Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=1)[C:5]2=O.O.[NH2:28][NH2:29]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:7][NH:29][N:28]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: O=c1c(-c2cccc(-c3ccc(F)cc3)c2)coc2cc(O)c(Cl)cc12
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2cccc(-c3ccc(F)cc3)c2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(4′-fluoro-biphenyl-3-yl)-7-hydroxy-chromen-4-one (0.2 g, 0.54 mmol), hydrazine hydrate (2.5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil which was purified by column chromatography to give 4-Chloro-6-[4-(4′-fluoro-biphenyl-3-yl)-1H-pyrazol-3-yl]-benzene-1,3-diol as an off white solid (0.13 g, 63.3%); Rf 0.2 cf SM 0.7 ethyl acetate/hexane (80/20).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3ccccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-piperazin-1-yl-quinoline hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1[CH:9]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1/[CH:9]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1=C(Cl)C2CCC1C2
Solvent: ClCCl
Product: CCOC(=O)/C=C/C1=C(Cl)C2CCC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 167a (9.0 g, 57.7 mmol) in methylene chloride (250 mL) was added ethyl 2-(triphenyl-λ5-phosphanylidene)acetate (20 g, 57.7 mmol). The mixture was stirred at room temperature overnight. It was then evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:100 ethyl acetate/petroleum ether to afford 167b as a yellow oil (6.0 g, 46%). MS: [M+H]+ 227.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[CH2:20]([N:22]([CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:21]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:29][C:26]2[CH:25]=[CH:24][C:23]([N:22]([CH2:30][CH3:31])[CH2:20][CH3:21])=[CH:28][CH:27]=2)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: CCN(CC)c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(CC)c1ccc(N=Cc2cc(OC)c(OC)cc2[N+](=O)[O-])cc1
Yield: 83 %

Procedure:
To a refluxing, stirred suspension of 63.3 g (0.3 mole) of 6-nitroveratraldehyde and 1.0 ml glacial acetic acid in 800 ml ethanol was added over 15 min a solution containing 54 g (0.33 mole) of N,N-diethyl-p-phenylenediamine in 50 ml ethanol. The resulting solution was stirred and refluxed for 1 hr, then stored at 0°. The solid was collected, washed with 200 ml cold ethanol, and air dried to give 89 g (83%) of the product m.p. 117°-122°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:10][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[Cl:9])[CH2:2][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[CH3:20]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)ccc1OCc1ccc(Cl)c(Cl)c1
Yield: 99.8 %

Procedure:
0.5M solution of 4-chloromethyl-1,2-dichloro-benzene (1.55 g, 8.0 mmol) in DMF was added dropwise to a suspension of 4-hydroxy-3-methyl-benzaldehyde (990 mg, 7.3 mmol), K2CO3 (1.51 g, 11 mmol) and KI (120 mg, 0.73 mmol) in DMF (100 ml). The reaction mixture was treated as described in Example 6. The residue was purified on silica gel, obtaining 2.15 g of the title compound in a quantitative yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:28]([O:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[N:1]([CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:34])[CH:2]=[CH:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6[nH]ccc6c5)sc4n3)CC2)cc1
Reactant: C=CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CCn1ccc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Reaction time: 3 h

