Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>C(Cl)Cl.CCOC(C)=O>[N:14]1[CH:13]=[CH:12][C:11]([C:3]2[O:4][C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:6][C:2]=2[NH:1][C:26]([NH:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[Cl:17])=[O:27])=[CH:16][CH:15]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)c1cc(N)c(-c2ccncc2)o1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)c(-c2ccncc2)o1
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A solution of 3-amino-2-(4-pyridinyl)-5-tert-butylfuran (Method A2; 0.10 g, 0.46 mmol) and 2,3-dichlorophenyl isocyanate (0.13 g, 0.69 mmol) in CH2Cl2 was stirred at room temp. for 2 h, then was treated with 2-(dimethalamino)ethylamine (0.081 g, 0.92 mmol) and stirred for an additional 30 min. The resulting mixture was diluted with EtOAc (50 mL), then was sequentially washed with a 1 N HCl solution (50 mL), a saturated NaHCO3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using column chromatography (gradient from 10% EtOAc/90% hexane to 40% EtOAc/60% hexane) to give the desired compound as a white solid (0.12 g, 63%); mp 195-198° C.; TLC (60% EtOAc/40% hexane) Rf 0.47; 1H NMR (DMSO-d6) δ1.30 (s, 9H); 6.63 (s, 1H); 7.30-7.32 (m, 2H), 7.58 (dm, J=6.62 Hz, 2H), 8.16 (dd, J=2.57, 6.99 Hz, 1H), 8.60 (dm, J=6.25 Hz, 2H), 8.83 (s, 1H), 9.17 (s, 1H); 13C NMR (DMSO-d6) δ 28.5 (3C), 32.5, 103.7, 117.3 (2C), 119.8, 120.4, 123.7, 125.6, 128.1, 131.6, 135.7, 136.5, 137.9, 150.0 (2C), 152.2, 163.5; CI-MS m/z (rel abundance) 404 (M+H)+, 15%), 406 ((M+H+2)+, 8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C[Sn](C)(C)c1ccncc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccncc3)c(F)c2)C(=O)O1
Reaction time: 4 h

Procedure:
A slurry of (±)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (PREPARATION 18, 0.063 g, 0.165 mmol) and trimethyl(4-pyridyl)tin (0.060 g, 0.248 mmol) in 1,4-dioxane (5 ml) is degassed by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium (II) chloride (0.012 g, 0.0165 mmol) is added, the reaction again degassed, and then the mixture is brought to reflux under nitrogen. After 4 hr TLC (silica gel, 10% methanol/chloroform) reveals some of the iodide still remains. The mixture is refluxed a further 20 hr, cooled to 20°-25°, and concentrated under reduced pressure. The residue is chromatographed over silica gel, eluting with a little chloroform and then methanol/chloroform (1%, 2%, and then 5%). The appropriate fractions are pooled and concentrated to give the enantiomerically enriched title compound, mp 190.5°-191.0°; [α]25D -16.4° (c 0.5, CHCl3). The following characteristics are no for a racemic sample, mp 179°-180°; IR (internal reflectance) 3279, 3063, 1756, 1752, 1657, 1626, 1600, 1542, 1522, 1485, 1412, 1407, 1377, 1222, 1198 cm-1 ; NMR (CDCl3, 300 MHz) 8.67, 7.59, 7.50, 7.47, 7.33, 6.15, 4.84, 4.11, 3.85, 3.78-3.62, 2.04 δ; MS (m/z) 329 (39.8, M+), 285, 257, 201, 172, 73 and 42. ##STR3##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[NH:11][C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>CN(C)C=O>[CH2:35]([O:34][C:32]([CH2:31][N:11]1[C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N:15][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]1=[O:27])=[O:33])[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21
Temperature: 5 °C
Yield: 100 %

