Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH3:17][O:18][C:19](=[O:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[C:30](=[O:31])[CH2:29][CH:28]([O:32][C:33](=[O:35])[CH3:34])[CH:27]1[CH:36]=O>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[C:30](=[O:31])[CH2:29][CH:28]([O:32][C:33](=[O:35])[CH3:34])[CH:27]1[CH:36]=[CH:3][C:2](=[O:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CCCCCCC1C(=O)CC(OC(C)=O)C1C=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)C=CC1C(OC(C)=O)CC(=O)C1CCCCCCC(=O)OC

Procedure:
70 Mg. of dimethyl 2-oxoheptylphosphonate in 2 ml. of tetrahydrofuran is added to 12 mg. of 48% sodium hydride in 1 ml. of tetrahydrofuran, and the mixture stirred at 0°C. under nitrogen for 30 minutes. 70 Mg. of 3-acetoxy-2-formyl-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene ketal in 2 ml. of tetrahydrofuran is then added dropwise and the mixture allowed to warm to 20°-25°C. After 3 hours the mixture is chilled, added to cold saturated aqueous NaH2PO4, extracted with ethyl acetate, and the latter extract dried over Na2SO4 and concentrated to dryness. The residue is purified by silica gel chromatography (7.8 g. silica gel), eluting with 7% acetone in chloroform to give 3-acetoxy-2-(3-oxo-1-octenyl)-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal: ir (CHCl3) 5.78, 5.9, 6.0, 6.17, 8.00, 10.55 μ; U.V. λmaxCH3OH 228 mμ (Em 10,050).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[N:5]=[CH:4][C:3]=1[NH:22][C@@H:23]1[CH2:28][C@@H:27]2[CH2:29][C@@H:25]([C:26]2([CH3:31])[CH3:30])[C@H:24]1[CH3:32].O.NN>CO>[NH2:11][CH2:10][CH2:9][N:6]1[C:7](=[O:8])[C:2]([Br:1])=[C:3]([NH:22][C@@H:23]2[CH2:28][C@@H:27]3[CH2:29][C@@H:25]([C:26]3([CH3:31])[CH3:30])[C@H:24]2[CH3:32])[CH:4]=[N:5]1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCN3C(=O)c4ccccc4C3=O)c(=O)c1Br)C2(C)C
Agent: NN
Solvent: CO
Solvent: O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCN)c(=O)c1Br)C2(C)C
Yield: 28 %

Procedure:
2-{2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione prepared above in methanol (6 mL) was stirred with hydrazine monohydrate (50 μL, 1.6 mmol) at 80° C. for 6 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=4/1) to give the desired product (32 mg, 28% yield).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][S:30]([C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH2:37][CH2:36]2)(=[O:32])=[O:31].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([N:38]3[C:39]4[C:35](=[CH:34][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:41][CH:40]=4)[CH2:36][CH2:37]3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: COc1c(OC2CCN(C(=O)OC(C)C)CC2)ncnc1N1CCc2cc(S(C)(=O)=O)ccc21
Temperature: 90 °C

Procedure:
A mixture of 8a (49 mg, 0.15 mmol), cesium carbonate (0.11 g, 2 eq), 5-Methanesulfonyl-2,3-dihydro-1H-indole (35 mg, 1.2 eq), tris(dibenzylideneacetone)-dipalladium (31 mg, 0.1 eq), tri-t-butylphosphonium tetrafluoroborate (37 mg, 0.8 eq) and dioxane (1.5 mL) was heated at 90° C. for 4 h. The mixture cooled to room temperature, dioxane was added and the mixture was filtered and washed with DCM. The filtrate was concentrated under a stream of nitrogen and the residue was taken up in 1 mL of THF and was purified by preparative HPLC to afford 8-1; LCMS 491.2 (MH+), tR=5.35 (Method 6). EC50: 201 nM.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)C.[CH3:15][C:16]1[CH:17]=[C:18]([NH2:21])[NH:19][N:20]=1>CCOC(C)=O>[CH3:15][C:16]1[CH:17]=[C:18]2[NH:21][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:5][C:4](=[O:14])[N:19]2[N:20]=1
Reactant: CCOC(=O)CC(=O)c1ccccn1
Reactant: Cc1cc(N)[nH]n1
Solvent: CCOC(C)=O
Product: Cc1cc2[nH]c(-c3ccccn3)cc(=O)n2n1
Temperature: 25 °C
Yield: 79 %

