12
Yield: 112.8 %

Procedure:
To a stirred suspension of dimethyl 4-hydroxyquinoline-2,3dicarboxylate (1.00 g, 3.83 mM, prepared as described by H. Biere and W. Seelen, Liebigs Ann. Chem. 1976, 1972) in ethanol (15 mL) was added hydrazine hydrate (9.64 g, 193 mM) whereupon the solids dissolved. The resulting solution was refluxed for 3 hr during which time a thick precipitate formed. The cooled reaction mixture was filtered and the collected yellow solids were washed with ethanol and then ether. Air drying provided 0.99 g of the hydrazine salt of 2,3-dihydro-10-hydroxypyridazino[4,5-b]quinoline-1,4-dione. This material was boiled in glacial acetic acid (40 mL) and, after cooling to room temperature, the mixture was filtered. The collected solids were washed with several portions of ethyl acetate and then ether. Air drying provided the title pyridazinodione (0.72 g, 82%) as a yellow solid, mp >400° C.; Mass Spectrum (Chemical Ionization): 230 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: O=Cc1sccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Brc1ccsc1C1OCCO1
Yield: 74.1 %

Procedure:
3-Bromothiophen-2-aldehyde (2) (7.44 g, 39 mmol), ethylene glycol (2.7 ml, 48 mmol), anhydrous benzene (130 ml) and a few crystals of p-toluenesulphonic acid were refluxed in a Dean-Stark apparatus until no more water separated. The benzene layer was washed with a solution of bicarbonate, dried (Na2SO4), and evaporated under reduced pressure to give the derivative 3 (6.8 g, 28.9 mmol, 74% yield) as an oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[Cl:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:27][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCN(C(=O)c2cccc(Br)n2)CC1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2cccc(Oc3ccc(Cl)c(Cl)c3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.1 %

Procedure:
To a solution of (6-bromo-pyridin-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone (76.7 mg, 0.25 mmol) in DMF (2.5 mL) was added 3,4 dichlorophenol (40.07 mg, 0.25 mmol) and K2CO3 (101.93 mg, 0.74 mmol). After 18 h at 120° C., the mixture was cooled to rt, diluted with water, and extracted with DCM. Purification by FCC followed by reverse phase HPLC (basic conditions) provided the desired product (10.0 mg, 3.5%). MS (ESI): mass calcd. for C19H21Cl2N3O2, 393.10; m/z found, 394.3 [M+H]+. 1H NMR (CDCl3): 7.82 (dd, J=8.2, 7.4 Hz, 1H), 7.52-7.44 (m, 2H), 7.26 (d, J=2.7 Hz, 1H), 7.06-6.98 (m, 2H), 3.75-3.67 (m, 2H), 3.50-3.44 (m, 2H), 2.70-2.61 (m, 1H), 2.55-2.48 (m, 2H), 2.23-2.15 (m, 2H), 1.01 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:25])=O.O>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([Cl:25])=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3-Di-cyclopropylmethyl-8-nitro xanthine (6 g, 0.023 mol) was dissolved in dimethylformamide (20 ml) and reacted with phosphorus oxychloride (14 g), for 1 hour at 120° C. The mixture was then treated with water and stirred for 1 hour at room temperature. The precipitate was filtered off, dissolved in ethyl acetate, dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yield 2.5 g (40%), m.pt. 220° C.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:24]([F:27])([F:26])[F:25])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:19]1[CH:23]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=1[C:24]([F:27])([F:25])[F:26])=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 5-fluoro-2-(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ PPM 0.89 (t, 3 H) 1.28-1.37 (m, 2 H) 1.56-1.63 (m, 2 H) 2.18 (s, 3 H) 2.21 (s, 3 H) 3.90-3.97 (m, 2 H) 5.99 (2, 1 H) 7.36-7.44 (m, 2 H) 7.79-7.83 (m, 1 H); MS (ESI) m/z 374 (M+H)+.