Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[S:27][C:28]([S:32](Cl)(=[O:34])=[O:33])=[C:29]([CH3:31])[N:30]=1.O>N1C=CC=CC=1>[CH3:25][C:26]1[S:27][C:28]([S:32]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=2[CH3:24])[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)(=[O:34])=[O:33])=[C:29]([CH3:31])[N:30]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(C)c(S(=O)(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) in pyridine (4.0 mL) was added 2,4-dimethyl-1,3-thiazole-5-sulfonyl chloride (157 mg, 0.74 mmol), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) and washed with hexane/ethyl acetate to give the title compound (196 mg, 64%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([NH:8][CH3:9])[CH:7]=1.O.O.Cl[Sn]Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1cc(Cl)ccc1N

Procedure:
A mixture of (5-chloro-2-nitro-phenyl)-methyl-amine (59) (500 mg, 2.7 mmol, 1 eq), SnCl2.2H2O (3.0 g, 13.3 mmol, 5 eq) in ethyl acetate (25 ml) was refluxed overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated potassium carbonate solution. The organic phase was concentrated and the crude residue was purified with flash chromatography to give 4-chloro-N2-methyl-benzene-1,2-diamine (60).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH3:21][C:22]1[S:26][C:25]([C:27]#[N:28])=[CH:24][CH:23]=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:8][CH2:21][C:22]1[S:26][C:25]([C:27]#[N:28])=[CH:24][CH:23]=1
Reactant: Cc1ccc(C#N)s1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: N#Cc1ccc(CBr)s1
Temperature: 25 °C

Procedure:
1.69 kg (9.51 moles) of NBS and 156 g (0.95 moles) of AIBN were well mixed and placed in a vinyl wrapper (at this time, the previous reaction was regarded to be proceeded to 100%). The benzene solution of Example 2 was heated. The NBS-AIBN mixture was portionwise added to the heated solution at 73° C. for 40 minutes. The solution was refluxed for 1.5 hours after the addition was done. After confirming completion of the reaction by HPLC, the solution was cooled to room temperature. The reaction solution was washed with [1 L of H2O+4 L of 5% NaHCO3], and then [2 L of H2O+1 L of 5% NaCl].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH2:37]([C:40]1([CH2:50][CH:51]=[CH2:52])[CH2:49][N:43]2S(=O)(=O)O[CH2:46][C@H:42]2[CH2:41]1)[CH:38]=[CH2:39]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:46][C@H:42]1[CH2:41][C:40]([CH2:37][CH:38]=[CH2:39])([CH2:50][CH:51]=[CH2:52])[CH2:49][NH:43]1
Reactant: C=CCC1(CC=C)C[C@@H]2COS(=O)(=O)N2C1
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: C=CCC1(CC=C)CN[C@@H](Cc2c(Cl)cncc2Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a solution of 3,5-dichloropyridine (1.069 g, 7.22 mmol) in THF (12.04 ml) at −78° C. was added lithium diisopropylamide, 2.0 M heptane/THF/ethylbenzene (4.57 ml, 9.15 mmol) dropwise. After stirring for 1 h, a solution of (R)-5,5-diallyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (1.172 g, 4.82 mmol) in THF (10 mL) was added dropwise at −78° C. and the mixture was allowed to warm to room temperature with stirring for 6 h. After evaporating of the solvent, the resulting beige foam was treated with hot 2 N HCl (12 ml) and EtOH (12 ml) overnight. The mixture was cooled to room temperature and basified with 1 N NaOH and extracted with EtOAc. The extracts were dried, evaporated and purified by chromatography through a REDISEP™ pre-packed silica gel column (40 g), eluting with a gradient of 1% to 6% MeOH in DCM, to provide (R)-3,5-dichloro-4-((4,4-diallylpyrrolidin-2-yl)methyl)pyridine (0.70 g, 2.249 mmol, 46.7% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 2H), 5.66-5.86 (m, 2H), 5.03-5.18 (m, 4H), 3.59-3.72 (m, 1H), 3.25 (d, J=7.15 Hz, 1H), 2.97 (d, J=11.51 Hz, 1H), 2.82 (d, J=11.51 Hz, 1H), 2.10-2.28 (m, 4H), 1.78 (dd, J=13.06, 6.95 Hz, 1H), 1.51-1.61 (m, 1H); LCMS (ESI) m/z 311.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4Cl)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4Cl)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(2-chlorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 203°-206° C.) and piperazine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)#[CH:17]>C(#N)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:17]#[C:16][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:7]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1ccc(C#Cc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
Heat a suspension of 3,5-dibromopyridine (4.00 g, 16.88 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.59 g, 0.84 mmol) and copper (I) iodide (0.32 g, 1.69 mmol) in triethylamine (4.7 mL, 33.8 mmol) to 80° C. Add a solution of 1-ethynyl-4-fluorobenzene (2.03 g, 16.88 mmol) in acetonitrile (34 mL), stir for 2 h, cool to room temperature and dilute with ethyl acetate. Wash with an aqueous saturated solution of sodium bicarbonate, dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with a 1% solution of ethyl acetate in 1:1 chloroform:hexanes, and then recrystallize from methanol to give the title compound (2.4 g, 51.5%).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[C:19]([NH2:26])=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:13]=[CH:12]2)(C)(C)C.[C:29](O)(=O)C.C(N)=N>COCCO>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]4[C:16](=[C:7]([OH:6])[CH:8]=[CH:9][CH:10]=4)[N:15]=3)[CH:29]=[N:26][C:19]=2[CH:20]=1
Reactant: CC(=O)O
Reactant: COc1ccc(Nc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c(N)c1
Agent: N=CN
Solvent: COCCO
Product: COc1ccc2c(c1)ncn2-c1ccc2cccc(O)c2n1
Temperature: 125 °C