Procedure:
(prepared according to an analogous procedure described in Polish J. Chem., 56 (1982) p 963) 3-Oxo-3-(pyridin-2-yl)propionic acid ethyl ester (2 g, 0.01035 mol) and 5-methyl-2H-pyrazol-3-ylamine (1 g, 1 eq) were heated together at 140° C. for 2 h; after cooling to rt, the solid residue was stirred with EtOAc and the solid collected by filtration to give 1.84 g of 2-methyl-5-pyridin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one. Step B: The product of step A (1.84 g) was dissolved in POCl3 (24 ml) and cooled to 0° C. N,N-dimethylaniline (3.1 ml, 3 eq) was added and the mixture heated at 60° C. for 16 h. The mixture was cooled to rt and the volatiles removed. The resulting residue was dissolved in CH2Cl2, poured onto ice, and taken to pH 8 with NaHCO3 (s). The CH2Cl2 layer was removed, washed with water, and dried (MgSO4). The mixture was concentrated under reduced pressure and the residue chromatographed (SiO2, hexane-EtOAc/hexane 1:1) to give 1.2 g of the title compound. 1H NMR (CDCl3) δ 8.71 (m, 1H), 8.49 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 7.87 (t, J=9.6 Hz, 1H), 7.41 (m, 1H), 6.64 (s, 1H), 2.60 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C@@:11]34[C@@H:16]([O:17][C:4]=1[C:5]=23)[CH2:15][C@@H:14]([OH:18])[CH:13]=[CH:12]4.I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([CH:29]1[CH2:38][C:37]2[C:32]3=[C:33]([CH2:39][C:40](=[O:41])[N:31]3[CH2:30]1)[CH:34]=[CH:35][CH:36]=2)=[O:28].C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[OH:18][C@H:14]1[CH:13]=[CH:12][C@@:11]23[CH2:10][CH2:9][N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([CH:29]4[CH2:38][C:37]5[C:32]6=[C:33]([CH2:39][C:40](=[O:41])[N:31]6[CH2:30]4)[CH:34]=[CH:35][CH:36]=5)=[O:28])[CH2:7][C:6]4=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[CH:20]=[CH:19]4)[O:17][C@H:16]3[CH2:15]1
Reactant: O=C(CCCCCI)C1Cc2cccc3c2N(C1)C(=O)C3
Reactant: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCN(CCCCCC(=O)C1Cc3cccc4c3N(C1)C(=O)C4)C2

Procedure:
Norgalanthamine (1.13 g, 1.64 mmol), 5-(6-iodo-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (1.50 g, 3.75 mmol) and N-ethyldiisopropylamine (1.46 g, 11.3 mmol) are stirred in absolute chloroform (20 ml) for 54 hours at boiling temperature.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[CH:21]([NH:25][CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[CH2:20][CH2:19]4)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl>O1CCOCC1>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[CH:21]([NH:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:20][CH2:19]4)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CCc3cc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)ccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(N2CCC(Oc3ccc4c(c3)CCC4NC3CCNCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-ylamino)piperidine-1-carboxylate (0.73 g, 1.3 mmol) and 4N hydrochloric acid in dioxane (4 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and washed with diethyl ether (2×5 mL) and then dried under reduced pressure to afford the title compound (as the 3.HCl salt) as a off-white solid (0.57 g, 97%). 1H NMR (CD3OD, 300 MHz) 7.73 (m, 2H), 7.58 (m, 3H), 7.07 (s, 1H), 7.01 (m, 1H), 4.93 (m, 1H), 4.78 (m, 1H), 3.65 (m, 6H), 3.20 (m, 5H), 2.62 (m, 1H), 2.35 (m, 6H), 2.08 (m, 5H) ppm; MS (ES) 460.7 (M+H)
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([CH3:18])[CH:9]=[C:10]([CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:5]2=[N:4][C:3]=1[CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[S:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CN(C=O)C>[Cl:20][C:21]1[N:22]=[C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[S:24][C:25]=1[C:2]1[N:6]2[N:7]=[C:8]([CH3:18])[CH:9]=[C:10]([CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:5]2=[N:4][C:3]=1[CH3:19]
Reactant: Clc1csc(N2CCOCC2)n1
Reactant: CCCC(CCC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCC(CCC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Cl)c(C)nc12
Temperature: 130 °C

