Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])/[CH:20]=[CH:21]/[C:22]1[N:27]=[C:26]([CH:28]=[O:29])[CH:25]=[CH:24][CH:23]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+].C(OCC)(=O)C.[O:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>>[OH:29][CH:28]([C:26]1[CH:25]=[CH:24][CH:23]=[C:22](/[CH:21]=[CH:20]/[CH:19]([OH:18])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[N:27]=1)[CH2:50][CH2:49][CH2:48][CH2:47][OH:46]
Reactant: C1CCOC1
Reactant: CCCCCCCCC(/C=C/c1cccc(C=O)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCCCCCC(O)/C=C/c1cccc(C(O)CCCCO)n1
Temperature: -80 °C
Reaction time: 2 h

Procedure:
5.1 ml of a Grignard solution (produced from 385 mg of magnesium and 1.76 g of 4-chloro-1-tert-butyldimethylsilyloxybutane in tetrahydrofuran) is instilled at -80° C. in a solution of 370 mg of 6-[(1E)-(3RS)-3-tert-butyldiphenylsilyloxy-1-undecenyl]-pyridine-2-carbaldehyde in 3 ml of tetrahydrofuran. After 2 hours of stirring at -80° C., the reaction mixture is poured into 10 ml of saturated ammonium chloride solution, shaken out with ethyl acetate, the organic phase is dried and concentrated by evaporation. The residue is dissolved in 10 ml of tetrahydrofuran, mixed with 2.47 g of tetrabutylammonium fluoride and stirred for 17 hours at room temperature. The reaction mixture is poured into 50 ml of diethyl ether, washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/0-30% ethyl acetate. 110 mg of the title compound is obtained as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:22][CH:19]2[CH2:21][CH2:20]2)[CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCC1CC1
Reactant: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COCCN(CC1CC1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (525 mg), cyclopropylmethyl bromide (218 μL) and potassium carbonate (340 mg) was heated to reflux in MeCN for 16 h. After cooling the reaction mixture was diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-[cyclopropylmethyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (475 mg). Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].[H-].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:16]=1)=[O:14])[CH3:11]>CN(C=O)C>[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[C:19]([O:7][CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[CH:18]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:16]=1)=[O:14])[CH3:11]
Reactant: [N-]=[N+]=NCCCO
Reactant: CCOC(=O)c1cc(Br)cc(C(=O)OCC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCCCN=[N+]=[N-])cc(C(=O)OCC)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
3-Azido-1-propanol (0.266 mL, 3.64 mmol) was dissolved in DMF (5 mL) and cooled to 0° C. NaH (146 mg, 3.64 mmol) was added and the mixture was stirred for 15 minutes. Diethyl-4-bromo-2,6-pyridinedicarboxylate was dissolved in DMF (5 mL) an added to the reaction mixture dropwise. The reaction was complete as indicated by TLC in 1 hour. The reaction mixture was partitioned between CH2Cl2 and water. The water was separated and extracted with CH2Cl2. The CH2Cl2 layers were combined, dried (MgSO4) and concentrated to an oil. The oil was purified by silica gel flash column chromatography to give a yield of 40%. 1H NMR (CDCl3) δ 1.44 (t, 6H, 2× CH2), 2.11 (m, 2H, CH2), 3.54 (t, 2H, CH2), 4.23 (t, 2H, CH2), 4.45 (q, 4H, 2× CH2), 7.78 (2, 2H, 2× Ar).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Br)=[O:8])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=[O:31])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:21][C:20]=1[NH2:30])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl.Cl>[C:12]([O:16][C:17](=[O:31])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:21][C:20]=1[NH:30][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(Br)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
4-Bromomethyl-benzoyl bromide (0.70 g, 2.52 mmol) was made 0.21 M in anhydrous DCM and cooled to −78° C. To this stirring solution was added (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (0.73 g, 2.52 mmol) followed by DIPEA (0.98 g, 7.56 mmol). The resulting solution was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was then diluted with 0.1 N HCl and extracted with EtOAc. The organic layer was then washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), and concentrated in vacuo to afford the title compound: 1H NMR (DMSO-d6, 600 MHz) 9.90 (s, 1H), 8.72 (s, 1H), 7.94 (d, J=7.8. Hz, 2H), 7.78-7.80 (m, 1H), 7.57-7.62 (m, 3H), 7.47-7.51 (m, 2H), 7.42-7.44 (m, 1H), 7.09-7.12 (m, 1H), 4.77 (s, 2H), 1.43 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:14]2[N:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:21])[C:17]([OH:35])=[C:16]([OH:36])[N:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:7][C:8]1([C:14]2[N:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:21])[C:17]([OH:35])=[C:16]([OH:36])[N:15]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1(c2nc(O)c(O)c(C(=O)NCc3ccc(F)cc3S(C)(=O)=O)n2)CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(F)ccc1CNC(=O)c1nc(C2(N)CCOCC2)nc(O)c1O

