Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[F:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:20])[N:9]=2)[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: C[O+](C)C
Reactant: COC(=O)c1ccc(F)c2[nH]ncc12
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c2nn(C)cc12
Reaction time: 5 h
Yield: 66.8 %

Procedure:
To a solution of methyl 7-fluoro-1H-indazole-4-carboxylate (2.93 g, 15.1 mmol) in ethyl acetate (60 mL) was added trimethyloxonium tetrafluoroborate (2.90 g, 19.6 mmol) at room temperature, and the mixture was stirred for 5 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (2.10 g, yield 67%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.Cl.[CH2:12]([N:16]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Cl)[CH3:17])[CH:13]([CH3:15])[CH3:14].[OH-].[Na+]>C(O)C>[CH2:12]([N:16]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][S:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2)[CH3:17])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CN(C)c1ccccc1CCl
Reactant: Sc1nc2ncccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CN(C)c1ccccc1CSc1nc2ncccc2[nH]1

Procedure:
2-Mercaptoimidazo[4,5-b]pyridine and 2-(N-isobutyl-N-methylamino)benzyl chloride hydrochloride were reacted in an aqueous ethanol solution in the presence of sodium hydroxide to obtain 2-[2-(N-isobutyl-N-methylamino)benzylthio]imidazo[4,5-b]pyridine in the same manner as in Example 1-(2). The obtained 2-[2-(N-isobutyl-N-methylamino)benzylthio]imidazo[4,5-b]pyridine was oxidized by m-chloroperbenzoic acid in chloroform in the same manner as in Example 9-(3) to give 2-[2-(N-isobutyl-N-methylamino)benzylsulfinyl]imidazo[4,5-b]pyridine as a pale yellow crystalline product. m.p.: 116°-118° C. (decompn.)
Reaction SMILES: N1(C([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:23](=[O:24])[NH:22][C:21]4[C:16]3=[N:17][C:18]([N:25]3[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[N:27]=[CH:26]3)=[N:19][CH:20]=4)[CH2:11][CH2:10]2)=O)C=CN=C1.Cl>CS(C)=O.CCOC(C)=O>[N:25]1([C:18]2[N:17]=[C:16]3[C:21]([NH:22][C:23](=[O:24])[N:15]3[C@H:12]3[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]3)=[CH:20][N:19]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: O=C(O[C@H]1CC[C@H](n2c(=O)[nH]c3cnc(-n4cnc5ccccc54)nc32)CC1)n1ccnc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]c2cnc(-n3cnc4ccccc43)nc2n1[C@H]1CC[C@H](O)CC1

Procedure:
trans-4-(2-(1H-benzo[d]imidazol-1-yl)-8-oxo-7,8-dihydropurin-9-yl)cyclohexyl 1H-imidazole-1-carboxylate (30 mg) was dissolved in DMSO (6 mL) and treated with 1N HCl (5 ml) at 50° C. for 3 hours. The mixture was diluted with EtOAc and washed with brine three times. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to obtain 16 mg of the title compound. 1H-NMR (300 MHz, CDCl3) δ 10.0 (s, 1H), 8.9 (dd, 1H), 8.2 (s, 1H), 7.9 (dd, 1H), 7.6 (dd, 2H), 4.4 (m, 1H), 4.1 (s, 1H), 2.9 (m, 2H), 2.0 (m, 2H), 1.6 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:26]1[C:27]([CH3:43])=[C:28]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:29]=[CH:30][CH:31]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:17][CH2:16][CH:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:14]3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:35]([O:34][C:33]([NH:32][C:28]1[C:27]([CH3:43])=[C:26]([CH:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21])[CH2:14]5)=[CH:10][CH:11]=4)[NH:6][C:5]=3[CH:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[NH:1][CH2:2]2)[CH:31]=[CH:30][CH:29]=1)=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)C3)ccc12
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NCC(c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(N3CCC(O[Si](C)(C)C(C)(C)C)C3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl 3-(2-amino-1-(6-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (0.1010 g, 0.169 mmol) in 1,4-dioxane (4.82 mL) was added 50% ethyl 2-oxoacetate/toluene (0.067 mL, 0.337 mmol) at 10° C. The cold bath was removed, and the reaction was stirred to room temperature for 3 h. The reaction was concentrated in vacuo to give crude ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate which was used in the subsequent step. This was added to p-xylene (41.6 mL) and 10% Pd/C (0.310 g, 0.291 mmol). The reaction was heated to 125° C. for 4.5 hr and cooled to room temperature. The solution was filtered through a pad of CELITE® and rinsed with EtOAc (150 mL). The filtrate was washed with water (40 mL), dried over MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 120 g column eluting with 0-30% EtOAc/CH2Cl2. Appropriate fractions (20% elution) were combined, concentrated in vacuo to give the desired product (0.1487 g, 0.219 mmol, 15.0% yield) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][C:16]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15]2.N1C=CC=CC=1.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:16]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15]2
Reactant: COC(=O)Cc1cc2cc(Br)ccc2c(=O)[nH]1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1cc2cc(Br)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
Copper (II) acetate (67.5 mg, 0.371 mmol, 1.10 equiv.) and 4-fluorophenylboronic acid (95 mg, 0.675 mmol, 2.00 equiv.) were added to a stirred mixture of methyl 2-(6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (100 mg, 0.338 mmol) and pyridine (54.6 μl, 0.675 mmol, 2.00 equiv.) in CH2Cl2 (3 mL) and the mixture was stirred in air at room temperature overnight in the presence of 4 Å molecular sieves. 1 N HCl (3 mL) was added to the reaction mixture and extracted with DCM (2×5 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-15-20% EtOAc/hexanes to give 34 mg of methyl 2-(6-bromo-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21]>>[CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[C:19]3[S:15][C:16](=[O:21])[NH:17][C:18]3=[O:20])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CNc1ncnc2ccc(C=O)cc12
Reactant: O=C1CSC(=O)N1
Product: CNc1ncnc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 4-methylamino-quinazoline-6-carbaldehyde (intermediate 11) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:35][C:36]1[CH:37]=[N:38][C:39]2[CH2:40][CH2:41][N:42]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:43][C:44]=2[CH:45]=1>CN(C)C=O.ClCCl>[CH2:46]([N:42]1[CH2:41][CH2:40][C:39]2[N:38]=[CH:37][C:36]([NH:35][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=3)=[CH:45][C:44]=2[CH2:43]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Nc1cnc2c(c1)CN(Cc1ccccc1)CC2
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cnc3c(c2)CN(Cc2ccccc2)CC3)cc1Br
Temperature: 2.5 °C
Reaction time: 72 h
Yield: 49.2 %

