Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][NH:11][CH:12]=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.NC1C=CC(NNC=O)=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][NH:11][CH:12]=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=CNNc1cccc([N+](=O)[O-])c1
Agent: Nc1ccc(NNC=O)cc1
Product: Nc1cccc(NNC=O)c1

Procedure:
By reacting 2-(3-nitrophenyl)-1-formylhydrazine in the same manner as in (2) above, 21.0 g of 2-(3-aminophenyl)-1-formylhydrazine was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9]([N:22]1[C:18](=[O:28])[C:19]2[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21]1=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)NCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
To a solution of (2-hydroxy-2-phenyl-ethyl)-carbamic acid tert-butyl ester (34.4 g, 145.0 mmol), phthalimide (21.3 g, 145 mmol), and PPh3 (49.4 g, 188.5 mmol) was added drop-wise DEAD (32.8 g, 188.5 mmol) under stirring at 0° C. After addition, the mixture was stirred at room temperature for an additional 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate, 20:1 to 5:1) to give [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester as a white solid. (Yield 39 g, 74%) 1H NMR (300 MHz, CDCl3): δ 7.88-7.80 (m, 2H), 7.74-7.68 (m, 2H), 7.49-7.47 (m, 2H), 7.38-7.26 (m, 3H), 5.56-5.50 (m, 1H), 4.83 (brs, 1H), 4.28-4.22 (m, 1H), 3.93-3.87 (m, 1H), 1.35 (s, 9H). LC-MS: [M-Boc+H]+ 267.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[Br:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([NH2:28])[N:24]=[CH:25]2)=[CH:20][CH:19]=1.BrC1C=CC=C2C=1C=C(N)N=C2>ClCCl>[Br:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([N:28]=[C:1]=[S:2])[N:24]=[CH:25]2)=[CH:20][CH:19]=1
Reactant: Nc1cc2ccc(Br)cc2cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Agent: Nc1cc2c(Br)cccc2cn1
Solvent: ClCCl
Product: S=C=Nc1cc2ccc(Br)cc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one 1.145 g, 4.93 mmol) in dichloromethane at room temperature was added the mixture of 7-bromoisoquinolin-3-amine and 5-bromoisoquinolin-3-amine from step B (1.0 g, 4.5 mmol). The orange solution was stirred at room temperature for 18 hours. LCMS indicated the formation of product. The deep orange solution was purified by silica gel chromatography (0-5% ethyl acetate-hexanes). The first product fractions were combined and concentrated in vacuo to afford 7-bromo-3-isothiocyanatoisoquinoline (0.27 g, 0.377 mmol, 22% yield) as a yellow solid. 1H NMR (400 MHz, Acetone) δ ppm 9.19 (1H, s), 8.41 (1H, s), 7.86-8.02 (2H, m), 7.76 (1H, s). R.T.=4.28; [M+H]+=267.04. The second product fractions were combined and concentrated in vacuo to afford 5-bromo-3-isothiocyanatoisoquinoline (0.25 g, 0.377 mmol, 21% yield) as a yellow solid. 1H NMR (400 MHz, Acetone) δ ppm 9.24 (1H, s), 8.23 (1H, d), 8.15 (1H, d), 7.81 (1H, s), 7.64 (1H, t). LCMS:R.T.=4.61; [M+H]+=267.04.