Procedure:
To a solution of (3RS)-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (5.88 g) in N,N-(1imethylformamide (100 ml) was added portionwise sodium hydride (60% dispersion in mineral oil, 0.76 g) under stirring and cooling at 5° C. The mixture was stirred under the same condition for 0.5 hour and at ambient temperature for 1 hour. To the mixture was added dropwise a solution of ethyl bromoacetate (3.19 g) in N,N-dimethylformamide (10 ml) under cooling in an ice-bath. After the addition was completed, the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was poured into water (300 ml) under vigorous stirring. The resultant precipitates were collected by filtration, washed with water and dried under reduced pressure over phosphorus pentoxide to afford (3RS)-1-ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (7.25 g) as a crystalline powder, which was used in a following reaction step without further purification.
Reaction SMILES: [C:1](#[N:3])C.[F:4][C:5]([F:13])([F:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C[Si](C#N)(C)C>C(N(CC)CC)C>[F:4][C:5]([F:13])([F:12])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:1]#[N:3])[CH:7]=1
Reactant: CC#N
Reactant: FC(F)(F)c1ccncc1
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(F)(F)F)ccn1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To 70 ml of acetonitrile were added 6 g of 4-trifluoromethylpyridine=N-oxide, 10.26 ml of triethylamine, and 10.95 g of trimethylsilyl cyanide, and the mixture was stirred at 90° C. for 20 hours. Thereafter, the reaction solution was allowed to cool to room temperature, and concentrated. The residue was subjected to silica gel column chromatography to obtain 4.5 g of 4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.C1COCC1.[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])[CH3:20].C(=O)([O-])O.[Na+]>O>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[S:21][CH2:19][CH3:20])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCSc1ccccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a mixture of N2-methyl-5-trifluoromethylpyridine-2,3-diamine (3.82 g) and THF (40 ml), 2-ethylsulfanylbenzoic acid chloride (4.42 g) was added, stirred at 50° C. for 2 hours, then stirred under reflux for hours. After the mixture was allowed to cool to room temperature, sodium hydrogen carbonate (1.85 g) was added thereto, and stirred at 50° C. for 2 hours. After the mixture was allowed to cool to room temperature, water was poured thereinto, and then the precipitated solid was collected by the filtration. The resulting solid was washed with water and hexane, and dried to give 7.15 g of N-(2-methylamino-5-trifluoromethylpyridine-3-yl)-2-ethylsulfanyl-benzamide (Compound ((1B)-19).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[Br:16][C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1>COCCOC.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl malonate (7.8 mL, 68.2 mmol) in DME (100 mL) at 0° C. was added K2CO3 (12.6 g, 91.0 mmol). The reaction mixture was stirred for 30 min, and then 4-bromo-1-fluoro-2-nitrobenzene (10.0 g, 45.5 mmol) was added. The reaction mixture stirred at 40° C. overnight. The reaction was cooled, diluted with water (200 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated. The residue was triturated with PE:EtOAc=8:1 (30 mL) to 13.0 g (86%) of the title compound as a yellow solid. [M+H] Calc'd for C11H10BrNO6, 332, 334. Found, 332, 334.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:27](O)=[O:28]>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH:27]=[O:28])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCCCc1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Product: CCCCCCCCc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 29 %

Procedure:
A mixture of n-octylbenzene (1.2 g; 6.3 mmol) hexamethylenetetramine (0.97 g; 6.93 mmol) in trifluoroacetic acid was refluxed for 4 h, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was neutralized with 5% NaHCO3 and extracted with diethyl ether (3×5 ml). The combined organic phase was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane) to give the title compound (0.4 g; 29%) as a colourless oil and starting n-octylbenzene (0.8 g; 67%). 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.9 Hz); 1.26 (m, 10H); 1.6 (m, 2H); 2.67 (tr, 2H, J=7.9 Hz); 7.31 (d, 2H, J=8.1 Hz); 7.77 (d, 2H, J=8.1 Hz); 9.96 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:24](=[O:27])[CH2:25][CH3:26])[C:20](=[O:23])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:20](=[O:23])[CH2:21][CH3:22])[C:24](=[O:27])[CH2:25][CH3:26])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: CCC(=O)C(CCCCCCBr)C(=O)CC
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)C(CCCCCCOc1ccc(S(N)(=O)=O)cc1)C(=O)CC

Procedure:
A mixture of 18.2 g, of 4-hydroxybenzenesulfonamide, 33.6 g of 4-(6-bromohexyl)-3,5-heptanedione, 18.3 g. of powdered anhydrous potassium carbonate and 175 ml. of acetone was stirred at reflux for 24 hours. The reaction mixture was cooled, filtered to remove salts, and concentrated in vacuo. The solid residue was recyrstallized from an acetone-ether mixture to give 4-[6-(4-aminosulfonylphenoxy)hexyl]-3,5-heptanedione, m.p. 86°-87° C. (light yellow solid).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]([CH3:23])[CH3:22])[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[CH3:32][C:33]([Si:36](OS(C(F)(F)F)(=O)=O)([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]([CH3:22])[CH3:23])[CH:13]([O:20][Si:36]([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)CC(O[Si](C)(C)C(C)(C)C)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Under an argon atmosphere, to a solution (228 mL) of ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-5-methylhexanoate (14.74 g) in dehydrated THF was added 2,6-lutidine (7.33 g) with stirring under ice-cooling, and tert-butyl dimethylsilyl trifluoromethanesulfonate (14.46 g) was added dropwise. The mixture was gradually warmed to room temperature and stirred for 1.5 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=19/1→4/1) to give ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-{[tert-butyl(dimethyl)silyl]oxy}-5-methylhexanoate as colorless oil (yield: 17.7 g).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH3:23])[CH:12]=O.C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:16]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])=[CH:10][C:9]=1[O:8][CH3:7])[CH2:19][C:20]#[C:21][CH2:22][CH3:23]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCC#CCCOc1ccc(C=O)cc1OC
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCC#CCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 63.5 %

