Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].[OH-].[K+]>O1CCOCC1>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: OCC1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1OCC1CCNCC1
Temperature: 70 °C
Yield: 22.2 %

Procedure:
A mixture of 23.0 g (0.2 mole) of 4-hydroxymethylpiperidine, 31.5 g (0.2 mole) of 2-chloronitrobenzene, 11.8 g (0.21 mole) of potassium hydroxide and 200 ml of dioxane is heated to 70° C. for 3 days. The reaction mixture is then evaporated in a vacuum and the residue is taken up in diethyl ether, washed with water, extracted with dilute hydrochloric acid, rendered alkaline and the aqueous mixture extracted with diethyl ether. After evaporation of the solvent, there are obtained 10.5 g of 4-(2-nitrophenoxymethyl)-piperidine (22% of theory); b.p. 130°-132° C./0.01 mm. Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[C:17]#[N:18].[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:7]1[C:2]([Cl:1])=[C:3]([C:17]#[N:18])[C:4](=[O:16])[N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[CH:6]=1
Reactant: N#Cc1c(Cl)ccn(-c2c(F)cccc2F)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)c(Br)cn(-c2c(F)cccc2F)c1=O
Temperature: 50 °C
Yield: 43.8 %

Procedure:
To a solution of 4-chloro-1-(2,6-difluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (670 mg) in N,N-dimethylformamide (5.0 mL) was added N-bromosuccinimide (548 mg) at room temperature. The reaction mixture was heated at 50° C. for 4 hr, and cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (380 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=O)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:43][NH2:44])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:43][NH:44][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:28])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: COc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.564 g, 1.25 mmol), {[3-bromo-4-(methyloxy)phenyl]methyl}amine (0.27 g, 1.25 mmol, HBTU (0.474 g, 1.25 mmol), and TEA (0.348 mL, 2.5 mmol) were combined in CH2Cl2 (30 mL). The mixture was stirred overnight at room temperature. The solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried and concentrated to give the crude product which was purified using CombiFlash on a 40 g column eluted with 0-10% MeOH/CH2Cl2 to afford the title compound as a white solid. LC-MS m/z 649.5 (M+H)+, 1.76 min (ret time); mp 130-132° C.; analytical HPLC shows 100% purity, (ret time 12.776 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[OH-].[K+].Cl>O.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cc1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(-n2ccc3cc(OCc4ccccc4)ccc32)cc1
Yield: 59.9 %

Procedure:
To 22.3 g (0.1 mol) 5-benzyloxyindole in 110 ml (1.0 mol) 1-bromo-4-fluorobenzene were added 28 g (0.5 mol) powdered potassium hydroxide and 6.4 g (0.1 mol) Cu as powder. The suspension was heated to reflux for 2 h. At RT, ether and water were added, the mixture was acidified with 2M HCl and extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with a gradient hexane-hexane/EtOAc 19:1-9:1 yielded 19 g (60%) 5-Benzyloxy-1-(4-fluoro-phenyl)-1H-indole as colorless solid, MS: 318 (MH+).
Reaction SMILES: ClC(Cl)(Cl)[CH2:3][O:4][C:5]([N:7]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:8][C:9]([NH:11][CH:12]1[C:29](=[O:30])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])[C:16]([CH3:20])([CH2:18]Br)[S:17][C@H:13]12)=[O:10])=[O:6].N1C=CC=CC=1.[CH:45]([Cl:48])([Cl:47])[Cl:46]>>[Cl:46][C:45]([Cl:48])([Cl:47])[CH2:3][O:4][C:5]([N:7]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][C:9]([NH:11][CH:12]1[C:29](=[O:30])[N:14]2[C:15]([C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:26])[Cl:27])=[O:22])=[C:16]([CH3:18])[CH2:20][S:17][C@H:13]12)=[O:10])=[O:6]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)CN(C(=O)OCC(Cl)(Cl)Cl)c3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CN(C(=O)OCC(Cl)(Cl)Cl)c3ccccc3)[C@H]2SC1