Procedure:
A 15 mL round bottom flask is charged with 3-iodo-2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine (0.200 g, 0.000539 moles), 4-(4-chloro-thiazol-2-yl)-morpholine (0.165 g, 0.000808 moles), Cs2CO3 (0.361 g, 0.00108 moles, 2.0 equiv), Pd(dba)2 (0.0092 g, 0.0000161 moles, 0.03 equiv), PPh3 (0.00847 gram, 0.000323 moles, 0.060 equiv) and DMF (2.0 mL). Nitrogen is bubbled through the reaction mixture for 15 minutes; then, the reaction mixture is heated at 130° C. overnight. The next day, the reaction mixture is partitioned between Et2O and a saturated solution of NH4Cl. The aqueous layer is extracted twice more with Et2O. The organic extracts are combined, washed 2-3 times with H2O, washed once with brine, and dried over Na2SO4. The solvents are evaporated in vacuo and the crude reaction mixture is purified via silica gel chromatography. Yield=0.1737 g (72%). 1H-NMR (CDCl3), δ 0.87 (t, J=7 Hz, 6H), 1.14-1.37 (m, 4H), 1.74 (q, J=8 Hz, 4H), 2.54 (s, 3H), 2.50 (s, 3H), 3.48 (m, 1H), 3.53 (t, J=5 Hz, 4H), 3.83 (t, J=5 Hz, 4H), 6.71 (br s, 1H) ppm. LC/MS (m/z): calcd. for C22H30ClN5OS (M+H)+: 448; found: 448.
Reaction SMILES: [Cl:1][CH:2]([Cl:36])[CH2:3][O:4][C:5](=[O:35])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:31])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:30])[CH3:29])[CH:23]=3)=[CH:16][C:15]=2[N+:32]([O-])=O)=[CH:9][CH:8]=1.[NH4+].[Cl-]>[Fe]>[Cl:36][CH:2]([Cl:1])[CH2:3][O:4][C:5](=[O:35])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:31])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:30])[CH3:29])[CH:23]=3)=[CH:16][C:15]=2[NH2:32])=[CH:9][CH:8]=1
Reactant: CN(C)c1cccc(C(=O)Nc2ccc(Sc3ccc(NC(=O)OCC(Cl)Cl)cc3)c([N+](=O)[O-])c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CN(C)c1cccc(C(=O)Nc2ccc(Sc3ccc(NC(=O)OCC(Cl)Cl)cc3)c(N)c2)c1
Yield: 58.8 %

Procedure:
The product from Example 239d (2.0 g, 3.6 mmol) was reacted with Fe and NH4Cl as described for Example 9E to give the desired product (1.1 g, 58%).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([OH:26])=O)[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:28]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([NH:37][S:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:36])=[O:35])=[O:26])[O:21][C:22]=3[CH3:23])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccc(OC(F)F)cc2)cc1
Reactant: NS(=O)(=O)c1ccccc1
Product: Cc1oc(C(=O)NS(=O)(=O)c2ccccc2)cc1CNc1ccc(-c2ccc(OC(F)F)cc2)cc1

