Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH2:13][N:12]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1B(O)O>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH2:13][N:12]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3[nH]c(-c4ccnc(Cl)n4)cc3C2=O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3[nH]c(-c4ccnc(-c5cc6ccccc6o5)n4)cc3C2=O)cc1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 69.5 %

Procedure:
A mixture of tert-butyl 2′-(2-chloropyrimidin-4-yl)-5′-(4-methoxybenzyl)-4′-oxo-1′,4′,5′,6′-tetrahydrospiro[piperidine-4,7′-pyrrolo[3,2-c]pyridine]-1-carboxylate (A5) (4.5 g, 8.36 mmol), 2-benzofuranboronic acid (4.06 g, 25.09 mmol) and potassium phosphate tribasic heptahydrate (8.49 g, 25.09 mmol) was dissolved in anhydrous dioxane (105 mL). The resulting solution was purged with nitrogen, followed by addition of 1,1′-bis(diphenylphosphino)ferrocene palladium(II)chloride (676 mg, 0.836 mmol). The resulting mixture was again purged with nitrogen and stirred at 140° C. for 45 min in the microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed three times with aqueous NaHCO3, once with brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude product was triturated with toluene which gave tert-butyl 2′-(2-(benzofuran-2-yl)pyrimidin-4-yl)-5′-(4-methoxybenzyl)-4′-oxo-1′,4′,5′,6′-tetrahydro spiro [piperidine-4,7′-pyrrolo[3,2-c]pyridine]-1-carboxylate (A6) as a white solid (3.60 g, 70%). 1H NMR (400 MHz, DMSO-D6, 300K): δ=1.42 (9H, s), 1.55 (2H, br d, J=13.0 Hz), 2.08 (2H, br dt, J=13.4 Hz), 2.65 (2H, br s), 3.56 (2H, br s), 3.74 (3H, s), 3.80 (2H, br s), 4.57 (2H, br s), 6.92 (2H, d, J=8.6 Hz), 7.31 (2H, d, J=8.6 Hz), 7.35 (1H, t, J=7.6 Hz), 7.43 (1H, s), 7.46 (1H, t, J=7.8 Hz), 7.75 (1H, d, J=8.2 Hz), 7.80 (1H, d, J=5.5 Hz), 7.82 (1H, d, J=7.7 Hz), 8.03 (1H, s), 8.77 (1H, d, J=5.4 Hz), 11.75 (1H, s). MS (ES) C36H37N5O5 requires: 619. found: 620.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[K+].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>>[CH:1]1([C:7]2[CH:12]=[C:11]([CH2:27][CH2:26][C:25]([O:29][CH3:30])=[O:28])[CH:10]=[C:9]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:8]=2[OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CC(=O)OC
Reactant: Oc1c(C2CCCCC2)cccc1C1CCCCC1
Agent: CC(=O)[O-]
Agent: [K+]
Product: COC(=O)CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1

Procedure:
The yield of crude product is 1217 g. The crude product contains 800 g of product, 120 g of 2,6-dicyclohexylphenol, 27 g of potassium acetate and also oligomerised methyl acrylate.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([NH:23][CH:24]=[C:25]([C:31]([O:33]CC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[O:33]=[C:31]1[N:12]2[CH:13]=[C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:10][C:11]2=[N:23][CH:24]=[C:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(=CNc1cc(OCc2ccccc2)c(OCc2ccccc2)cn1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(OCc3ccccc3)c(OCc3ccccc3)cn2c1=O
Temperature: 225 °C
Reaction time: 0.5 h