Procedure:
3-Bromo-4-methoxybenzoic acid (270 mg; 1.17 mmol) was dissolved in N,N-dimethylformamide (5 ml), the solution was cooled to 0-5° C. and treated with 1-hydroxybenzotriazole(158 mg; 1.17 mmol) then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (224 mg; 1.17 mmol) and the mixture stirred at 0-5° C. for 0.5 h and treated with a solution of 3-amino-6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridine (255 mg; 1.06 mmol) in DMF (5 ml). The reaction mixture was stirred at ambient temperature for 72 h then diluted with dichloromethane (100 ml). The resulting mixture was washed with water (5×25 ml), saturated brine, dried (anhydrous magnesium sulfate) and evaporated to dryness in vacuo to yield a mobile, brown oil, which on trituration under 60-80° C. petroleum ether gave a biege powder, which was collected by filtration, washed with 60-80° C. petroleum ether and dried in air. Recrystallisation from ethyl acetate 60-80° C. petroleum ether gave the title compound as a beige powder (236 mg; 49%), m.p. 214-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:25]([O:29][C:30](=[O:33])[NH:31][NH2:32])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[CH3:26][C:25]([CH3:28])([O:29][C:30]([NH:31][NH:32][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])[C:9]([F:11])=[CH:10][C:2]=1[Cl:1])=[O:33])[CH3:27]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)Cl)c(Cl)cc2F)c1=O
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)NNC(=O)OC(C)(C)C)c(Cl)cc2F)c1=O
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoyl chloride (0.5 g) in tetrahydrofuran (20 ml) was added t-butylcarbazate (0.18 g) at ambient temperature. After 1 hour, the resulting mixture was concentrated under reduced pressure and the residue was subjected to column chromatography on silica gel eluted with a mixed solvent of ethyl acetate and hexane (2:3) to give the titled compound (0.48 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH3:12][C:13]([OH:19])([C:15]([CH3:18])(O)[CH3:16])[CH3:14]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][C:13]1([CH3:14])[C:15]([CH3:18])([CH3:16])[O:11][B:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]3[O:19][C:13]([CH3:14])([CH3:12])[C:15]([CH3:18])([CH3:16])[O:2]3)[CH:4]=2)[O:10]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(C)(O)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cccc(C3OC(C)(C)C(C)(C)O3)c2)OC1(C)C
Yield: 76.8 %