Procedure:
A mixture of 2,2,2-trichloroethyl 6-[N-(2,2,2-trichloroethoxycarbonyl)phenylglycyl]amino-2-methyl-2-bromomethylpenam-3-carboxylate (0.43 g.), dry pyridine (0.09 g.) and dry chloroform (10 cc) was heated under reflux for 4.5 hours. The chloroform layer was separated, washed with water, dried and then concentrated. The residue was recrystallized from ether to yield needles (0.23 g.) of 2,2,2-trichloroethyl 7-[N-(2,2,2-trichloroethoxycarbonyl)phenylglycyl]amino-3-methyl-3-cephem-4-carboxylate, m.p. 99°-100.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[C:26]([C:33]([F:36])([F:35])[F:34])[CH:27]=[C:28]4[C:32]=3[NH:31][N:30]=[CH:29]4)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[C:26]([C:33]([F:34])([F:35])[F:36])[CH:27]=[C:28]4[C:32]=3[NH:31][N:30]=[CH:29]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C2(COCc3cc(C(F)(F)F)cc4cn[nH]c34)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (75 mg, 0.148 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 59 mg (98%). 1H-NMR (CDCl3, 500 MHz) δ 8.06 (s, 1H), 7.94 (s, 1H), 7.20-7.40 (m, 3H), 7.07 (m, 2H), 4.71 (s, 2H), 3.50 (s, 2H), 3.43 (s, 2H), 2.88 (m, 2H), 2.72 (m, 2H), 2.12 (m, 2H), 1.85 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 162.5, 160.5, 139.6, 139.5, 135.3, 128.64, 128.58, 124.7 (q, J=272 Hz), 123.2 (q, J=32 Hz), 122.9, 121.8, 120.6, 118.5 (q, J=3.8 Hz), 115.8, 115.6, 80.3, 71.6, 50.5, 42.4, 41.4, 33.7. Mass spec.: 408.09 (MH)+. Accurate mass spec.: m/z 408.1680 [MH]+, Δ=4.7 ppm.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:10])[CH:8]=[CH2:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[CH:8]=[CH2:9]
Reactant: c1ccccc1
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Benzene (1 mL), acryloyl chloride (0.4 mL), and aluminium chloride (0.33 g) were added to dichloromethane (4 mL), followed by stirring at 0° C. for 2 hours. After reaction, 1 N hydrochloric acid and dichlormethane (5 mL) were added in order. The organic phase was concentrated. The obtained residue was applied to a silica gel column to obtain the title compound (120 mg).
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[Cl-].[Li+].[CH2:13]1[O:16][CH:14]1[CH3:15]>OS(O)(=O)=O.CN(C)C=O>[OH:16][CH:14]([CH3:13])[CH2:15][N:8]1[CH:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:10])[N:6]([CH2:13][CH:14]([OH:16])[CH3:15])[C:7]1=[O:9]
Reactant: CC1CO1
Reactant: CC(C)C1NC(=O)NC1=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(O)CN1C(=O)C(C(C)C)N(CC(C)O)C1=O
Temperature: 50 °C