Procedure:
N1-[8-(tert-Butyl-dimethyl-silanyloxy)-quinolin-2-yl]-4-methoxy-benzene-1,2-diamine D (18.3 g, 46.1 mmol) was dissolved in 40 mL of 2-methoxyethanol under an atmosphere of dry N2. To this solution was added formamidine acetate (5.28 g, 50.7 mmol) and the reaction mixture was heated to 125° C. and reacted at this temperature for 1.5 hours. The solvent was removed under vacuum and the resulting solid was triturated with ethyl ether (Et2O), dried under vacuum to give 13.3 g of E as a pink solid.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.[CH:13]1C=CC=CC=1>[Rh].C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>[CH:5]([C:6]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH2:13])=[O:4]
Reactant: c1ccccc1
Reactant: CC(=O)OCC=CCOC(C)=O
Agent: [Rh]
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: C=C(C=O)CCOC(C)=O
Temperature: 85 °C
Yield: 90 %

Procedure:
A mixture of 1,4-diacetoxy-2-butene (170 g.), triphenylphosphite (0.51 g.), 5% rhodium on charcoal (1.12 g.) and benzene (340 g.) was loaded into a 1 liter stainless steel autoclave and heated with stirring to 85° C. The autoclave was then pressured to 2000 psig with synthesis gas. When gas uptake had ceased (approximately 3 hours), the autoclave was cooled to room temperature and vented. The reaction mixture was filtered and heated under vacuum until all the benzene had been removed. After the addition of p-toluenesulphonic acid (0.5 g.), the reaction product was heated in an oil bath at 105°-110° C. under a vacuum of 5 mm Hg. and the distillate so produced was collected and then fractionally distilled to give 2-formyl-4-acetoxybutene (126.3 g., 90% yield, b.p. 67°-72° C./ 6 mm Hg.).
Reaction SMILES: CN(C)C(=N)N(C)C.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[CH2:26]([O:28][CH:29]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>C(Cl)(Cl)Cl>[CH2:33]([O:32][C:30](=[O:31])[C:29]([O:28][CH2:26][CH3:27])=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1)[CH3:34]
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Tetramethylguanidine (42.3 g; 0.37 mole) was slowly added to a solution of 4-benzyloxybenzaldehyde (75.6 g; 0.36 mole) and (1,2-diethoxy-2-oxoethyl) (triphenyl)phosphonium chloride (130.7 g; 0.304 mole) dissolved in chloroform (800 ml) at 0° C. After stirring at room temperature over night, the solvent was evaporated in vacuo. The residue was dissolved in diethyl ether, insoluble material was filtered off and the filtrate was washed with sodium bicarbonate and dried (magnesium sulfate). The procedure was repeated once and thereafter the crude product was stirred over night with a sodium bisulfite saturated water solution. The solid material was filtered off, the product was extracted with diethyl ether, dried (magnesium sulfate) and the solvent was evaporated in vacuo to give 85 g (yield 73%) of 3-(4-benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: COc1cccc(CCCN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(CCCN2Cc3ccccc3C2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-(3-methoxy-phenyl)-propylamine (0.110 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(3-methoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.088 g, 62%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.0 (m, 2H), 2.66 (t, 2H), 3.64 (t, 2H), 3.82 (s, 3H), 4.36 (s, 2H), 6.78 (m, 2H), 7.16-7.58 (m, 5H), 7.84 (d, 1H). GC-MS: m/z 281 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[CH:13][C:12]=1[N+:28]([O-:30])=[O:29])C(OCC)=O)[CH3:2].CS(C)=O.O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[CH:13][C:12]=1[N+:28]([O-:30])=[O:29])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 87.5 %