Procedure:
To 2-(1H-indol-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (90 mg, 0.245 mmol) was added acetonitrile (2.4 mL), ethylacrylate (80 μl, 735 μmol), and cesium carbonate (160 mg, 0.490 mmol) before it was stirred at ambient temp. for 3 h; the reaction mixture was quenched with 2 N HCl, concentrated, and was diluted with 75 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 1 time with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give ethyl 3-(5-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-1H-indol-1-yl)propanoate.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:31]1([CH2:37][CH2:38][NH2:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:31]1([CH2:37][CH2:38][NH:39][C:26]([C:23]2[CH:24]=[CH:25][C:19]3[O:18][C:17]([CH2:16][O:15][C:14]4[CH:13]=[CH:12][C:11]([C:1]56[CH2:10][CH:5]7[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]7)[CH2:8]5)[CH2:2]6)=[CH:30][CH:29]=4)=[N:21][C:20]=3[CH:22]=2)=[O:27])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Reactant: NCCN1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCCC1)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (70.2 mg, 0.17 mmol) and 2-piperidine-1-yl-ethylamine (0.049 ml, 0.35 mmol) in DMF 5.0 mL was added HBTU (132.7 mg, 0.35 mmol) and DIPEA (0.061 ml, 0.35 mmol). After stirring at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=20:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (2-piperidine-1-yl-ethyl)-amide as a white foam (18.9 mg, 22% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:41]([O:43][C:44](=[O:48])[CH:45](Br)[CH3:46])[CH3:42]>C1COCC1.ClCCl>[CH2:41]([O:43][C:44](=[O:48])[CH:45]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:22])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:46])[CH3:42]
Reactant: O=C1Nc2ccccc2C1=Cc1ccc(O)c2ncccc12
Reactant: CCOC(=O)C(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 8-hydroxyquinoline-5-carbaldehyde (346 mg, 2 mmol), 2-oxindole (266 mg, 2 mmol) and piperidine (43 mg, 0.5 mmol) in absolute ethanol (10 ml) was heated for 3 h at 60-70° C. under nitrogen. Then the reaction mixture was chilled and evaporated under vacuum to dryness. The residue was submitted to column chromatography over silica gel using dichloromethane/ethanol 4% as eluant to give pure 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole in 60% yield (365 mg). To a solution of 3-(8-hydroxy-5-quinolylmethylen)-2-oxindole (300 mg, 0.99 mmol) in THF (5 ml) was added at room temperature a solution of 1M tetrabutylammonium fluoride (5 ml) and 2-bromopropionic acid ethylester (0.9 ml, 6.9 mmol). The reaction mixture was stirred at room temperature for another 1 h and then diluted with dichloromethane. The organic layer was washed with 5% NaHCO3 solution and water, dried over sodium sulfate and then evaporated under vacuum. The oily residue was chromatographed on silica gel using ethyl acetate as eluant to give pure title compound in 86% yield (330 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:19]([Zn]CC)[CH3:20].CCCCCC>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:20]
Reactant: Cc1csc(Nc2nccc3ccc(Cl)nc23)n1
Reactant: CC[Zn]CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc2ccnc(Nc3nc(C)cs3)c2n1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a solution of (2-chloro-[1,7]naphthyridin-8-yl)-(4-methyl-thiazol-2-yl)-amine (0.055 g, 0.20 mmol) in 2 ml dry tetrahydrofuran (purged with argon) were subsequently added tetrakis(triphenylphosphine)palladium (0.011 g, 0.0095 mmol) and a 1.0 M solution of diethylzinc in n-hexane (0.4 ml, 0.4 mmol). The reaction mixture was heated at reflux for 1 h. Cooling to room temperature was followed by quenching with saturated aqueous ammonium chloride solution at 0-5° C. The aquous layer was basified to pH 12 with 1 M aqueous sodium hydroxide solution and extracted with three portions of methyl-tert.-butyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. Flash-chromatography gave the title compound (0.015 g, 28%) as light yellow solid, MS m/e (%): 271 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)/[CH:10]=[C:11](\O)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].[CH3:19][NH:20][NH2:21]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:20]([CH3:19])[N:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)/C(O)=C/C(=O)c1ccc(C#N)cc1
Reactant: CNN
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(C#N)cc2)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
Under argon atmosphere (Z)-ethyl 4-(4-cyanophenyl)-2-hydroxy-4-oxobut-2-enoate (500 mg, 2.04 mmol, Eq: 1.00) was dissolved in Ethanol (10 ml) at rt. Methylhydrazine (95.9 mg, 110 μl, 2.04 mmol, Eq: 1.00) was added dropwise (The solution became yellow). The solution was stirred overnight at rt followed by 6 h heating at 50° C., cooled down to rt and concentrated. in vacuo. The residue was directly purified by column chromatography (20 g) Heptane/EtOAC:9/1 to give the expected pyrazole (173 mg, 33.2%) as a white solid. MS (ISP): 256.3 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].[Cl:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][C:11]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:10]([F:28])[CH:9]=1.O>CN(C=O)C>[Cl:7][C:8]1[C:13]([CH2:14][O:6][CH2:3][C:4]#[CH:5])=[CH:12][C:11]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:10]([F:28])[CH:9]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(CBr)c(Cl)cc2F)c1=O
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOCc1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 91 %