Procedure:
A solution of tert-butyl-4-[4-({[4-fluoro-2-(methylsulfonyl)benzyl]amino}carbonyl)-5,6-dihydroxypyrimidin-2-yl]tetrahydro-2H-pyran-4-yl-carbamate (C-31) in dichloromethane was treated with an excess of trifluoroacetic acid for 3 hours at room temperature. The acid in excess was removed in vacuo to obtain the crude title compound (C-32) as a pale yellow solid, after trituration with ethyl ether.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[F:7][C:8]1[C:9]([C:18]([F:21])([F:20])[F:19])=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2[NH2:17]>N1C=CC=CC=1>[F:7][C:8]1[C:9]([C:18]([F:21])([F:19])[F:20])=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2[NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1n[nH]c2c(F)c(C(F)(F)F)ccc12
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2c(F)c(C(F)(F)F)ccc12
Temperature: 3 °C
Reaction time: 76 h

Procedure:
1.0 cm3 of butyryl chloride is added to 2.1 g of 7-fluoro-6-(trifluoromethyl)-1H-indazole-3-amine, prepared as in patent application WO 02/22608, in 20 cm3 of pyridine, after cooling to about 3° C., and the mixture is then left at room temperature for 76 hours. The reaction medium is concentrated under reduced pressure (2 kPa; 40° C.) and the residue is taken up in 50 cm3 of ethyl acetate and 20 cm3 of water. The organic phase is washed with 2×20 cm3 of distilled water and then with 20 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulphate, filtration and concentration under reduced pressure (2 kPa; 40° C.), the residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.); after drying (90 Pa; 40° C.), 875 mg of N-[7-fluoro-6-(trifluoromethyl)-1H-indazol-3-yl)butanamide are obtained in the form of a pink solid melting at 220°-222° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: COC(=O)c1ccc(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
g (2.78 mmol) of 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 10 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:29][C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=4[F:37])[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:38])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[O:29][C:20]1[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]2[N:24]=[C:16]([C:12]3[CH:11]=[C:10]([CH3:38])[C:9]([O:8][CH2:7][C:6]([OH:39])=[O:5])=[C:14]([CH3:15])[CH:13]=3)[O:17][C:18]=2[N:19]=1
Reactant: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Yield: 114.8 %

Procedure:
69 mg of {4-[5-(2,5-difluoro-phenoxy)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetic acid tert-butyl ester were dissolved in 1.6 ml of dichloromethane and treated with 0.8 ml of trifluoroacetic acid. After 16 h the mixture was concentrated and freeze-dried. 71 mg of the title compound were obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7](=[O:11])OCC)=[O:5])#[N:2].[CH3:12][O:13][C:14]1[CH:25]=[C:24]2[C:17]([NH:18][CH:19]=[C:20]2[CH2:21][CH2:22]N)=[CH:16][CH:15]=1>C(O)(=O)C.[Pd]>[CH3:12][O:13][C:14]1[CH:25]=[C:24]2[C:17](=[CH:16][CH:15]=1)[NH:18][C:19]1[CH:1]3[CH2:3][C:4](=[O:5])[NH:6][C:7](=[O:11])[N:2]3[CH2:22][CH2:21][C:20]2=1
Reactant: CCOC(=O)NC(=O)CC#N
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CCN1C(=O)NC(=O)CC31
Reaction time: 72 h
Yield: 40 %