Procedure:
A 2 L, 3-necked round bottomed flask equipped with a heating mantle, condenser, overhead stirrer, thermocouple, and N2(g) inlet was charged with 2-[2-Nitro-4-(3-nitro-benzoyl)-phenyl]-malonic acid diethyl ester (105 g, 0.24 mol), DMSO (1 L) and H2O (87 mL) The reaction was heated at 110° C. for 11 h. Thin layer chromatographic analysis (Hexanes/ethylacetate 6:4) indicated completion of reaction. The reaction mixture was cooled to room temperature and was diluted with ethyl acetate (4 L). The organic layer was washed with brine (3×4 L), dried over Na2SO4 and concentrated. Methyl t-butyl ether (1 L) was added to the solids and stirred. The product was filtered and washed with Methyl t-butyl ether (2×250 mL). The solids collected were dried in the vacuum oven at 45° C. for 24 hours to yield 89% of pure [2-Nitro-4-(3-nitro-benzoyl)-phenyl]-acetic acid ethyl ester (77 g, 0.21 mol).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[NH:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[N:7]=1.[ClH:19].Cl.NCCCC1N=C(N)NC=1>>[ClH:1].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[NH:15][C:16]([Cl:19])=[C:17]([Cl:1])[CH:18]=2)=[O:13])[N:7]=1
Reactant: Nc1nc(CCCNC(=O)c2ccc[nH]2)c[nH]1
Agent: Cl
Agent: NCCCc1c[nH]c(N)n1
Product: Nc1nc(CCCNC(=O)c2cc(Cl)c(Cl)[nH]2)c[nH]1
Yield: 65 %

Procedure:
Using the same general procedure as used for the synthesis of 1H-pyrrole-2-carboxylic acid [3-(2-amino-1H-imidazol-4-yl)-propyl]-amide hydrochloride 17, 0.200 g of 4-(3-amino-propyl)-1H-imidazol-2-ylamine dihydrochloride 16 afforded 0.204 g (65%) of the title compound 20 as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.32 (t, 1H, J=4.8 Hz), 6.91 (s, 2H), 6.53 (s, 1H), 3.21 (dt, 2H, J=6.6, 12.6 Hz), 2.42 (t, 2H, J=7.2 Hz), 1.72 (tt, 2H, J=7.5, 14.1 Hz); 13C NMR (75 MHz, DMSO-d6) δ 159.15, 147.11, 127.31, 125.14, 114.75, 109.82, 108.99, 107.77, 37.83, 28.03, 22.04; HRMS (ESI) calcd for C11H14Cl2N5O (MH+) 302.0569. found 302.0569.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[C:9](=[O:17])[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22](=[O:23])[C:7]1=2)C.C([O:27]C(C1C(=O)C2C=C(NC(=O)C)C=CC(=O)C=2NC=1)=O)C.C(OC(=O)CN1C=C(C(OCC)=O)C(=O)C2C=C(Cl)C=CC(=O)C1=2)C>>[C:12]([C:10]1[C:9](=[O:17])[C:8]2[CH:18]=[C:19]([OH:27])[CH:20]=[CH:21][C:22](=[O:23])[C:7]=2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[CH:11]=1)([OH:14])=[O:13]
Reactant: CCOC(=O)c1c[nH]c2c(=O)ccc(NC(C)=O)cc2c1=O
Reactant: CCOC(=O)Cn1cc(C(=O)OCC)c(=O)c2ccccc(=O)c21
Agent: CCOC(=O)Cn1cc(C(=O)OCC)c(=O)c2cc(Cl)ccc(=O)c21
Product: O=C(O)Cn1cc(C(=O)O)c(=O)c2cc(O)ccc(=O)c21