Procedure:
Compound (172) was prepared from compound (171) and benzenesulphonamide by adapting the procedure of Example 38(f). LC/MS System D; Rt=10.38 mins, m/z (ES+)=513 (M+H for C26H22F2N2O5S).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[N:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:16]=2)[C:11]([NH:31][C@@H:29]([C:26]2[CH:27]=[N:28][C:23]([C:22]([F:33])([F:21])[F:32])=[CH:24][CH:25]=2)[CH3:30])=[O:13])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)nc1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C(F)(F)F)nc3)cc(S(C)(=O)=O)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask were charged 3-(5-methylpyridin-2-yl)-5-(methylsulfonyl)benzoic acid (40% mixture with BaCl2, 250 mg, 0.34 mmol), (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (130 mg, 0.69 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (130 mg, 0.69 mmol), 1-hydroxybenzotriazole hydrate (100 mg, 0.69 mmol), triethylamine (87 mg, 0.86 mmol) and CH2Cl2 (3 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified via flash chromatography to afford the desired product as a white solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].C(O)CC(C)C>[Cu].CCOCC.O>[C:16]([C:15]1[CH:24]=[CH:25][C:12]([NH:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])=[C:13]([N+:26]([O-:28])=[O:27])[CH:14]=1)(=[O:17])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1C(=O)O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccccc1)c1ccc(Nc2ccccc2C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
A mixture of anthranilic acid (1.37 g, 10 mmol.), 4-chloro-3-nitrobenzophenone (2.88 g, 11 mmol.), anhydrous potassium carbonate (powder, 2.77 g, 20 mmol.), copper (powder, 50 mg), and isoamyl alcohol (25 mL) was stirred and heated for one hour under reflux. The reaction mixture was cooled to room temperature, and stirred for 15 minutes after addition of water (30 mL) and ether (30 mL). The insoluble red-brown solid was collected by filtration and washed with water and ether. The red-brown solid mainly comprising a potassium salt of the desired compound was suspended in water (40 mL). To the suspension was added 2M hydrochloric acid until an aqueous portion of the suspension showed approximately pH 2. The suspension was vigorously stirred for one hour at room temperature. The deposited crystalline precipitate was collected by filtration and washed with several portions of water and ether. The washed precipitate was placed under reduced pressure at 60° C. for 3 hours to dryness. Thus, 2.34 g (65%) of the desired compound was obtained as a yellow-orange crystalline product.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:36]([C:31]2[NH:32][C:33]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:26][CH3:25])=[CH:35][CH:34]=3)=[O:37])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c(C(=O)N[C@H]3CCN(C(=O)c4cc(Cl)cc(Cl)c4)[C@H](Cc4ccccc4)C3)cc2c1