Procedure:
0.04 g (1.10 mmol) of sodium hydride was suspended in 5 ml of DMF, and 0.06 g (1.10 mmol) of propargyl alcohol was dropwise added thereto at room temperature, followed by stirring for 30 minutes. Then, 0.40 g (1.00 mmol) of 3-(4-chloro-2-fluoro-5-bromomethylphenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 5 ml of DMF, and dropwise added thereto, followed by stirring for 2 hours. The reaction mixture was poured into water and extracted with ethyl ether. The extract was dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.34 g (yield: 91%) of the desired product. Melting point: 99-101C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:40]([C:47]2[CH:52]=[CH:51][C:50]([S:53]([CH3:56])(=[O:55])=[O:54])=[CH:49][CH:48]=2)=[CH:41][CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:42]1([CH:41]=[C:40]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH2:21][OH:22])[CH:18]=[C:13]3[CH:12]=2)[C:47]2[CH:52]=[CH:51][C:50]([S:53]([CH3:56])(=[O:55])=[O:54])=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)[Si](OCCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(OCCO)cnc3[nH]2)cc1
Yield: 99.9 %

Procedure:
A solution of 1-benzenesulfonyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethoxy]-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (870 mg, 1.08 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 10 mL, 10 mmol) was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethanol (460 mg, quant.) as a white solid: LC/MS m/e calcd for C23H26N2O4S [M+H]+ 427.54, observed 427.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:25][C@H:14]23)=[O:7])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: COc1ccc(C(=O)O)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1N
Yield: 77 %