Procedure:
In the same manner, but replacing 3-(ethoxycarbonyl)4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-1-acetic acid ethyl ester with an equivalent amount of either 3-(ethoxycarbonyl)-4,9-dihydro-6-(N-methylacetylamino)-4,9-dihydro-1H-cyclohepta[b]pyridine-1-acetic acid ethyl ester, 6-(acetylamino)-4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-3-carboxylic acid ethyl ester or 6-chloro-3-(ethoxycarbonyl)-4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-1-acetic acid ethyl ester, gave the same product, namely 3-carboxy-4,9-dihydro-6-hydroxy-4,9-dioxo-1H-cyclohepta[b]pyridine-1-acetic acid (I; R1 =COOH and R2 =6-OH); mp>250° C. (after recrytallization from acetone); nmr (DMSO-d6) δ5.5 (s, 2H), 7.5 (d, H), 8.3 (d, 1H),8.9 (s, 1H); ir (Nujol*) 2900, 1743, 1694 cm-1 ; uv λ max (MeOH) 341 nm (ε12,500), 237 (32,000); Anal Calcd for C13H9NO7 : C, 53.62% H, 3.12% N, 4.81%; Found: C, 53.22% H, 3.05% N, 4.73%.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][NH2:8])[C:3]([O:5][CH3:6])=[O:4].[OH-].[K+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=O)=O)=[CH:14][CH:13]=1>CO.C(Cl)Cl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:8]=[CH:7][C:2]([C:3]([O:5][CH3:6])=[O:4])=[N:1][C:20]=2[C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)C(N)CN
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1
Temperature: 65 °C

Procedure:
Methyl 2,3-diaminopropionate example 1A (2.4 g, 12.6 mmol) was shaken vigorously for 5 min in a solution of KOH (2.1 g, 37.7 mmol) in 20 mL of MeOH. The resulting milky solution was filtered to remove the solids, and the filtrate was added to a solution of 4,4′-dimethylbenzil (4.48 g, 18.8 mmol) in 20 mL of MeOH. The resulting mixture was heated to 65° C. for 14 h with a reflux condenser open to air. Solvent was evaporated and the residue was dissolved in 300 mL of EtOAc and 200 mL of 1N HCl. The layers were extracted and the organic layer was evaporated to give a thick oil that was redissolved in 5 mL of CH2Cl2 and this solution was loaded onto dry 120 g silica cartridge. The solvent was evaporated with a stream of N2, and the desired product example 1B was eluted with a gradient of 0-40% EtOAc/hexanes to give 1.71 g of a yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([Cl:32])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH:23]=1)[O:14][C:15]([N+:20]([O-:22])=[O:21])([CH3:19])[C:16](O)=[O:17].CN(C)C=O.C>ClCCCl>[Cl:32][C:24]1[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:6]([Cl:5])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH:23]=1)[O:14][C:15]([N+:20]([O-:22])=[O:21])([CH3:19])[C:16]([Cl:3])=[O:17]
Reactant: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)(C(=O)O)[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)(C(=O)Cl)[N+](=O)[O-]
Yield: 84 %

