Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([Cl:37])=[O:36])=[CH:30][CH:29]=1>>[ClH:37].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[O:36])=[CH:30][CH:29]=1.[ClH:37]
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1ccc(CC(=O)N2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: Cl

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and (4-methoxyphenyl)acetyl chloride (60 mg) were reacted in the same manner as in Example 46 to obtain the title compound in the form of a hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:9]1.[N:23]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:16]([N:13]1[CH2:14][CH2:15][C:10]2([C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9]2)[CH2:11][CH2:12]1)#[N:23]
Reactant: CN1CCC2(CC1)CN(c1ccccc1F)c1ccccc12
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CN1CCC2(CC1)CN(c1ccccc1F)c1ccccc12
Reaction time: 16 h

Procedure:
A mixture of 0.82 g of 1-(2-fluorophenyl)-1'-methylspiro[indoline-3,4'-piperidine], free base of Example 10, 0.92 g of cyanogen bromide and 1. g of potassium carbonate in 24 ml of methylene dichloride is stirred at ambient temperature for 5 hours and then an additional 0.20 g of cyanogen bromide is added. Stirring is continued for 16 hours before filtering the mixture. The filtrate is boiled with methyl alcohol and the hot solution is evaporated to dryness leaving a brown foam. This product is purified by passing through a silica gel column, ether methylene chloride (1:1) mixture eluant, to provide a tan solid. The solid is recrystallized from an acetone-hexane mixture to provide white needles (slight tan tint), mp 131°-132° C. of 1'-cyano-1-(2-fluorophenyl)spiro[indoline-3,4'-piperidine].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]1[C:38]2[C:33](=[N:34][C:35]([NH:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)=[CH:36][CH:37]=2)[N:32]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[N:31]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[N:13]([CH2:29][C:30]3[C:38]4[C:33](=[N:34][C:35]([NH:39][CH2:40][C:41]5[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=5)=[CH:36][CH:37]=4)[N:32]([CH2:49][C:50]4[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=4)[N:31]=3)[CH:14]=[CH:15][C:16]=2[C:17]([F:18])([F:19])[F:20])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Reactant: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(Cn4ccc(C(F)(F)F)c(Oc5cc(Cl)cc(C#N)c5)c4=O)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile (3C, 0.150 g, 0.477 mmol) and potassium carbonate (0.066 g, 0.477 mmol) suspended in dimethylformamide (1 mL) was added 3-(chloromethyl)-N,1-bis(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (0.202 g, 0.477 mmol) as a solution in dimethyl formamide (1 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with brine (3×25 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-5% methanol in CH2Cl2 to afford the title compound. 1H NMR (DMSO-d6) δ 7.91 (d, J=7.0 Hz, 1H), 7.76-7.74 (m, 1H), 7.72-7.68 (m, 1H), 7.58-7.56 (m, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.49-7.47 (m, 1H), 7.26 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 6.59 (d, J=7.2 Hz, 1H), 6.40 (d, J=8.9 Hz, 1H), 5.30 (s, 2H), 5.28 (s, 2H), 4.50-4.46 (m, 2H), 3.71 (s, 3H), 3.69 (s, 3H). LRMS (M+1)=700.6.
Reaction SMILES: CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O.[OH:26][C@H:27]([C@H:32]([NH:36][C:37](=[O:77])[C@H:38]([NH:40][C:41](=[O:76])[C@H:42]([NH:46][C:47](=[O:75])[CH2:48][C@H:49]([OH:74])/[CH:50]=[CH:51]/[CH2:52][CH2:53][S:54][C:55]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH:43]([CH3:45])[CH3:44])[CH3:39])[CH:33]([CH3:35])[CH3:34])[CH2:28][C:29]([OH:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C1COCC1.CN(C=O)C>[OH:26][C@H:27]1[CH2:28][C:29](=[O:31])[O:30][O:74][C@H:49](/[CH:50]=[CH:51]/[CH2:52][CH2:53][S:54][C:55]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:48][C:47](=[O:75])[NH:46][C@H:42]([CH:43]([CH3:44])[CH3:45])[C:41](=[O:76])[NH:40][C@H:38]([CH3:39])[C:37](=[O:77])[NH:36][C@@H:32]1[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)[C@@H](NC(=O)[C@@H](C)NC(=O)[C@H](NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C)[C@@H](O)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)[C@H]1NC(=O)[C@@H](C)NC(=O)[C@@H](C(C)C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OOC(=O)C[C@@H]1O
Yield: 19.4 %