Procedure:
Piperidine (0.17 mL, 1.7 mmol) was added to a suspension of 3-methoxy-4-(hex-3-ynyloxy)benzaldehyde (0.40 g, 1.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.35 g, 1.6 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH providing (E)-2-[[3-(4-(hex-3-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.40 g, 65%) as a colourless crystalline solid; mp 165-166° C.; δH (400 MHz, DMSO-d6) 1.04 (t, J=7.6 Hz, 3H, CH3), 2.14 (q, J=7.6 Hz, 2H, CH3CH2), 2.61 (t, J=7.6 Hz, 1H, OCH2CH2C), 3.83 (s, 3H, OCH3), 4.05 (t, J=7.6 Hz, 2H, OCH2), 6.79 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.99 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.7, 14.0, 19.2, 55.7, 66.9, 76.1, 83.0, 110.9, 113.0, 116.6, 120.1, 120.3, 122.5, 122.6, 127.6, 131.1, 134.0, 141.0, 141.5, 149.1, 149.5, 164.1, 169.4; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1647; vmax 755, 1235, 1510, 1601, 1669, 3234, 3563 cm−1.
Reaction SMILES: [CH2:1]([CH:5]1[O:9][C:8](=[O:10])[C:7]([OH:11])=[C:6]1[OH:12])[CH2:2][C:3]#[CH:4].I[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.OC1C(=O)OC(CCC#CC2C=CC=CC=2)C=1O>>[OH:11][C:7]1[C:8](=[O:10])[O:9][CH:5]([CH2:1][CH2:2][C:3]#[C:4][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:6]=1[OH:12]
Reactant: C#CCCC1OC(=O)C(O)=C1O
Reactant: Ic1ccc2ccccc2c1
Agent: O=C1OC(CCC#Cc2ccccc2)C(O)=C1O
Product: O=C1OC(CCC#Cc2ccc3ccccc3c2)C(O)=C1O
Yield: 78.2 %

Procedure:
5-(3-Butynyl)-3,4-dihydroxy-2(5H)-furanone (0.1 7 g, 1.0 mmol) and 3 00 μL (2.0 mmol) of 2-iodonaphthalene were coupled in an analogous fashion as described for the synthesis of 3,4-dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-furanone. The residue was purified over silica gel using CHCl3/MeOH/AcOH (96/3/1) as eluant and dried at 0.05 mm Hg at 58° C. for 2 h to provide 230 mg (75%) of 3,4-dihydroxy-5-[4-(2-naphthyl)-3-butynyl]-2(5H)-furanone as a yellow wax: 1H NMR (acetone-d6) δ 8.4-8.3 (m, 1H), 7.96-7.88 (m, 2H), 7.70-7.43 (m, 4H), 4.98 (dd, J=3.4, 8.3 Hz, 1H), 2.82-2.75 (m, 2H), 2.48-2.29 (m, 1H), 2.00-1.85 (m, 1H); Anal Calcd for C18H14O4+0.5 H2O: C, 71.27; H, 4.98. Found: C, 71.33; H, 4.87.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[C:3]=1[Cl:9].C([Li])CCC.[CH3:15][S:16]SC.O>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:16][CH3:15])[C:3]=1[Cl:9]
Reactant: Clc1c(Br)cccc1Br
Reactant: CSSC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CSc1cccc(Br)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
To a solution of 1,3-dibromo-2-chlorobenzene (3.4 g, 12.6 mmol) in dry diethyl ether (60 ml), under nitrogen, at −78° C., was added dropwise n-butyllithium (2.5 M in hexane, 5.0 ml, 12.6 mmol). The mixture was stirred for 1 h after which dimethyldisulfide (1.0 ml, 13.9 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 30 min and then brought to ambient temperature. Water (100 ml) was added and the mixture was extracted with ethylacetate (3×100 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (isooctane) to give the title compound (1.23 g). MS m/z (rel. intensity, 70 eV) 240 (M+, 28), 238 (M+, bp), 236 (71), 205 (29), 142 (27).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[CH:27]1)[CH:19]=[CH:18]2.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:27]1)[CH:19]=[CH:18]2
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4nc(-c5ccccc5)oc4C)ccc3c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(Cn3cc(CCC(=O)O)c(-c4ccccc4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84.1 %