Procedure:
9.7 g (82 mmol) of thionyl chloride were added dropwise to a solution of 30 g (68 mmol) of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-α-phenoxy-propionic acid and 0.5 ml of dimethylformamide in 100 ml of 1,2-dichloroethane at room temperature. The mixture was heated under reflux for 4 hours. Active charcoal was added, the mixture was filtered and the filtrate was concentrated. After digesting the oily residue with 100 ml of ligroin, 26.2 g (84% of theory) of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-α-phenoxy-propionyl chloride were obtained in the form of yellow crystals of melting point 92° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH:13]=[N:14][OH:15])=[CH:12][C:4]1=2)[CH3:2].C1C(=O)N(Cl)C(=O)C1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[CH:30]=[C:29]([Cl:39])[CH:28]=1.CC(=O)OCC>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]2([C:35]([F:38])([F:36])[F:37])[O:15][N:14]=[C:13]([C:11]3[CH:10]=[CH:9][C:5]4[B:6]([OH:8])[O:7][C:3]([CH2:1][CH3:2])([CH2:16][CH3:17])[C:4]=4[CH:12]=3)[CH2:34]2)[CH:30]=[C:29]([Cl:39])[CH:28]=1
Reactant: CCC1(CC)OB(O)c2ccc(C=NO)cc21
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1(CC)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
To a solution of 3,3-diethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (251 mg, 1.07 mmol) in DMF (15 ml) at rt was added NCS (151 mg, 1.13 mmol). The reaction mixture was warmed to 45° C., stirred for 1.5 h and cooled to −10° C. To this mixture was successively added 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (516 mg, 2.15 mmol) and TEA (326.3 mg, 3.23 mmol) below −10° C. The mixture was stirred at this temperature for 2 h, poured into ice-water and extracted with EA (40 ml×2). The combined organic layers were washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1 to 5:1) to give the desired title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol (180 mg, yield 35.5%) as white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.85-7.45 (m, 6H), 4.48-4.22 (m, 2H), 2.00-1.70 (m, 4H), 0.68-0.42 (m, 6H) ppm. MS: m/z=472 [M+1]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)=[O:5].[CH2:16]([Mg]Br)[CH3:17]>CCOCC>[O:13]1[C:9]2[CH:8]=[CH:7][C:6]([C:4](=[O:5])[CH2:16][CH3:17])=[CH:14][C:10]=2[CH:11]=[CH:12]1
Reactant: CON(C)C(=O)c1ccc2occc2c1
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCC(=O)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An ice-cooled mixture comprising N-methoxy-N-methylbenzofuran-5-carboxamide (1 g, 4.87 mmol) in dry ether (20 ml) under N2 is treated dropwise with ethylmagnesium bromide (2.437 ml, 7.31 mmol). After stirring for 30 mins the mixture is allowed to warm to RT. The reaction is quenched by careful addition of NH4Cl followed by 1M HCl and the contents are transferred to a separating funnel. The mixture is extracted with EtOAc and the organic portion is washed with 1M NaOH, brine, dried (MgSO4), evaporated down to give a light brown oil, which began to crystallise on standing. Purification by chromatography on silica eluting with 25% EtOAc/iso-Hex affords the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 8.2 (d, 1H), 7.9 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 6.8 (d, 1H), 3.0 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: OC[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1O.C(Cl)Cl.[C:15]([Br:19])(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=[O:43])C>>[Br:19][CH2:15][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([OH:43])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(CO)c(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(CBr)cc1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Hydroxymethyl-3-hydroxybenzonitrile (0.20 g, 1.34 mmol) was dissolved in DMF (5 mL): CH2Cl2 (5 mL), treated with CBr4 (0.666 g, 2.01 mmol) and Ph3P (0.527 g, 2.01 mmol), and stirred for 1.5 hr at ambient temperature. The reaction mixture was partitioned between EtOAc (100 mL)--H2O (100 mL), the organic layer separated, dried (MgSO4), filtered, and concentrated to give the title compound after chromatography (SiO2, 15% EtOAc in hexane).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([C:10]2([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:9])=[N:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C)C=[O:30]>>[N:21]1([C:2]2[S:6][C:5]([NH:7][C:8]([C:10]3([C:13]4[CH:18]=[CH:17][C:16]5[O:19][CH2:20][O:30][C:15]=5[CH:14]=4)[CH2:12][CH2:11]3)=[O:9])=[N:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C)C=O
Reactant: COc1ccc(C2(C(=O)Nc3ncc(Br)s3)CC2)cc1
Reactant: C1CCNCC1
Product: O=C(Nc1ncc(N2CCCCC2)s1)C1(c2ccc3c(c2)OCO3)CC1
Yield: 2.96 %

Procedure:
1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid (5-bromo-thiazol-2-yl)-amide (110.4 mg, 0.3125 mmol) was dissolved in 3 mL of N,N-dimethylformamide containing piperidine (148.2 μL, 1.500 mmol). The reaction mixture was placed in a sealed tube and subjected to microwave irradiation for 5 minutes at 100° C. The resulting crude product was purified by reverse-phase preparative liquid chromatography to give the pure product (3.44 mg, 0.00926 mmol, 2.96%) ESI-MS m/z calc. 371.1. found; 372.3 (M+1)+ Retention time 3.29 minutes.