Procedure:
(3-formylphenyl)boronic acid (5 g, 33.3 mmol), 2,3-dimethylbutane-2,3-diol (19.70 g, 167 mmol) and p-toluensulfonic acid monohydrate (0.317 g, 1.667 mmol) were dissolved in toluene (278 mL) and refluxed with a Dean-Stark equipment for 3 h until reaction completion. The mixture was dried under reduced pressure and the residue diluted with AcOEt (250 mL) and washed three times with abundant water, once with saturated NaClaqueous (250 mL), anhydrified over Na2SO4 and the solvent removed under reduced pressure. The crude was purified via flash chromatography on silica gel using a Biotage 100G+50G SNAP with a gradient of hexane and AcOEt to give the title compound (8.5 g, 77%) as white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN(C)C=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][C:43]1([CH3:60])[C:47]2[C:48]([O:52][C:53]3[N:58]=[CH:57][C:56]([NH2:59])=[CH:55][N:54]=3)=[CH:49][CH:50]=[CH:51][C:46]=2[O:45][CH2:44]1>C(OCC)(=O)C>[CH3:42][C:43]1([CH3:60])[C:47]2[C:48]([O:52][C:53]3[N:54]=[CH:55][C:56]([NH:59][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:57][N:58]=3)=[CH:49][CH:50]=[CH:51][C:46]=2[O:45][CH2:44]1
Reactant: CC1(C)COc2cccc(Oc3ncc(N)cn3)c21
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
To a solution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (20.14 mg, 0.099 mmol) in N,N-dimethylformamide (1.5 mL) DIPEA (0.029 mL, 0.165 mmol) and TBTU (33.9 mg, 0.106 mmol) were added. The mixture reaction was stirred during 15 minutes at room temperature, then 2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinamine (Intermediate 65, 17 mg) was added. The reaction mixture was stirred during 48 hours at room temperature. The mixture was diluted with ethyl acetate (5 ml) and washed with brine (3×5 ml). The organic layer was separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel flash chromatography using a 10 g-SNAP column and cyclohexane/ethyl acetate from 100/0 to 40/60 as eluent to afford the title compound as a white solid (4.4 mg).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH2:30])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:2](=[O:4])[CH3:1])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
In a stream of nitrogen and under ice-cooling, 162 mg (1.44 mmol) of potassium t-butoxide was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.04 mmol) of 2-(3-benzyloxybenzamido)benzenesulfonamide produced in Reference Example 1, and the mixture was stirred for 1 hour. This solution was mixed with 121 mg (1.54 mmol) of acetyl chloride and stirred at room temperature for 3 hours. After completion of the reaction, this was neutralized by adding an ammonium chloride aqueous solution and then the solvent was evaporated. The resulting residue was extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 160 mg (yield: 35%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1)=[O:23]
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: COC(=O)c1ccc2nc(-c3c(-c4ccccc4)noc3C)cn2c1
Yield: 38 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using methyl 6-aminonicotinate instead of 2-aminopyridine, to the title compound (64 mg, 38%) which was obtained as a light yellow solid. MS: m/e=334.3 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([Br:15])=[C:9]([F:16])[C:8]=1[F:17].[C:18](=[O:20])=[O:19].Cl>O1CCCC1.O>[Br:15][C:10]1[C:11]([F:14])=[C:12]([F:13])[C:7]([C:18]([OH:20])=[O:19])=[C:8]([F:17])[C:9]=1[F:16]
Reactant: O=C=O
Reactant: Fc1c(F)c(Br)c(F)c(F)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(F)c(F)c(Br)c(F)c1F
Temperature: -70 °C
Yield: 81.5 %

Procedure:
n-Butyllithium (42 ml, 2.4M in hexane) was slowly added to a solution of 30.78 g 1,4-dibromo-2,3,5,6-tetrafluorobenzene in 200 ml tetrahydrofuran cooled to -70° C. under nitrogen. Solid carbon dioxide (about 12 g) was then added to the stirred mixture which was then allowed gradually to warm to 0° C. at which point 16 ml 6M hydrochloric acid and 16 ml water were added. The reaction mixture was concentrated and the residue extracted with methylene dichloride. The extract was washed with concentrated sodium chloride solution, dried (magnesium sulfate) and concentrated to dryness to give 22.23 g (81.5%) 4-bromo-2,3,5,6-tetrafluorobenzoic acid, m.p. 128°-135° C.
Reaction SMILES: Br.C([N:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12]C1C#N)(=O)C1C=CC=CC=1.N.[C:25]([OH:28])(=[O:27])[CH3:26]>O>[C:25]([C:26]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:10]=1)([OH:28])=[O:27]
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)C=CC(C#N)N2C(=O)c1ccccc1
Agent: Br
Agent: N
Solvent: O
Product: COc1ccc2nc(C(=O)O)ccc2c1
Temperature: 90 °C