Procedure:
A mixture of 995.0 g of 5-isopropylhydantoin (7 mols), 2000 ml of dimethylformamide and 14.8 g of lithium chloride is stirred at 50° C. 1220 g of propene oxide (21 mols) are slowly added dropwise over the course of 6 hours. Thereafter the temperature is gradually raised to 70° C. and after a total of 15 hours the reaction mixture is allowed to cool. It is adjusted to pH=7 with a few drops of 2 N H2SO4 and the pale yellow solution is filtered. The solution is completely concentrated at 90° C. bath temperature on a rotational evaporator under a waterpump vacuum and is subsequently treated at 90° C./0.1 mm Hg until constant weight is reached. 1654.5 g of a pale yellow highly viscous product (91.7% of theory) are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([C:28](Cl)=[O:29])[C:24]([CH3:31])=[N:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH:11][C:28]([C:25]3[C:24]([CH3:31])=[N:23][N:22]([CH3:21])[C:26]=3[CH3:27])=[O:29])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Reactant: Cc1nn(C)c(C)c1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc2c1[C@H](C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
Into a solution composed of 0.15 g of (R)-1,1,3-trimethyl-4-aminoindane (optical purity: 99% ee), 0.13 g of triethylamine, 5 mg of 4-dimethylaminopyridine and 1 mL of THF, a solution of 0.15 g of 1,3,5-trimethylpyrazole-4-carbonyl chloride in THF was dropped under ice cool. The mixture was stirred at room temperature for 15 minutes, then, to the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline sequentially, then, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to obtain 0.17 g of (R)-(−)-N-(1,1,3-trimethylindan-4-yl)-1,3,5-trimethylpyrazole-4-carboxamide (hereinafter, referred to as present carboxamide compound (3)) (optical purity: 99% ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:34]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])=[O:35])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was dissolved in chloroform (10 ml), and 2-methoxyphenyl isocyanate (49 μl) was added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to quantitatively give the title compound.
Reaction SMILES: C([NH:4][C@@:5]1([C:22](NC(C)(C)C)=[O:23])[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][CH2:11][CH2:12][B:13]1[O:17]C(C)(C)C(C)(C)[O:14]1)(=O)C.[OH2:29]>Cl>[NH2:4][C@@:5]1([C:22]([OH:23])=[O:29])[CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17]
Reactant: O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CCC[C@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Product: N[C@@]1(C(=O)O)CCC[C@H]1CCCB(O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A stirred mixture of (1S,2R)-1-acetamido-N-tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)cyclopentanecarboxamide (0.627 g, 1.59 mmol) in 6 N HCl (15 mL) was heated to 90° C. for 20 h, cooled to room temperature, and diluted with water (15 mL). The mixture was extracted with dichloromethane (2×15 mL) and concentrated. Water (20 mL) was then added to the concentrated crude mixture and the aqueous solution is re-concentrated in vacuo (2×) to remove excess HCl. The resulting residue was dissolved in methanol (5 mL) and diluted to a volume of 40 mL with ether and stirred for 1 hour, to remove solid tertbutylamine hydrochloride by filtration. The resultant filtrate, upon concentration was treated with a solution of concentrated ammonium hydroxide (15 mL), followed by removal of the excess ammonium hydroxide under vacuum (3×). The resulting solid white residue was triturated using acetonitrile and dried to afford the target compound (1S,2R)-1-amino-2-(3-boronopropyl)cyclopentanecarboxylic acid (0.397 g, 93%) as a white powder that exists as a 1:1 mixture of the cyclized and uncyclized forms. 1H NMR (DMSO, 300 MHz) δ 6.38 (br d, J=11.4 Hz, NH, 0.5 H), 5.97 (br d, J=12 Hz, NH, 0.5 H), 2.22-2.05 (m, 1 H), 1.98-1.42 (m, 6 H), 1.43-1.00 (m, 3 H), 0.95-0.88 (m, 1 H), 0.60-0.42 (m, 1 H), 0.38-0.20 (m, 1 H); MS (+CI): m/z for C9H18BNO4: expected 215.1; found 215.3 (M+H)+.
Reaction SMILES: CN(N=O)C([O:5][CH2:6][CH3:7])=O.[CH2:10]([N:17]1[CH2:22][CH2:21]C(=O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-2].[Ba+2]>CO>[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:7][C:6](=[O:5])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)N(C)N=O
Agent: [Ba+2]
Agent: [O-2]
Solvent: CO
Product: O=C1CCCN(Cc2ccccc2)CC1
Temperature: -5 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
N-methyl-N-nitrosourethane (1.39 ml, 10.8 mmol) was added dropwise to a solution of 1-benzyl-4-piperidone (2.0 g, 10.6 mmol) in methanol (4 ml) at −15° C. over a period of 30 minutes while maintaining the temperature at −5° C. or lower. During the addition, barium oxide (65 mg, 0.423 mmol) was added thereto in small portions. The resulting mixture was stirred overnight at −15° C. and then filtered, and the filtrate was distilled under reduced pressure to remove the solvent and diethyl ether was added to the residue. The insoluble material was filtered off and a saturated aqueous sodium hydrogencarbonate solution was added to the filtrate, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain 1-benzyl-4-azepanone (662 mg, 31%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([O:12][CH:9]1[CH2:8][CH2:7][C:6]2[N:5]=[CH:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([OH:1])[C:11]=2[CH2:10]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1cnc2c(c1O)CC(O)CC2
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2c(c1O)CC(OC(=O)OCc1ccccc1)CC2