Procedure:
Ethyl cyanoacetylcarbamate (156 mg) and palladium-on-charcoal (0.6 g) are successively added to 5-methoxytryptamine (119 mg) dissolved in acetic acid. The mixture is stirred under a hydrogen atmosphere for 72 h. The medium is then filtered and the palladium is washed with a chloroform/methanol mixture. After evaporation of the solvent, the crude product obtained, dissolved in toluene, is refluxed overnight. The 9-methoxy-1,2,3,4,6,7,12,12b-octahydropyrimido[6,1-a]-β-carboline-2,4-dione precipitates and is recovered by simple filtration (40% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[F:37])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: Oc1ccccc1F
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1CC(Oc2ccccc2F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
(2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS Reg. No. 74844-91-0) (300 mg, 1.22 mmol) was dissolved in THF (10 ml), and triphenylphosphine (385 mg, 1.47 mmol) and 2-fluorophenol (164.5 mg, 1.47 mmol) were added. The reaction was cooled in ice, DIAD (0.23 ml, 1.2 mmol) added dropwise and the reaction stirred at room temperature overnight. The mixture was concentrated in vacuo, CH2Cl2 (20 ml) added and the solution washed with 2N NaOH (10 ml). The phases were separated and the organic phase washed with saturated brine (10 ml), dried over MgSO4 and evaporated. The residue was dissolved in a minimum of diethylether and pentane added until solution just maintained. After seeding with triphenylphosphine oxide, the solution was cooled in ice and the resultant precipitate filtered. The filtrate was evaporated and the residue purified by flash chromatography on silica (50 g) eluting initially with pentane:diethylether (2:1 by volume), then pentane:diethylether (1:1 by volume) to give the title product (388 mg, 58%) as an impure oil containing diisopropylbicarbamate as an impurity.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([O:24]CC)=O)[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].O1CCOCC1.[NH2:43][NH2:44]>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:43][NH2:44])=[O:24])[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:35])([F:34])[F:36])=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 90 °C
Yield: 69.2 %

Procedure:
To a solution of ethyl 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carboxylate (2.63 g, 5.110 mmol) in 8 mL of 1:1 PhMe:Dioxane was added hydrazine (1 mL, 31.86 mmol). The reaction was heated at 90° C. for 12 h and then cooled to room temperature. The reaction was filtered through a small amount of celite to remove a black precipitate and then concentrated and placed on the high vacuum pump. The residue was dissolved in a minimum amount of dichloromethane and slowly added to 200 mL ether with stirring. 100 mL of ether was added and the white precipitate was filtered and rinsed with ether to afford 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carbohydrazide (1.77 g, 70%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 9.21 (s, 1H), 8.16 (s, 1H), 8.14-8.13 (m, 1H), 8.03-8.00 (m, 1H), 7.92-7.89 (m, 1H), 7.85-7.89 (m, 3H), 7.74-7.64 (m, 4H), 7.36 (d, J=8.58 Hz, 2H), 4.44 (brs, 2H), 3.28 (s, 3H); MS (ES): 501.3 [M+H]+ and 523.2 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[C:19]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]([CH3:30])[NH:25][CH2:24][CH2:23]3)=[C:18]([CH3:31])[O:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([C:19]5[C:15]([CH3:14])=[N:16][O:17][C:18]=5[CH3:31])[CH:21]=4)[CH:26]3[CH3:30])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)CCNC2C
Product: Cc1noc(C)c1-c1ccc2c(c1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[OH:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:26]3[CH2:27][CH2:28][CH2:29][CH:24]([OH:23])[CH2:25]3)=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: OC1CCCNC1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCN3CCCC(O)C3)ccc21
Yield: 66.9 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (50 mg, 0.17 mmol) and 3-hydroxypiperidine (300 mg, 2.67 mmol) are reacted to provide the title compound (45 mg, 67%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].Br[CH:28]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:32]([O:31][C:29]([CH:28]([C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:43][CH:44]=1)[O:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)Cc1ccc(C(Br)C(=O)OCc2ccccc2)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(O)c2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(OC(C(=O)OCc3ccccc3)c3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 165.9 %