Procedure:
To a solution of MNBA (73.5 mg, 0.21 mmol) and DMAP (51.9 mg, 0.42 mmol) in CH2Cl2/THF (33 mL, 2:1) was added dropwise a solution of acid 8 (129 mg, 0.18 mmol) in CH2Cl2/THF (134.5 mL, 2:1) with 3 drops of DMF over 4 h. After a further 16 h the reaction mixture were concentrated in vacuo. Purification by flash column chromatography on silica (eluent 1:0-98:2-96:4-94:6-92.8 CH2Cl2/MeOH) gave 9 (24.7 mg, 0.035 mmol, 17%) as a white solid: Rf 0.43 CH2Cl2/MeOH (90:10); IR (thin film) 3293 (b), 2963 (m), 1732 (m), 1660 (s), 1536 (m) cm−1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>ClCCl.C(#N)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H]1CCCN1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.2 %

Procedure:
A suspension of 4-(trifluoromethyl)phenylboronic acid (190 mg), copper (II) acetate (27 mg) and 4 Å molecular sieves (188 mg) in dichloromethane (4 mL) was stirred at room temperature for 5 min, and (R)-tert-butyl pyrrolidine-2-carboxylate (86 mg) in acetonitrile (0.5 mL) was added followed by triethylamine (0.07 mL). The reaction vial was flushed with oxygen, sealed and stirred at 50° C. for 24 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC eluting with 10% ethyl acetate/90% hexanes to give the title compound as a colorless oil (43 mg). HPLC retention time: 1.99 min (method A). MS (ESI) (M+H)+ 316.14. 1H NMR (400 MHz, CDCl3) δ 7.41 (1H, d, J=8.4 Hz), 6.52 (1H, d, J=8.4 Hz), 4.15 (1H, m), 3.53 (1H, m), 3.40 (1H, m), 2.0-2.3 (3H, m), 1.41 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24].O>C1(C)C=CC=CC=1.ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:22]([C:21]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCOC(=O)CCCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A solution of ethyl 4-[(3-aminoquinolin-4-yl)amino]butanoate (72.0 g, 263 mmol) in toluene (700 mL) was heated at reflux for 10 minutes and then cooled slightly. Trimethyl orthobutyrate (42 g, 280 mmol) and pyridinium p-toluenesulfonate (1.0 g, 4.0 mmol) were added, and the reaction was heated at reflux under a Dean-Stark trap for two hours while the distillate was periodically removed. The reaction was then stirred overnight at ambient temperature. Charcoal (5 g) was added, and the resulting mixture was heated at reflux for three hours and then filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure to provide an oil that crystallized upon standing. The solid was dissolved in hot methanol (125 mL), and water (50 mL) was added. After one hour, the mixture was cooled in an ice bath to form a precipitate. The precipitate was isolated by filtration and dissolved in dichloromethane. A layer of water was present and was removed. The remaining solution was dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 53.2 g of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([OH:19])[CH2:11][C@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=[O:14])=[CH:6][C:5]=1[CH3:20].[CH3:21]I>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([O:19][CH3:21])[CH2:11][C@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=[O:14])=[CH:6][C:5]=1[CH3:20]
Reactant: C=CC[C@@H](C[C@@H](O)c1ccc(F)c(C)c1)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C[C@@H](OC)c1ccc(F)c(C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 217 mg NaH in 20 mL THF was added (S)-2-((R)-2-(4-fluoro-3-methylphenyl)-2-hydroxyethyl)pent-4-enoic acid in 5 mL THF slowly at room temperature. To this mixture was added methyl iodide (289 μL) dropwise followed by stirring for 3 h at 25° C. The reaction was quenched by the addition of 10 mL 1M HCl and then extracted with ethylacetate (3×30 mL). The combined organic layers were washed with brine (2×20 mL) and dried over sodium sulfate. Evaporation of solvent afforded an oil which was used without further purification in the next reaction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Mg]Br.[CH3:8][N:9]([CH3:32])[C:10]1(C#N)[CH2:15][CH2:14][CH:13]([CH:16]([O:24][CH:25]([O:27][CH2:28][CH3:29])[CH3:26])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1.O.[Cl-].[NH4+]>O1CCCC1>[CH2:28]([O:27][CH:25]([O:24][CH:16]([CH:13]1[CH2:14][CH2:15][C:10]([N:9]([CH3:32])[CH3:8])([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:12]1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:26])[CH3:29]
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Reactant: Br[Mg]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)OC(Cc1ccccc1)C1CCC(c2cccs2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 1 M solution of 2-thienylmagnesium bromide in tetrahydrofuran (9.25 ml, 9.25 mmol) was added dropwise to a solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with ice and under an argon atmosphere. The mixture was stirred at room temperature for 48 h and water and saturated ammonium chloride solution (10 ml of each) were then added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH3:4].Br[CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16]>>[C:8]([C:7]1[CH:6]=[C:5]([CH:3]([N:2]([CH3:1])[C@H:14]([C:15]([O:17][CH3:18])=[O:16])[CH3:19])[CH3:4])[CH:12]=[CH:11][CH:10]=1)#[N:9]
Reactant: CNC(C)c1cccc(C#N)c1
Reactant: COC(=O)C(C)Br
Product: COC(=O)[C@H](C)N(C)C(C)c1cccc(C#N)c1