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 126 mg (0.661 mmol) of 5-methoxyindole-2-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR88## is obtained (118 mg, 41%) as white crystals of melting point 251° C. TLC: methylene chloride/methanol/conc. ammonia (2000:50: 1) Rf =0.81, FD-MS: M+ =535, 537; IR: 3440, 3280, 1625 cm-1.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O1COCO[CH2:19]1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[C:11]([C:10]1[CH:14]=[C:15]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[O:16][CH2:19]2)([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C1OCOCO1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To 153 ml of fuming sulfuric acid, containing about 27% of SO3, 50 g (0.3 m) of terephthalic acid are added, under stirring, at room temperature, then 23 g (0.25 m) of 1,3,5-trioxane are added thereinto in two portions, by cooling to a temperature of 15-18° C. after any addition. At the end of the addition, the mixture is left 30 minutes under stirring at room temperature, then it is heated at 135-145° C. and let under stirring for 2-2.5 hours at this temperature until the end of the reaction. The reaction mixture is cooled to a temperature lower than 3° C., then 100 ml of glacial acetic are added thereto by keeping the temperature at about 25° C. At the end of the addition, the mixture is let to stand 60 minutes under stirring at 20-25° C. and filtered. The wet product is suspended in 1900 ml of water. The suspension is heated up to 25-30° C. under stirring, its pH is adjusted to about 8 by gradual addition of 175 g of sodium bicarbonate. The solid is filtered off on Celite® by washing with hot water (40-45° C.). The pH of the mother liquors is brought to 1.5 by addition of about 125 ml of 37% hydrochloric acid and the obtained precipitate is filtered at 20-25° C. by washing with water until the filtrate reaches a neutral pH. Thus, 32 g of 5-carboxyphthalide with a titer (HPLC) >93% are obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]2[C:14]([C:15]([O-:17])=[O:16])=[C:13]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])[N:12]=[N:11]2)=[CH:7][CH:6]=1.Cl>O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])[N:12]=[N:11]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2nnc(C(=O)c3ccccc3[N+](=O)[O-])c2C(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc(C(=O)c3ccccc3[N+](=O)[O-])c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1N aqueous sodium hydroxide solution (50 ml) was added to a solution of 1-(4-methoxybenzyl)-4-(2-nitrobenzoyl)-1,2, 3-triazole-5-carboxylate (b-1) (10.17 g, 24.8 mmole) in tetrahydrofuran (100 ml), which was stirred at room temperature for 2 hours. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate and washed with saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 1-(4-methoxybenzyl)-4-(2-nitrobenzoyl)-1,2,3-triazole-5-carboxylic acid (c-1': LP) as a colorless crystalline powder. The product was dissolved in methanol (80 ml), 10% palladium on carbon (800 mg) was added, and the mixture was stirred in the hydrogen atmosphere at room temperature for 10 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Precipitates were collected by filtration to give 4-(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylic acid (c-1:LP) (6.62 g, 75.8% over two steps) as a yellow crystalline powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][O:5][CH:4]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[NH:3]1.C([Li])CCC.[CH3:20][S:21]C>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[CH2:6][O:5][CH:4]([C:7]2[S:8][C:9]([S:21][CH3:20])=[CH:10][C:11]=2[O:12][CH3:13])[NH:3]1
Reactant: CSC
Reactant: COc1ccsc1C1NC(C)(C)CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(SC)sc1C1NC(C)(C)CO1
Temperature: -45 °C
Reaction time: 1.5 h

Procedure:
27 g (0.128 moles) of 3,4-dihydro-4,4-dimethyl-2-(3-methoxy-2-thienyl)-oxazole are dissolved in 400 ml of absolute tetrahydrofuran, the solution is cooled to -45° C. and 88 ml (0.141 moles) of a 1.6 molar solution of butyllithium in n-hexane is added dropwise such that the temperature in the reaction mixture does not exceed -45° C. After completion of the addition it is stirred further for 1.5 hours at -45° C., a solution of 13.9 g (0.147 moles) of dimethylsulfide in 70 ml of absolute tetrahydrofuran is added and stirring continues for an additional 30 minutes at this temperature. Then it is heated to -20° C., poured onto water and extracted several times with ether. The combined ether phases are dried with sodium sulfate, decolored with activated charcoal, evaporated in vacuo and the crystalline residue is recrystallized from petroleum ether. Yield: 24.7 g (75%), m.p. 56°-58° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9](=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccccc2)c2ccccc2[nH]1
Product: Clc1nc(-c2ccccc2)c2ccccc2n1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
A flask was charged with 4-phenylquinazolin-2(1H)-one (110 g, 0.51 mol) and phosphorus oxychloride (300 mL), and the mixture was stirred at 105° C. for 30 min. The reaction mixture was cooled to rt and slowly poured over an ice/water mixture. The solid was collected by filtration, washed with water (50 mL) and dried under reduced pressure. The product, 2-chloro-4-phenylquinazoline, was isolated as an off-white solid (110 g, 91%).