Procedure:
At 225° C. [[[4,5-bis(phenylmethoxy)-2-pyridinyl]amino]methylene]malonic acid, diethyl ester (10.7 g, 22.45 mmol) was added to 135 g of diphenylether. After stirring for 30 minutes at 225° C., the mixture was allowed to cool at room temperature, and 150 ml of petroleum ether was added. After standing overnight in the refrigerator, the resulting crystals were collected by filtration, washed with petroleum ether and recrystallized from ethanol. Yield: 4.77 g; melting point 175.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)([OH:16])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].O.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)([OH:16])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(O)(c2cccc(F)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)cnc1N1CC(O)(c2cccc(F)c2)C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
To a solution of methyl 5-chloro-2-(3-(3-fluorophenyl)-3-hydroxyazetidin-1-yl)nicotinate (D80) (70 mg, 0.207 mmol) in a mixture 3:1 1,4-dioxane/water (2 ml), lithium hydroxide monohydrate (133 mg, 0.312 mmol) was added and the resulting mixture was stirred 4 h at 70° C. After solvent evaporation the residue was taken in a mixture water/1M HCl (10 ml/10 ml) and extracted with ethylacetate (2×30 ml). Collected organics after solvent evaporation afforded the title compound (D111) (64.6 mg).
Reaction SMILES: C([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[O:26])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:7][CH2:6]1)(O)=O.C[C:36]1([CH3:44])[O:43][C:41](=[O:42])[CH2:40][C:38](=[O:39])O1.CN(C1C=CC=CN=1)C.CCN=C=NCCCN(C)C>ClCCl>[CH2:36]([O:43][C:41]([CH2:40][C:38](=[O:39])[CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[O:26])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:9][CH2:10]1)=[O:42])[CH3:44]
Reactant: O=C(O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1

Procedure:
To a dichloromethane (10 mL) suspension of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester (939 mg) obtained in Example 2, Meldrum's acid (317 mg), dimethylaminopyridine (293 mg), and EDCI (460 mg) were added at 0° C. The reaction mixture was diluted with dichloromethane, washed with 1 N hydrochloric acid and saturated brine, then dried over sodium sulfate, and then concentrated. A mixture of the residue and ethanol (10 mL) was heated to reflux for 4 hours and concentrated. The residue was purified by column chromatography (dichloromethane/ethyl acetate) to obtain the title compound (820 mg, 76%) as a yellowish-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1>>[CH3:30][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH2:14][CH2:15]3)=[CH:8][CH:9]=2)=[O:3])=[CH:24][CH:23]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Product: Cc1ccc(CCC(=O)c2ccc(N3CCN(c4ccncc4)CC3)cc2)cc1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 39, but using as starting material 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine in place of 1-(4-formylphenyl)-4-(4pyridyl)piperazine and 4-tolualdehyde in place of 4-methylacetophenone, was prepared 1-[4-(4-methylphenylpropionyl)-phenyl]-4-(4-pyridyl)piperazine (27% yield), m.p. 130-132° C.
Reaction SMILES: CC1C=C(C(=O)CC(C2C=C(C3C=CC=C(C(O)=O)C=3)C=CC=2)C2C=CC=CC=2C)C=CN=1.Cl.COC(=O)CN.C[O:42][C:43](=[O:78])[CH2:44][NH:45][C:46]([C:48]1[CH:49]=[C:50]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH:60]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=3[CH3:77])[CH2:61][C:62]([C:64]3[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[CH:65]=3)=[O:63])[CH:55]=2)[CH:51]=[CH:52][CH:53]=1)=[O:47]>>[CH3:70][C:66]1[CH:65]=[C:64]([C:62](=[O:63])[CH2:61][CH:60]([C:56]2[CH:55]=[C:54]([C:50]3[CH:51]=[CH:52][CH:53]=[C:48]([C:46]([NH:45][CH2:44][C:43]([OH:78])=[O:42])=[O:47])[CH:49]=3)[CH:59]=[CH:58][CH:57]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=2[CH3:77])[CH:69]=[CH:68][N:67]=1
Reactant: COC(=O)CNC(=O)c1cccc(-c2cccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)c2)c1
Agent: COC(=O)CN
Agent: Cc1cc(C(=O)CC(c2cccc(-c3cccc(C(=O)O)c3)c2)c2ccccc2C)ccn1
Agent: Cl
Product: Cc1cc(C(=O)CC(c2cccc(-c3cccc(C(=O)NCC(=O)O)c3)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 89, step 2, from 3′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carboxylic acid (example 102, step 1) and glycine methyl ester hydrochloride was prepared ({3′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carbonyl}-amino)-acetic acid methyl ester as a white foam, which was directly subjected to the next step. In analogy to example 75, from ({3′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carbonyl}-amino)-acetic acid methyl ester was prepared the title compound as a white foam, MS (ESI−): m/z=491.3 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:15]([N+:16]([O-])=O)=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[N+:19]([O-])=O)=[CH:6][C:5]([CH3:22])=[CH:4][N:3]=1.O>CC(O)=O.[Fe]>[NH2:19][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([NH2:16])[C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[C:5]([CH3:22])[CH:6]=1)[C:12]#[N:13]
Reactant: Cc1cnc(F)c(-c2c([N+](=O)[O-])cc(C#N)cc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cnc(F)c(-c2c(N)cc(C#N)cc2N)c1
Temperature: 76 °C
Yield: 156.6 %