Procedure:
Compound was prepared following the general procedure 11 starting from 3-[1-(methylamino)ethyl]benzonitrile and methyl 2-bromopropionate, affording the title compound as a colorless oil. HPLC (Method A) Rt 1.54 min (Purity: 74%).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][N:4]1[CH3:17])=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[CH3:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:41]#[C:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1>C1(C)C=CC=CC=1>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([C:42]#[C:41][N:9]2[C:10]3[C:15](=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:7]3[CH2:6][CH2:5][N:4]([CH3:17])[CH:3]([CH2:1][CH3:2])[C:8]2=3)=[CH:44][CH:45]=1
Reactant: Clc1ccc(C#CBr)cc1
Reactant: CCC1c2[nH]c3ccc(C)cc3c2CCN1C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: CCC1c2c(c3cc(C)ccc3n2C#Cc2ccc(Cl)cc2)CCN1C
Temperature: 80 °C

Procedure:
1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (228 mg, μmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite, and the Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 9-((4-chlorophenyl)ethynyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as brown semi solid (30 mg). 1H NMR (CDCl3) FREE BASE 7.50-7.40 (m, 3H), 7.37-7.33 (m, 2H), 7.28 (s, 1H), 7.20-7.15 (d, 1H), 5.25-5.20 (t, 1H), 3.06 (s, 3H), 3.02 (s, 3H), 2.98-2.88 (m, 2H), 2.80-2.60 (m, 2H), 1.20-1.18 (m, 2H), 1.10-1.07 (t, 3H).
Reaction SMILES: CC(C)=O.N[C:6]1([O:15]O)[CH2:11][CH:10]([CH3:12])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7]1.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[CH3:12][CH:10]1[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6](=[O:15])[CH2:11]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: CCO
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 1 h

Procedure:
Acetone (11.6 g.) in ethanol (50 c.c.) was stirred at below 0°C and 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g.; 80% pure) added. After stirring for ca. 1 hour the solid had dissolved. To the solution was added magnesium sulphate and it was stored at 0° overnight. Filtration and distillation gave acetone and dihydroisophorone (probably containing some symmetrical amino-peroxide ##EQU20## and a product (2.2 g.), b.p. 75° - 78°/1.0 mm, had a peroxide equivalent 239.4 and gave N, 6.3% an elemental analysis.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>>[C:1]1([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][N:9]([C:20](=[O:21])[C:19]3[CH:18]=[C:17]([O:16][CH3:15])[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccccc2)CCNC1
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepared by the method of example 3.1 using 2-(3-phenyl-pyrrolidin-3-yl)-ethanol (10.47 mmol) and 3,4,5-trimethoxy-benzoyl chloride (10.49 mmol). Chromatographed on silica gel (200 g ) eluting with ethyl acetate and then 3% methanol in dichloromethane to give the title compound:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[CH2:22]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:30].[N:31]1[CH:36]=C[CH:34]=[CH:33][CH:32]=1.ClC(OC1C=CC=CC=1)=[O:39].C1(N)CC1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:30][C:3]1[CH:4]=[C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][N:23]([CH3:27])[CH2:22]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH:28]=[CH:29][C:2]=1[NH:1][C:36]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:39]
Reactant: CN1CCCC(COc2cc3nccc(Oc4ccc(N)c(Cl)c4)c3cc2C#N)C1
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)c3cc2C#N)C1
Reaction time: 1 h
Yield: 67.5 %