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[CH3:23]CN(C(C)C)C(C)C.C[CH:33]1[CH2:38][N:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=2)[CH2:36][CH2:35][NH:34]1>CN(C=O)C>[CH3:23][CH:38]1[N:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=2)[CH2:36][CH2:35][N:34]([C:1]([O:2][CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]2)=[O:22])[CH2:33]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Cc1cccc(N2CCNC(C)C2)c1
Solvent: CN(C)C=O
Product: Cc1cccc(N2CCN(C(=O)OCCN3CCN(C)CC3)CC2C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 2.56 g, 8.28 mmol) was dissolved in DMF (20 mL). DIPEA (1.40 mL, 8.45 mmol) and 2-Methyl-4-(3-methylphenyl)piperazine (1.50 g, 7.87 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (200 mL) and washed with 1 M aq Na2CO3 solution (6×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo, give 2-(4-methylpiperazin-1-yl)ethyl 3-methyl-4-(3-methylphenyl)piperazine-1-carboxylate (1.97 g, 69%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]CCCCC.C([Li])CCC.CI.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH3:17])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)N1CCc2sccc2C1
Agent: [Li]CCCC
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (330 mg, 1.4 mmol) was dissolved in anhydrous tetrahydrofuran (18 ml), n-butyl lithium hexane solution (3.0 mmol) was added dropwise to the solution which was cooled in an ice bath, and then the mixture was stirred for 1 hour. This was further mixed with methyl iodide (430 mg, 3.0 mmol), and the stirring was continued while increasing the reaction temperature to room temperature spending 2 hours. The reaction solution was mixed with water and the reaction product was extracted therefrom with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was removed by evaporation under a reduced pressure and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 110 mg (0.42 mmol, 31% in yield) of the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][S:18]C(=O)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][SH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)SCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(CS)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.23 g of this acetamide was dissolved in a mixed solvent of 30 ml of methanol and 3 ml of water, and cooled in an ice bath. 0.48 g of 85% potassium hydroxide was added to this solution, and stirred at 0° C. for 1.5 hours. pH of the reaction solution was adjusted to 7 by adding 2N aqueous hydrochloric acid, and extraction was carried out by adding 100 ml of dichloromethane and 50 ml of water. The dichloromethane layer was washed twice with water, and dried over anhydrous magnesium sulfate. The solvent was evapoated in vacuo to obtain the captioned colorless oily N-[3-{3-(piperidinomethyl)phenoxy}propyl]-2-mercaptoacetamide. Yield: 1.86 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+:16].[OH-]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([CH2:12][NH2:16])([OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester is prepared from 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (Bourrain et al Bioorg. Med. Chem. Lett. 9(23):3369-3374 (1999)). Concentrated aqueous NH4OH (6 mL) is added to a solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (0.50 g, 2.3 mmol) in MeOH (4 mL) at 0° C. The reaction mixture is removed from the cooling and allowed to warm to room temperature. After 7 hours, the reaction mixture is concentrated under reduced pressure to afford desired product as a white solid.
Reaction SMILES: [CH2:1]([O:8]CC1C=CC=CC=1)[C:2]1C=CC=[CH:4][CH:3]=1.[CH2:16]([SH:18])C.B(F)(F)F.C[CH2:24][O:25][CH2:26][CH3:27]>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:27]=[C:1]([OH:8])[CH:2]=[CH:3][C:4]=1[S:18][CH3:16]
Reactant: CCOCC
Reactant: CCS
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: FB(F)F
Solvent: ClCCl
Product: COc1cc(O)ccc1SC
Reaction time: 8 h
Yield: 28 %

Procedure:
The benzylether from stage (iii) (9.27 g, 39.5 mmol) was dissolved in DCM (5 mL), ethanethiol (5 mL) and BF3.OEt2 (5 mL, 39.5 mol) were then added at room temperature under a nitrogen atmosphere. The mixture was stirred overnight before the reaction was quenched with hydrochloric acid (2 M) and stirred for a further 30 mins. The mixture was then basified by the addition of sodium hydroxide (2 M) until pH 10 was attained. The mixture was then washed with ethyl acetate (3×50 mL). The aqueous layer was reacidified by the addition of hydrochloric acid (2 M) to pH 1 and extracted with ethyl acetate (4×50 mL). The extracts were combined, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography [SiO2; EtOAc/ pentane (1:9→1:4)] afforded the desired phenol compound as a colourless solid (1.73 g, 28%); δH(CDCI3, 400 MHz) 2.21 (3 H, s), 3.70 (3 H, s), 6.30 (1 H, d), 6.35 (1 H, s), 6.96 (1 H, d), 9.39 (1 H, brs)
Reaction SMILES: BrCCO.OCC[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[CH:12]=[O:13]>>[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[CH:12]=[O:13]
Reactant: CC(C)Oc1ccc(C=O)cc1OCCO
Agent: OCCBr
Product: CC(C)Oc1ccc(C=O)cc1O
Yield: 75 %

Procedure:
from 3-hydroxy-4-isopropoxybenzaldehyde (prepared in 75% yield by monoalkylation of 3,4-dihydroxybenzaldehyde with isopropyl bromide and K2CO3 in DMF) and 2-bromo-ethanol there was obtained 3-(2-hydroxy-ethoxy)-4-isopropoxy-benzaldehyde, which was subsequently converted by reaction with 4-aminobenzonitrile and toluene-4-sulphonyl methylisocyanide into methyl (RS)-(4-cyano-phenylamino)-[3-(2-hydroxy-ethoxy)-4-isopropoxy-phenyl]-acetate and then into methyl (RS)-(4-carbamimidoyl-phenylamino)-[3-(2-hydroxy-ethoxy)-4-isopropoxy-phenyl]-acetate hydrochloride (1:1);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[CH:20]1([C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21]1.[O-]CC.[Na+]>CN(C)C=O.C1COCC1.O>[CH:20]1([C:24]2[O:6][N:5]=[C:4]([C:3]3[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])[C:25]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23]1
Reactant: ON=Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CC(=O)C1CCC1
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Yield: 38.5 %

Procedure:
To a water bath-cooled solution of 2,6-dichlorobenzaldehyde oxime (2.20 g, 11.6 mmol) in N,N-dimethylformamide (7 mL) was added solid N-chlorosuccinimide (1.55 g, 11.6 mmol). The solution was stirred while in the water bath for approximately 20 min and outside the bath for approximately 1 hr. The solution was poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and then concentrated. To a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (2.37 g, 13.9 mmol) in THF (3 mL) at 0° C. was added sodium ethoxide (25 wt % in ethanol, 4.36 mL, 13.9 mmol). The solution was stirred for a few minutes and then the above imidoyl chloride was added. The solution was stirred at 0° C. for 10 minutes and then at ambient temperature overnight. The solution was poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (1.52 g, 38%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63-7.53 (m, 3H), 4.29-4.20 (m, 1H), 4.02 (q, J=7 Hz, 2H), 2.43-2.36 (m, 4H), 2.15-2.06 (m, 1H), 1.97-1.89 (m, 1H), 0.94 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17])[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[Cl-].[CH2:19]=[N+:20]1[CH2:24][CH2:23][S:22][CH2:21]1>C(#N)C>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[CH:9]=[C:4]([C:1](=[O:3])[CH2:2][CH2:19][N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(=Cc1ccc(F)cc1Cl)C(C)=O
Reactant: C=[N+]1CCSC1
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)C(=Cc1ccc(F)cc1Cl)C(=O)CCN1CCSC1

Procedure:
3.24 g (12.6 mmol) of methyl 2-acetyl-3-(2-chloro-4-fluorophenyl)acrylate from Example VII are stirred with 1.74 g (12.6 mmol) of 3-methylene-1,3-thiazolidin-3-ium chloride [prepared in analogy to H. Mohrle et al., Z. Naturforsch. 42, 1035–1046 (1987)] in 50 ml of acetonitrile at 40° C. for 48 hours. After concentration, the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over sodium sulfate and concentrated, and the residue is chromatographed on silica gel with cyclohexane/ethyl acetate (5:1→2:1) as mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH2:18][N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)=[C:14]([C:26]2[N:27]([CH3:32])[N:28]=[CH:29][C:30]=2[Cl:31])[CH:13]=1>ClCCl.CN(C=O)C>[Cl:31][C:30]1[CH:29]=[N:28][N:27]([CH3:32])[C:26]=1[C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH:25]=[CH:24][C:15]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CC(O)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
4-Chlorophenylisocyanate (19.0 mg, 0.124 mmol) was added to a solution of 1-{2-[4-amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-azetidin-3-ol (40.0 mg, 0.124 mmol) in dichloromethane (2.0 mL) and DMF (0.1 mL), and the mixture stirred at room temperature overnight. The solution was concentrated and purified by RP-HPLC. The collected fractions were concentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid (28 mg, 47%). LCMS m/z (%)=476 (M+H35Cl, 100), 478 (M+H37Cl, 67). 1H NMR (400 MHz, DMSO-d6) δ: 8.81 (bs, 1H), 8.71 (bs, 1H), 7.60 (s, 1H), 7.53-7.50 (m, 1H), 7.47 (d, J=2.08 Hz, 1H), 7.46 (d, J=2.10 Hz, 1H), 7.36 (d, J=2.71 Hz, 1H), 7.32 (d, J=2.11 Hz, 1H), 7.30 (d, J=2.04 Hz, 1H), 7.11 (d, J=9.06 Hz, 1H), 5.19 (d, J=8.00 Hz, 1H), 4.10-4.00 (m, 1H), 3.99-3.85 (m, 2H), 3.65 (s, 3H), 3.40-3.30 (m, 2H), 2.70-2.55 (m, 4H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH:12]=[CH:11][CH:10]=[C:9]3[CH2:8]1.F>>[C:4]([C:12]1[C:13]2[C:18]3[C:9]([CH2:8][CH2:7][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: c1cc2c3c(cccc3c1)CC2
Reactant: C=C1CC(=O)O1
Agent: F
Product: CC(=O)CC(=O)c1ccc2c3c(cccc13)CC2

Procedure:
42 g (0.5 mol) of diketene were added dropwise to 77 g of acenaphthene (0.5 mol) in 300 mol of anhydrous hydrofluoric acid at -30° C while stirring. The temperature was maintained for 9 hours. The hydofluoric acid was distilled off under reduced pressure at a temperature of the still of -30° C, the residue was washed until it was free from acid and distilled under reduced pressure. 10 g of unreacted acenaphthene were recovered (87 % conversion). At a transition temperature of 150° -155° C under 0.4 torr 85 g (82 % of theory) of slightly yellowish 5-acetoacetyl-acenaphthene melting at 59° C were then obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH:5]=[CH2:6])[CH:3]=[CH2:4].[C:8]1([PH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:15]1([P:14]([CH2:4][CH2:3][Si:2]([CH2:5][CH2:6][P:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:7])[CH3:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=C[Si](C)(C)C=C
Product: C[Si](C)(CCP(c1ccccc1)c1ccccc1)CCP(c1ccccc1)c1ccccc1

Procedure:
A mixture of 9.0 g (0.8 mole) dimethyl divinyl silane and 32.7 g (0.176) diphenyl phosphine (10% excess over equivalent amounts) was reacted for 22 hours in the manner described in Example 1. The reaction mixture was fractionated in vacuo to obtain minor amounts of the clear, colorless, slightly viscous liquid monoadduct, and major amounts of the clear, colorless, highly viscous liquid diadduct, i.e. the desired bis-(diphenylphosphinoethyl) dimethyl silane. The distillation yield of desired product was 84%. The bis-diphenylphosphinoethyl) dimethyl silane product had a boiling point of 238°-239° C. at 0.20 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]2([CH3:29])C.