Procedure:
270 ml of 48% hydrobromic acid are added to a solution of 217 g (0,747 mol) of 1-benzoyl-2-cyano-6-methoxy-1,2-dihydroquinoline in 270 ml of acetic acid, and the mixture is heated at reflux for 30 min. It is filtered and rinsed with diethyl ether, and the solid obtained is then suspended in 2 l of water and heated to 90° C. Aqueous ammonia is then added until the pH=8-9 and the mixture is filtered while hot. The filtrate is acidified at 50° C., by adding acetic acid until the pH=4-5, and is then cooled. The crystallized product is filtered off, rinsed with water and then recrystallized from 250 ml of acetic acid and rinsed with diethyl ether. 129 g of product are obtained.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:40])[C@H:11]([N:15]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[S:16]([C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH3:27])=[C:21]([CH3:28])[C:20]=1[CH3:29])(=[O:18])=[O:17])[C@@H:12]([OH:14])[CH3:13])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[OH:8][NH:9][C:10](=[O:40])[C@H:11]([N:15]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[S:16]([C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH3:27])=[C:21]([CH3:28])[C:20]=1[CH3:29])(=[O:18])=[O:17])[C@@H:12]([OH:14])[CH3:13]
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)NOCc2ccccc2)[C@H](C)O)c(C)c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)NO)[C@H](C)O)c(C)c1C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-hydroxybutyramide (1.25 g, 2.19 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran (100 mL) was added 10% Pd-C (0.7 g), and the resulting mixture was hydrogenated at atmospheric pressure for 60 min. The reaction mixture was degassed under argon and the slurry was filtered over Celite. The Celite cake was washed with ample 80% ethanol-methylene chloride and the filtrate was concentrated to almost dryness. The mixture was dissolved in 4 mL of ethyl acetate which was added slowly dropwise to 100 mL of vigorously stirring hexanes. The slurry was filtered to afford N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-hydroxybutyramide (0.67 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(F)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a solution of conc. H2SO4 (700 mL) was added portion-wise 5-fluoro-2-methylbenzoic acid (80 g, 520 mmol) at −5˜0° C. Then a mixture of conc. HNO3 (60.4 g, 624 mmol) in conc. H2SO4 (60 mL) was added drop-wise at −5˜0° C. in a period of about 1.5 hrs. After the addition, the mixture was stirred at this temperature for 2 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. The mixture was poured into crash ice with vigorous stirring and the precipitate was collected by filtration. The precipitate was dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4, concentrated to give crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g). A solution of this crude 5-fluoro-2-methyl-3-nitrobenzoic acid (54 g) in dry methanol (500 mL) was cooled to 0° C., SOCl2 (64.52 g, 542.3 mmol) was added drop-wise. After the addition, the mixture was heated to reflux for 16 hrs. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. Solvent was removed under reduced pressure to give crude product. The crude product was purified by silica gel chromatography (petroleum ether to petroleum ether/EtOAc=50:1) to give methyl 5-fluoro-2-methyl-3-nitrobenzoate (28 g, yield 25% for two steps) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.59 (s, 3H), 3.95 (s, 3H), 7.60-7.63 (dd, 1H), 7.74-7.77 (dd, 1H); LC-MS (ESI) m/z: 214 (M+1)+, 216 (M+3)+.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[CH2:29][N:28]([S:30]([O-:33])(=[O:32])=[O:31])[C:27]1=[O:34])=O)(C)(C)C>C(O)=O.C(Cl)Cl>[NH2:25][C@H:26]1[CH2:29][N:28]([S:30]([OH:33])(=[O:32])=[O:31])[C:27]1=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(S(=O)(=O)[O-])C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=CO
Solvent: ClCCl
Product: N[C@H]1CN(S(=O)(=O)O)C1=O
Reaction time: 4 h
Yield: 51.9 %

Procedure:
(S)-3-[(t-Butoxycarbonyl)amino]-2-oxo-1-azetidinesulfonic acid, tetra-n-butylammonium salt (3.06 g) is dissolved in 18 ml of 97% formic acid, stirred for 4 hours, diluted with methylene chloride, filtered, washed and dried to give 0.52 g of the title compound; melting point 208°-210° C., dec.; [α]D21 =-39.9[c=2, water].
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:4]=2[S:3]1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:11])[C:9]([N+:17]([O-:19])=[O:18])=[CH:10][C:4]=2[S:3]1
Reactant: O=c1[nH]c2cc(Cl)ccc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2s1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
To a mixture of 2-oxo-5-chlorobenzothiazoline (465 g) in conc.sulfuric acid (500 ml) was added dropwise a solution of nitric acid (d=1.42, 275 g) in conc.sulfuric acid (500 ml) with stirring at 10° C. during an hour. After the stirring was continued for an hour under ice-cooling, to the resultant mixture was added ice-water (10 liters) to give crystals, which were separated by filtration, washed with water and dried to give 2-oxo-5-chloro-6-nitrobenzothiazoline (539 g).