Procedure:
After dissolving 4-(4-amino-3-chlorophenoxy)-6-cyano-7-((1-methyl-3-piperidyl)methoxy)quinoline (246 mg, 0.582 mmol) in dimethylformamide (6 ml) under a nitrogen atmosphere, pyridine (0.19 ml, 2.33 mmol) and phenyl chloroformate (0.15 ml, 1.16 mmol) were added dropwise at room temperature, and the mixture was stirred for 1 hour. Cyclopropylamine (0.20 ml, 2.91 mmol) was added dropwise, and the mixture was further stirred for 3 hours. The reaction solution was distributed between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was suspended in methanol and diluted with water, and the crystals were filtered out and dried at 70° C. to obtain the title compound (198.7 mg, 0.393 mmol, 67.5%) as light yellow crystals.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[C:14](B(O)O)=[CH:13][CH:12]=[CH:11][N:10]=1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[CH3:26])([CH3:21])([CH3:20])[CH3:19]>COCCOC.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>[C:18]([O:22][C:23](=[O:34])[NH:24][C@@H:25]([C:27]1[CH:28]=[CH:29][C:30]([C:14]2[C:9]([O:8][CH3:7])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:31][CH:32]=1)[CH3:26])([CH3:19])([CH3:20])[CH3:21]
Reactant: COc1ncccc1B(O)O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncccc1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 95 °C
Yield: 79.2 %

Procedure:
2M Aqueous sodium carbonate solution (3.25 ml, 6.50 mmol) was added to a mixture of 2-methoxypyridine-3-boronic acid (994 mg, 6.50 mmol), (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (650 mg, 2.16 mmol) and tetrakis(triphenylphosphine)palladium (0) (125 mg, 0.108 mmol) in 1,2 dimethoxyethane (27 ml). The mixture was heated at 95° C. for 16 h under nitrogen atmosphere. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed twice with brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting gum was chromatographed over silica gel eluting with heptane/dichloromethane and the solvent evaporated to give (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (593 mg, 1.71 mmol, 83.5%) as a crystalline solid. Trifluoroacetic acid (6.45 ml, 86.8 mmol) was added dropwise to a solution of (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester (645 mg, 1.97 mmol) in dichloromethane (6.45 ml) under a nitrogen atmosphere at 0° C. After stirring for 1 h at 0° C. the solvent was evaporated. Methanol (20 ml) was added and the mixture added to a Strata™ 5 g/20 ml SCX column. The intermediate amine was eluted with 2M ammonia in methanol. The solvent was evaporated to give (R)-1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethylamine as a gum (425 mg, 1.86 mmol, 94.6%). The title compound was then prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) using 4-bromo-3-thiophenesulfonyl chloride and 1-[4-(2-Methoxy-pyridin-3-yl)-phenyl]-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, 1H), 7.56 (d, 1H), 7.41, 7.20 (a/b, 4H), 7.38 (m, 1H), 6.99-6.92 (m, 2H), 5.27 (d, 1H), 4.60 (m, 1H), 3.97 (s, 3H), 1.54 (d, 3H) ppm; MS (ESI) m/z: 453 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:51][C:52]1[N:56]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[N:55]=[C:54]([NH2:64])[CH:53]=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1)[C:12]([NH:64][C:54]1[CH:53]=[C:52]([CH3:51])[N:56]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[N:55]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cc(N)nn1Cc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)nn1Cc1ccccn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 31 %

Procedure:
3-Benzyloxy-5-isopropoxy-benzoic acid (0.35 mmol) is dissolved in acetonitrile, di-isopropyl ethyl amine (3 eq.), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium (1.2 eq.) and 5-methyl-1-pyridine-2-ylmethyl-1H-pyrazole-3-ylamine (1.0 eq., prepared similar to 1-pyridine-2-ylmethyl-1H-pyrazole-3-ylamine) is added and stirred at RT for 14 hours. The solvent is removed in vacuo. 3-Benzyloxy-5-isopropoxy-N-(5-methyl-1-pyridine-2-ylmethyl-1H-pyrazole-3-yl)-benzamide is obtained after column chromatography (chloroform (methanol) as a colourless powder in a yield of 31%; HPLC (Method B): 3.25 min; LC-MS: 2.350 min, 457.15 (M÷H+);
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][CH:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.CO.O1CCCC1.[Li]>O.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH:8]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:9]([OH:11])=[O:10])=[CH:17][CH:18]=1
Reactant: COC(=O)C(CC(C)C)OCc1ccc(Br)cc1
Agent: Cl
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(OCc1ccc(Br)cc1)C(=O)O

Procedure:
Methyl 2-[(4-bromobenzyl)oxy]-4-methylpentanoate in a mixture of water (3 mL), methanol (3 mL) and tetrahydrofuran (6 mL) was treated with lithium hydroxyde monohydrate (560 mg, 13.3 mmoles) until disappearance of the starting material was observed by TLC. The reaction was diluted with 1.2 N hydrochloric acid until pH 1. The aqueous phase was extracted 3 times with dichloromethane. The organic phase was concentrated under reduced pressure to afford 2-[(4-bromobenzyl)oxy]-4-methylpentanoic acid which was used as such in the next reaction.