Procedure:
Compound 122 (119 mg, 0.39 mmol) was stirred in HOAc (3 mL) with H2O (0.5 mL) and stirred at 76° C. Iron powder (˜325 mesh, 88 mg, 1.56 mmol) was added, and the reaction stirred for 4 h. The solution was concentrated in vacuo, diluted with EtOAc (30 mL), and made basic with sat. NaHCO3. The material was then filtered through Celite, and the organics were separated, dried (MgSO4), and concentrated in vacuo to give 148 mg (66%) of the title compound as a brown oil. MS (ES) [m+H] calc'd for C13H11FN4, 243; found 243.
Reaction SMILES: [CH2:1]([N:8]([S:18]([C:21]1[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=1)(=[O:20])=[O:19])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>C(#N)C>[CH2:60]([NH:67][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[S:18]([C:21]2[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=2)(=[O:20])=[O:19])[CH:10]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: Cn1cnc(S(=O)(=O)N(Cc2ccccc2)c2cccc(C(=O)O)c2)c1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(S(=O)(=O)N(Cc2ccccc2)c2cccc(C(=O)NCc3ccccc3)c2)c1
Yield: 4.7 %

Procedure:
3-[Benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-benzoic acid (50 mg, 1.3 mmol), HATU (77 mg, 0.2 mmol), diisopropylethylamine (74 μL, 0.4 mmol) and benzylamine (22 μL, 0.2 mmol) were heated in dry acetonitrile under nitrogen as 60° C. for 18 hrs. After cooling, solvent was removed in vacuo and the residue purified by preparative TLC (100% ethyl acetate), to afford the title compound as a colourless oil (4.3 mg). HPLC retention time 5.46 min. Mass spectrum (ES+) m/z 462 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N+:13]([O-])=[O:14])=[CH:7][N:6]=1.CO.C[O-].[Li+].C(Cl)[Cl:26]>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][C:12]([Cl:26])=[N:13][OH:14])=[CH:9][CH:10]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])CCc1ccc(Oc2ccccc2F)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: ON=C(Cl)Cc1ccc(Oc2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 2-(2-fluoro-phenoxy)-5-(2-nitro-ethyl)-pyridine (150 mg, 0.59 mmol) described in Manufacturing Example 74-1-3 and methanol (1.5 mL) was added lithium methoxide (45 mg, 1.2 mmol) at room temperature, which was stirred for 5 minutes at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure. Titanium (IV) chloride (140 μL, 1.3 mmol) was added at −78° C. to a mixture of the resulting residue, methylene chloride (2 mL) and tetrahydrofuran (1 mL), and stirred for 80 minutes at 0° C. The reaction mixture was cooled to −78° C., water (1 mL) was added, and the temperature was gradually raised to room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water until the pH was 5, and then washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and was concentrated under a reduced pressure to obtain the title compound (160 mg) as a crude product. This compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[S:17][C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)=[N:15][C:14]=3[CH3:28])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].[H-].