Procedure:
A mixture of ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (304 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 7 hours, and 1N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionic acid (243 mg, yield: 84%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 122–123° C.
Reaction SMILES: [OH-].[K+].CN(C)C=O.[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[C:10]([CH:21]=O)[N:9]=1.[OH:23][NH:24]Cl>CO>[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[C:10]([CH:21]=[N:24][OH:23])[N:9]=1
Reactant: O=Cc1cc2c(cn1)[nH]c1ccccc12
Reactant: ONCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: ON=Cc1cc2c(cn1)[nH]c1ccccc12
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A solution of 3.1 g of potassium hydroxide in 40 ml of methanol is added to a mixture of 150 ml of dimethylformamide, 6.9 g of beta-carboline-3-carboxaldehyde and 3.1 g of hydroxylamino-hydrochloride. The reaction mixture is allowed to stand at room temperature overnight. After evaporation, 50 ml of water is added. The reaction product is filtered off. 6.9 g of the air-dried product is heated in the steam bath together with 35 ml of 2 propanol and, after cooling, is filtered off. 5 g of beta-carboline-3-carboxaldehyde-oxime with a melting point of 229°-231° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([OH:18])=[O:17])(=[O:10])=[O:9].[Li][CH2:21]CCC.IC>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:19])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[C:14]([CH3:21])[S:13][C:12]=1[C:16]([OH:18])=[O:17])(=[O:10])=[O:9]
Reactant: [Li]CCCC
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(S(=O)(=O)Nc2onc(C)c2Cl)c(C(=O)O)s1
Temperature: 25 °C

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2-thiophenecarboxylic acid (6 g, 18.60 mmol) in anhydrous tetrahydrofuran (240 mL) at −78° C. and under nitrogen was added nBuLi (2.5 M in hexane, 30 mL, 74.4 mmol). The mixture was stirred at this temperature for 2 h before the addition of iodomethane (6.6 g, 74.4 mmol). The mixture was then poured into crushed ice and then allowed to warm to room temperature. After acidification with concentrated HCl to pH ˜1, the mixture was extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried (MgSO4), the solids were filtered and the filtrate was concentrated to give N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid and the starting material in about a 2:1 ratio (8.5 g combined weight).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1.O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1)=[O:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)Cl
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1C(=O)Nc1ccc2ccc(Cl)nc2n1
Yield: 94 %

Procedure:
2-Methyl-4-nitro-benzoyl chloride (16.1 g.) is added all at once to a suspension of 2-amino-7-chloro-1,8-naphthyridine (14.5 g.) in pyridine (161 cc.). The temperature rises to 40° C. The mixture is stirred for a further hour and water (640 cc.) is then added. The precipitate is filtered off and washed with water (225 cc.) and then with acetone (150 cc.). After recrystallisation from acetonitrile (1,600 cc.), 2-methyl-4-nitro-N-(7-chloro-1,8-naphthyridin-2-yl)-benzamide (26 g.) melting at 229° C is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@@H:12]2[O:22][CH2:23][CH3:24])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[O:22][CH2:23][CH3:24])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2C#N)[C@@H](OCC)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1C#N
Yield: 55 %

Procedure:
A solution of ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate (Intermediate 32, 1.5 g, 3.92 mmol), potassium hydroxide (1.54 g, 27.48 mmol), and hydrazine hydrate (1.38 mL, 27.48 mmol) in ethylene glycol (200 mL) was stirred for 60 h at 120° C. The reaction mixture was poured in to water (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to yield the crude product which was triturated with water (150 mL) to afford 4-chloro-3-cyano-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (670 mg, 55%) as solid.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].COC(OC)(N(C)C)C.C(OCC)(=O)C.[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][C:32]2=[O:40])[CH:28]=[CH:29][CH:30]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[CH:3][N:4]([CH3:6])[CH3:5])[C:32]2=[O:40])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C1Cc2ccccc2N1c1cccc(Cl)c1
Reactant: COC(OC)N(C)C
Agent: COC(C)(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21

Procedure:
By the procedure of Example A1, but substituting an equivalent of dimethylformamide dimethylacetal for the dimethylacetamide dimethylacetal, using first methylene chloride and then 7.5% ethyl acetate in methylene chloride in chromatography and recrystallization from ether-pentane, 1-(3-chlorophenyl)-2(1H,3H)-indolone (10 g, 0.041 mole) was converted to title product, 3.73 g, m.p. 116°-118°.