Procedure:
A well stirred mixture of 5 g of ethyl 4,6-dihydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate and 3.0 g of KHCO3 in 300 mL of CHCl3 is ice-cooled. To the cooled mixture, benzyl chloroformate (3.6 g) is added over a period of 10 minutes maintaining the reaction temperature below 10°. The reaction mixture is vigorously stirred at room temperature overnight, then filtered. The filtrate is washed with H2O, dried (MgSO4), and evaporated to dryness. The dried residue is purified by flash chromatography on a silica gel column to yield ethyl 6-benzyloxycarbonyloxy-4-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].Cl>C(O)(=O)C>[CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([N+:16]([O-:18])=[O:17])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2cc3ccccc3cc2c1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc2cc3ccccc3c([N+](=O)[O-])c2c1
Temperature: 22.5 °C
Reaction time: 4 h

Procedure:
Synthesis of 2-methyl-9-nitroanthracene ##STR12## Nitration of 2-methylanthracene (Source Aldrich) was carried out using the same procedure as in example 1 to yield the 2-methyl-9-nitroanthracene as a yellow solid. 2-Methylanthracene (2.0 g; 0.010 mole) was suspended in glacial acetic acid (25 ml) and to the stirred solution was added concentrated nitric acid (0.6 ml; 0.014 mole). The solution was stirred in a water bath at 20-25° C. for 4 hours, until the solution became clear. To the clear solution a mixture of conc. HCl and acetic acid (20 ml; 1:1) was added via a dropping funnel over a period of 15 minutes. A yellow solid precipitated out. The solution was stirred for further 30 minutes and filtered under suction. The product was treated by the same method as described in example 1 to give the 2-methyl-9-nitroanthracene as a yellow solid (1.8 g; 73%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:20])([CH3:19])[C:17]#[CH:18].N1CCCCC1>O.[Cu](I)I>[CH3:15][C:16]([CH3:20])([CH3:19])[C:17]#[C:18][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Agent: I[Cu]I
Solvent: C1CCNCC1
Solvent: O
Product: CC(C)(C)C#Cc1ccc(S(=O)(=O)n2cccc2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
A mixture of N-(5-bromothiophene-2-sulfonyl)pyrrole (600 mg, 2.05 mmol), 3,3-dimethyl-1-butyne (338 mg, 4.1 mmol), copper iodide (39 mg, 0.21 mmol), tetrakistriphenylphosphine palladium [Pd(PPh3)4 ] (118 mg, 0.1 mmol) and piperidine (5 ml) was stirred at room temperature for a period of 24 hours under a nitrogen atmosphere. The mixture was then diluted with water (10 ml) and extracted with 3×25 ml portions of ether. The combined ether extracts are washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and crude product purified by column chromatography using 2% ethyl acetate/hexanes to give 423 mg N-[5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonyl]pyrrole as a yellow powder (70% yield).
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[S:11][C:12]3[CH2:23][CH2:22][CH2:21][CH2:20][C:13]=3[C:14]=2[C:15](OCC)=[O:16])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][NH2:25]>>[CH:1]1([C:7]([NH:9][C:10]2[S:11][C:12]3[CH2:23][CH2:22][CH2:21][CH2:20][C:13]=3[C:14]=2[C:15]([NH:25][CH3:24])=[O:16])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: CCOC(=O)c1c(NC(=O)C2CCCCC2)sc2c1CCCC2
Product: CNC(=O)c1c(NC(=O)C2CCCCC2)sc2c1CCCC2