[C:30](=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][C:4]=1[C:15]1[C:24]([CH3:25])=[CH:23][C:22]2[C:21]([CH3:26])([CH3:27])[CH2:20][CH:19]([CH3:30])[CH:18]([CH3:29])[C:17]=2[CH:16]=1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A mixture of 2-methoxy-5-formylphenylboronic acid (2.3 g, 12.80 mmol), 6-bromo-1,1,4,4,7pentamethyl1,2,3,4-tetrahydronaphthalene (3.0 g, 10.66 mmol) and potassium carbonate (5.89 g, 42.64 mmol) in 1,2-dimethoxyethane (100 mL) and water (5 mL) was degassed with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.4 g, 2.13 mmol) was added and the mixture heated at reflux under argon for 8 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: 0% to 25% ethyl acetate in hexane) to give 3.43 g (95%) of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde. 1H NMR (500 MHz; CDCl3): δ1.26 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.08 (s, 3H); 3.89 (s, 3H); 7.06 (d, J=8.5 Hz, 1H); 7.09 (s, 1H); 7.16 (s, 1H); 7.71 (d, J=2.0 Hz, 1H); 7.88 (dd, J1=8.5 Hz, J2=2.0 Hz 1H), 9.91 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]4[CH:27]=[N:28][CH:29]=[CH:30][C:25]=4[O:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].O1CCOCC1>C(Cl)Cl>[ClH:32].[ClH:32].[O:24]1[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C@H:11]3[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]3)[CH2:21][CH2:20]2)=[N:23]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
{trans-4-[2-(4-Isoxazolo[4,5-c]pyridin-3-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (930 mg, 2.2 mmol) was dissolved in CH2Cl2 (3 ml) and 4 N HCl in dioxane (10.8 ml, 43 mmol) was added. The resulting mixture was stirred 16 h at r.t. After dilution with iPr2O the product was collected by filtration and washed with one portion of iPr2O before drying it under high vacuum at 50° C. to obtain 686 mg (79%) as a white solid. m/z=330.3 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.N12CCN(CC1)CC2>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][C:23]3[NH:1][C:2]4[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=4[C:22]=3[CH2:21]2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: O=C1CCN(c2ccc(F)cc2)CC1
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]c3c(c2c1)CN(c1ccc(F)cc1)CC3
Temperature: 110 °C
Reaction time: 3.5 h
Yield: 39.4 %

Procedure:
A solution of methyl 4-amino-3-iodobenzoate (0.5 g, 1.8 mmol), 1-(4-fluorophenyl)piperidin-4-one (1.05 g, 5.4 mmol), 1,4-diazabicyclo[2.2.2]octane (0.61 g, 5.4 mmol) and palladium (II) acetate (20 mg, 0.09 mmol) in DMF (10.0 mL) was degassed, filled with argon (3×) and allowed to stir at 110° C. for 3.5 h. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc (40 mL) and water (40 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×20 mL), brine (1×20 mL), dried (MgSO4), filtered and concentrated. Column chromatography (25% EtOAc/hexane) provided, upon trituration with ethyl ether, methyl 2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylate (23 in Scheme 1(k)) as a yellow solid (0.23 g, 39%). 1H NMR (CDCl3, 300 MHZ) 8.17 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.23 (d, J=8.0 Hz, 3H), 7.09 (t, J=8.1 Hz, 2H), 4.53 (s, 2H), 3.96 (s, 3H), 3.73 (t, J=5.6 Hz, 2H), 3.12 (br s, 2H) ppm; MS (ES) 325 (M+H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[C:2]#[C:3][CH2:4][CH3:5].I[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][CH:12]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.O>[CH3:20][O:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11](/[C:2](=[C:3](\[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:21])/[CH2:4][CH3:5])/[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=1
Reactant: CCC#CC(=O)OCC
Reactant: COCOc1ccc(I)cc1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: N#Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C(=C(\CC)c1ccccc1C)c1ccc(OCOC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
A mixture of Ethyl 2-pentynoate (350 mg, 2.77 mmol), 1-iodo-4-(methoxymethoxy)benzene (1.46 g, 5.53 mmol), 2-Methylphenylboronic acid (753 mg, 5.53 mmol) and K2CO3 (766 mg, 5.54 mmol) in DMF (8.5 ml)-H2O (2.2 ml) was stirred at room temperature for 10 min. Then PdCl2(PhCN)2 (10.6 mg, 0.0276 mmol) was added under Ar atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction was quenched with H2O under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1) gave 2a (27%). 2a: colorless oil; 1H-NMR (CDCl3) δ 1.02 (3H, t, J=7.5 Hz), 1.33 (3H, t, J=7.1 Hz), 2.04 (3H, s), 2.56 (2H, m), 3.42 (3H, s), 4.30 (2H, m), 5.06 (2H, s), 6.72 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz), 7.00-7.12 (5H, m).