Procedure:
A mixture of ethyl 4-[3-(3-hydroxybenzoyl)indol-1yl]butyrate (984 mg), benzyl 2-bromo-2-[4-isobutylphenyl)acetate (362 mg) and diisopropylethylamine (362 mg) in dichloromethane (10 ml) was stirred at 25° C. for 20 hours, and then refluxed for 70 hours. The mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (20 g) eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-[3-[(benzyloxycarbonyl)(4isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyrate (1.05 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:22])=[CH:4][CH:3]=1.[CH3:25][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])([CH3:25])[CH3:20])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:22])=[CH:23][CH:24]=1
Reactant: CC(=O)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
According to Scheme 20: To a solution of 1-(4-chlorobenzyl)-5-(4-acetylphenyl)pyridin-2(1H)-one (1 eq, 0.20 mmol, 80 mg) in THF (5 mL) at −50° C. was added a solution of methyl magnesium bromide (3M, 1.3 eq, 0.30 mmol, 0.04 g) and the reaction stirred at −50° C. for 1 hour. The reaction was quenched at −78° C. with saturated aqueous NH4Cl. The reaction was allowed to warm to room temperature and diluted with AcOEt and the organic phase extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 80/20 and was recrystallized from pentane/Et2O to afford 1-(4-chlorobenzyl)-5-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2(1H)-one (0.08 mmol, 30 mg, 36%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:12][C:13]([CH3:15])=[CH2:14])[C:10]=1[OH:11])[CH:7]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:6][CH2:5]2.C(N(CC)CC)C.S([O-])([O-])(=[O:32])=S.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[C:10]2[O:11][C:13]([CH2:15][OH:32])([CH3:14])[CH2:12][C:9]=2[C:8]2[CH:7]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=S([O-])([O-])=S
Reactant: C=C(C)Cc1c(O)c(Br)cc2c1C(CCNC(=O)CC)CC2
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCCC1CCc2cc(Br)c3c(c21)CC(C)(CO)O3
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of N-(2-(5-bromo-6-hydroxy-7-(2-methyl-2-propenyl)indan-1-yl)ethyl]propionamide (550 mg, 1.5 mmol.) in dichloromethane (5 mL) was cooled with ice. To the solution were added triethylamine (0.2 mL, 1.5 mmol.) and methachloroperbenzoic acid (1.0 g, 4.1 mmol.). The mixture was stirred for two hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium thiosulfate. The organic matter was extracted with ethyl acetate. The extract solution was washed with 1N HCl and a saturated aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was dissolved in dichloromethane, to which was added triethylamine (1 mL). The mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by means of silica gel column chromatography (chloroform:methanol=10:1) to afford the title compound (yield 420 mg, 73%) as an oily product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>C(#N)C.C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:9]1[C:10]2[C:6](=[C:5]([O:4][CH2:3][CH2:2][N:27]3[CH2:28][CH2:29][CH:24]([C:15]4[CH:16]=[CH:17][C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:14]=4)[CH2:25][CH2:26]3)[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: ClCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc2cc(C3CCN(CCOc4cccc5[nH]ccc45)CC3)ccc2c1

Procedure:
A solution of 1-chloro-2-(4-indolyloxy)ethane, 4-(2-naphthyl)piperidine and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 29% overall yield as a white solid. mp. 119°-120° C. FDMS m/e=370 (M+ of free base).