Procedure:
The title compound is prepared from 3-amino-4-methoxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 77% of theory; LC (method 4): tR=1.75 min; Mass spectrum (ESI+): m/z=323 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:33]1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C1CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])[C:11]([CH2:30][CH3:31])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:33][CH2:16]1
Reactant: CCc1nc(Br)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.96-1.00, 1.26-1.32, 2.04, 2.35-2.40, 2.61-2.66, 3.0-3.04, 3.22-3.27, 4.09-4.14, 4.68-4.70, 5.08, 5.45-5.48, 7.23-7.31; MS (ESI+) for C24H23Cl2N3O m/z 440 (M+H)+.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][CH:34]1[C:41](=[O:42])[N:40]2[CH:35]1[S:36][CH2:37][C:38]([CH3:59])=[C:39]2[C:43]([O:45][CH:46]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>C(Cl)Cl>[CH:46]([O:45][C:43]([C:39]1[N:40]2[CH:35]([S:36][CH2:37][C:38]=1[CH3:59])[CH:34]([NH:33][C:27](=[O:29])[C:26](=[N:30][O:31][CH3:32])[C:24]1[N:25]=[C:21]([NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][CH:23]=1)[C:41]2=[O:42])=[O:44])([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of the anhydride of 2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetic acid (syn isomer)(7.2 g) in methylene chloride (22.5 cc) is added in a single shot to a solution of 7-amino-2-benzhydryloxycarbonyl-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3.15 g) in methylene chloride (31.5 cc). The temperature rises from 8° to 14° C. The mixture is kept stirred for one hour 15 minutes, during which the temperature returns to 20° C., and is then washed with 0.5 N hydrochloric acid (10 cc), distilled water (10 cc) and a saturated sodium bicarbonate solution (20 cc). The insoluble matter formed is filtered off, and the organic phase is washed again with distilled water (two×20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is chromatographed over a column (diameter: 3 cm, height: 33 cm) containing silica gel (125 g), and elution is carried out with ethyl acetate/cyclohexane mixtures (1.2 and 1 liter, of respective composition 20:80 and 40:60 by volume), 50 cc fractions of eluate being collected. Fractions 31 to 44 are evaporated and 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-[2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene, syn isomer (2.8 g) is obtained in the form of a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:5].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>CO>[CH2:34]([N:33]([CH2:36][CH3:37])[C:29]1[CH:28]=[C:27]([N:26]([CH2:24][CH3:25])[CH2:38][CH3:39])[CH:32]=[CH:31][C:30]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[Cl:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:5]1)[CH3:35]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(Cl)c1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c(Cl)c1
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2-(2-chloro-4-(diethylamino)benzoyl)benzoic acid (6.61 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (4.30 g.) and acetic anhydride (5 ml.) was allowed to stand overnight at room temperature, then diluted with methanol (10 ml.), affording 3-(2,4-bis(diethylamino)phenyl)-3-(2-chloro-4-(diethylamino)phenyl)phthalide (I: X=Y4 =(CH3CH2)2N, Y2 =Cl, Z4 =Z5 =Z6 =Z7 =H) (3.94 g., m.p. 141°-143° C.).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH:8]([OH:29])[CH:9]([N:14](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:6])[O:4][CH3:5]>CO.[C].[Pd]>[CH3:1][O:2][P:3]([CH2:7][CH:8]([OH:29])[CH:9]([NH2:14])[CH2:10][CH:11]([CH3:12])[CH3:13])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CC(O)C(CC(C)C)N(Cc1ccccc1)Cc1ccccc1)OC
Agent: [Pd]
Solvent: CO
Product: COP(=O)(CC(O)C(N)CC(C)C)OC
Temperature: 39.5 °C
Reaction time: 12 h

Procedure:
Reaction 4: A diastereomeric mixture of the crude (3-dibenzylamino-2-hydroxy-5-methyl-hexyl)-phosphonic acid dimethyl ester, compound 4, obtained in reaction 3, was treated with palladium-carbon (2.0% wt) as the catalyst in methanol (40 mL). The mixture reaction was stirred for 12 h under a hydrogen gas atmosphere at 37-42° C., and after this period of time, the mixture was filtered through a pad of Celite, and the solvents were removed under reduced pressure to leave (3-amino-2-hydroxy-5-methyl-hexyl)-phosphonic acid dimethyl ester, compound 5 as a crude oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[N:5]([CH2:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[C:6]=1Br.[O:24]1CCC[CH2:25]1.C([Mg]Br)C.CN(C)C=O>C(OC(C)C)(C)C>[Br:1][C:2]1[N:3]=[C:4]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[N:5]([CH2:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[C:6]=1[CH:25]=[O:24]
Reactant: C1CCOC1
Reactant: Clc1cc2c(cc1Cn1c(C3OCCO3)nc(Br)c1Br)OCO2
Agent: CC[Mg]Br
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: O=Cc1c(Br)nc(C2OCCO2)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.33 h

Procedure:
10 g of the product obtained in Stage 3 above is introduced into 200 ml of anhydrous tetrahydrofuran. 10 ml of ethyl magnesium bromide (3M solution in ethyl ether) is added and the reaction medium is left under agitation for 20 minutes at ambient temperature. Then an excess of anhydrous dimethylformamide is added. After 2 hours at ambient temperature, hydrolysis is carried out with 200 ml of 1N hydrochloric acid and extraction is carried out 3 times with 300 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride then dried and evaporated to dryness. The residue obtained is impasted in isopropyl ether. In this way 7.6 g of expected product is obtained, which is used without purification for the following stage.