[Na+]>>[C:34]([O:33][C:31](=[O:32])[CH2:30][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]3[S:17][C:16]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:23]=4)=[N:15][C:14]=3[CH3:28])[CH:6]=2)[C:2]([CH3:1])=[CH:3]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(C)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(C)cn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 27 f], 3-methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole was reacted with tert-butyl bromoacetate in the presence of sodium hydride to obtain {3-methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as brown oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[C:23]1[N:27]=[C:26]([C:28]2[C:32]([CH3:33])=[C:31](Br)[S:30][CH:29]=2)[N:25]([CH3:35])[N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[C:23]1[N:27]=[C:26]([C:28]2[C:32]([CH3:33])=[C:31]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)[S:30][CH:29]=2)[N:25]([CH3:35])[N:24]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)csc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: Cl
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)csc1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A mixture of 4-trifluoromethoxybenzeneboronic acid (0.4 g, 1.1 mmol), 3-(2-chloro-6-fluorophenyl)-5-[5-bromo-4-methylthien-3-yl]-1-methyl-1H-1,2,4-triazole (0.4 g, 1 mmol), sodium carbonate (0.2 g, 1.9 mmol), tri-o-tolylphosphine (32 mg, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (73 mg, 0.1 mmol) were refluxed under nitrogen for 16 hours in an acetonitrile (14 mL) and water (1.4 mL) solution. After cooling to room temperature, the reactants were poured into dilute hydrochloric acid (1 N, 50 mL) and extracted with ether (3×50 mL). The combined ethereal extracts were washed with water (100 mL), saturated aqueous bicarbonate (70 mL) and brine (50 mL), dried over magnesium sulphate, filtered and concentrated. The residue was chromatographed over silica to afford the product as a yellow gum (210 mg, 43%): 1H NMR (CDCl3) δ 7.55 (s, 1H), 7.49 (d, 2H), 7.28–7.39 (m, 4H), 7.11 (t, 1H), 4.03 (s, 3H), 2.33 (s, 3H); EI/MS 467 m/e (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[N:15]=[C:16]3O)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C1(P(Cl)([Cl:34])=O)C=CC=CC=1>>[Cl:34][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH:13]=[C:14]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:15]=1
Reactant: COc1cccc(-c2ccc3cc(-c4cccnc4)nc(O)c3c2)c1
Reactant: O=P(Cl)(Cl)c1ccccc1
Product: COc1cccc(-c2ccc3cc(-c4cccnc4)nc(Cl)c3c2)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinolin-1-ol (130 mg, 0.395 mmol) in phenylphosphonic dichloride (5 mL) was stirred at 120° C. overnight. After the reaction was completed, the mixture was added to ice-water slowly. The pH was adjusted to 7 by slow addition of NH3H2O at 0° C. Then the mixture was extracted with dichloromethane (100 mL×3). The combined organic layer were dried over MgSO4, filtered and concentrated in vacuo to give 130 mg of crude lxix-a as a white solid, which was used directly in the next step without purification. LCMS m/z=346.9 (M+1) (Method B) (retention time=1.80 min).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH2:24])[CH3:20]>Cl>[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH:24][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:24][CH2:23][CH2:22][N:21]([CH2:25][CH3:26])[CH2:19][CH3:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:20]
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Reactant: CCN(CC)CCN
Agent: Cl
Product: CCN(CC)CCNc1cccc2c1C(=O)c1cccc(NCCN(CC)CC)c1C2=O
Yield: 59.6 %