Procedure:
The product of Example 13 and methylamine were processed as in Examples 29A and 29B to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.20-1.40 (m, 3H), 1.45-1.61 (m, 2H), 1.65-1.73 (m, 1H), 1.78-1.89 (m, 6H), 1.97-2.06 (m, 2H), 2.37 (tt, J=11.6, 3.7, 3.6 Hz, 1H), 2.64-2.73 (m, 4H), 2.98 (d, J=5.1 Hz, 3H), 5.94 (s, 1H), 12.17 (s, 1H); MS (DCI/NH3) m/z 321 (M+H)+; anal. calculated for C17H24N2O2S: C, 63.72; H, 7.55; N, 8.74. Found: C, 63.47; H, 7.45; N, 8.55.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:8]([N:10]([CH2:19][CH3:20])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[CH3:9]>>[CH2:8]([N:10]([CH2:19][CH3:20])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]([NH:7][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[NH:7][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:13][CH:12]=1)[CH3:9]
Reactant: CCCCC(N)=O
Reactant: CCN(CC)c1ccc(C=O)cc1
Product: CCCCC(=O)NC(NC(=O)CCCC)c1ccc(N(CC)CC)cc1
Yield: 69 %

Procedure:
Compound 52 was prepared from pentanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 69%. 1H NMR (400 MHz, CD3OD) δ 7.18 (d, J=8.8 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H), 6.58 (t, J=8.4 Hz, 1H), 3.33-3.41 (m, 4H), 2.25 (t, J=7.2 Hz, 4H), 1.58-1.66 (m, 4H), 1.33-1.43 (m, 4H), 1.14 (t, J=7.2 Hz, 6H), 0.95 (t, J=2.8 Hz, 6H). LC-MS (ESI): m/z 362.2 (M+H)+. HRMS (ESI) for C21H36N3O2 (MH+): calcd, 362.2802. found 362.2792.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13]O)=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1onc(-c2cccc(F)c2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(-c2cccc(F)c2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (5.8 g, 28 mmol) in THF (339 mL) was added phthalimide (5.5 g, 37 mmol) and triphenylphosphine (9.8 g, 37 mmol) at ambient temperature under an argon atmosphere. Then a solution of diethyl azodicarboxylate (40% in toluene, 14.6 mL, 37 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. Concentration and repeated trituration with ethyl acetate afforded the title compound (6.3 g, 66%) as a white solid. MS: m/e=337.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][CH2:13][CH2:14][OH:15].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO.O>[NH2:9][C:4]1[C:3]([NH:12][CH2:13][CH2:14][OH:15])=[C:2]([Cl:1])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1NCCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(F)c(Cl)c1NCCO
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
2-[(2-Chloro-3-fluoro-6-nitrophenyl)amino]ethanol (5.52 g, 22.7 mmol) is dissolved in MeOH (40.0 mL). A premixed solution of Na2S2O4 (13.8 g, 79.5 mmol) in water (40.0 mL) is added to the first solution. The resulting solution is stirred for 5 minutes at 60° C. followed by 2 hours at room temperature. The solvents are evaporated, and the resulting residue is suspended in a saturated solution of NaHCO3 (40.0 mL). The aqueous phase is extracted 4 times with EtOAc (4×40.0 mL). The combined organic phases are dried with MgSO4, filtered and concentrated. The product is sufficiently pure by 1H NMR (2.07 g, 45%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.99 (m, 2H) 3.32 (s, 1H) 3.48 (t, J=5.57 Hz, 2H) 4.09 (s, 1H) 4.73-4.95 (m, 2H) 6.55 (dd, J=8.79, 5.66 Hz, 1H) 6.71 (t, J=8.89 Hz, 1H).