Procedure:
A solution of 5.52 g (0.02 mol) of 1,5-dichloroanthracene-9,10-dione in 23.2 g (0.2 mol) of 2-(diethylamino)ethylamine is heated at reflux temperature for 4 hours. The mixture is cooled in an ice-bath and 100 ml concentrated hydrochloric acid is added with stirring. This acidic mixture is extracted with three aliquots of 200 ml of diethylether followed by three aliquots of 200 ml of chloroform. The aqueous layer is collected and made alkaline with sodium hydroxide solution, extracted into chloroform and evaporated in vacuo at 30° C. The oily residue is washed with water, dissolved in methanol and titrated with hydrogen chloride in dry diethyl ether to give a precipitate which is dried to yield 5.2 g of the title compound as the hydrochloride in the form of a dark red solid, m.p. 158.5°-159.5° C.; λmax (deionised water) (E/cm/M) 231 nm (34280), 516 nm (10690).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1.BrC1C=CC=C(C(F)(F)F)C=1Cl.OC1CCNC1>>[F:11][C:8]([F:9])([F:10])[C:7]1[CH:2]=[C:3]([N:12]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]2)[CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCN(c2cccc(C(F)(F)F)c2Cl)C1
Agent: FC(F)(F)c1cccc(Br)c1Cl
Agent: OC1CCNC1
Product: OC1CCN(c2cccc(C(F)(F)F)c2)C1

Procedure:
A mixture of 1-[2-chloro-3-(trifluoromethyl)phenyl]pyrrolidin-3-ol and 1-[3-(trifluoromethyl)phenyl]pyrrolidin-3-ol was obtained as a brown oil (8.08 g, yield 90%) from 1-bromo-2-chloro-3-(trifluoromethyl)benzene and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1. This was used for the next reaction without performing further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH:16]=CC2C=CC=CC=2)[NH:14][C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:26]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][OH:26])[NH:14][C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1C=Cc1ccccc1)OCc1ccccc1
Reactant: CO
Solvent: ClCCl
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CO)OCc1ccccc1
Temperature: -78 °C

Procedure:
In a mixture of 80 ml of methanol and 16 ml of dichloromethane is dissolved 0.8 g of (3S,4R)-3-benzyloxycarbonylamino-4-styryl-2-azetidinone obtained in Example 33 and, with cooling at -78° C., ozone gas is bubbled into the solution for 30 minutes. Thereafter, the excess ozone is purged with nitrogen and 0.19 g of sodium borohydride is added, followed by warming the solution to about 0° C. and stirring with ice-cooling for 30 minutes. To the mixture is added 0.3 g of acetic acid and the resulting mixture is concentrated under reduced pressure. To the residue are added ethyl acetate and water, and the ethyl acetate layer is separated. The aqueous layer is extracted with ethyl acetate and the combined ethyl acetate layer is washed with aqueous sodium chloride, dried over mangesium sulfate and concentrated under reduced pressure. The residue is crystallized from diethyl ether and the crystals are collected by filtration to give 0.5 g of (3S,4S)-3-benzyloxycarbonylamino-4-hydroxymethyl-2-azetidinone.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[C:10]([O:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([OH:22])=O)[C:15]1=[O:23])(=[O:12])[CH3:11].[CH3:24][C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH3:31])[N:26]1[CH2:32][CH2:33][NH2:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH3:31])[N:26]1[CH2:32][CH2:33][NH:34][C:20](=[O:22])[CH2:19][N:16]1[CH2:17][CH2:18][CH:14]([O:13][C:10](=[O:12])[CH3:11])[C:15]1=[O:23]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: CC(=O)OC1CCN(CC(=O)O)C1=O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1CCN(CC(=O)NCCN2[C@H](C)CCC[C@@H]2C)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.81 g of 2-chloro-1-methyl-pyridinium iodide are suspended in 10 ml of methylene chloride and thereto there are added at room temperature 1.20 g of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid. Within 15 minutes there is added dropwise at 0° a solution of 0.98 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine and 3.02 ml of triethylamine in 20 ml of methylene chloride, whereupon the mixture is stirred at room temperature for 18 hours. Thereupon, the mixture is evaporated and the residue is chromatographed on aluminum oxide (activity grade III, neutral). The material which is eluted with chloroform is chromatographed on silica gel (granular size 0.2-0.5 mm). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with alcohol has a melting point of 120°-122° after crystallization from diethyl ether.