Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].[CH3:12][O:13][CH:14]([O:18][CH3:19])N(C)C.CN(C)C=O.C[Si](Cl)(C)C>C(OCC)(=O)C.CO>[CH3:12][O:13][CH:14]([O:18][CH3:19])[CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(Cc1cccc(C)c1[N+](=O)[O-])OC
Temperature: 25 °C
Yield: 14 %

Procedure:
Combine 2-nitro-meta-xylene (5 mL, 0.037 mol), N,N-dimethylformamide dimethylacetal (5.4 mL, 1.1 eq) and N,N-dimethylformamide (60 mL) in a flask and reflux under nitrogen for 2 days. Let cool to room temperature then concentrate to approximately one-half volume. Add methanol (40 mL) and trimethylsilylchloride (6.6 mL, 1.4 eq). Reflux overnight. Dilute with ethyl acetate after cooling to room temperature then extract with saturated sodium bicarbonate followed by brine. Dry over magnesium sulfate, filter and concentrate. Purification by column chromatography (9:1 Hexanes:ethyl acetate) gives 1.15 g (14%) product as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.80 (d, J=5.36 Hz, 2H), 3.19 (s, 6H), 4.45 (m, 1H), 7.32 (m, 2H), 7.42 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH2:13][S:14][CH3:15])=[CH:3]1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH2:13][S:14]([CH3:15])=[O:24])=[CH:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cn(C)c2ccccc2c1=O
Solvent: ClCCl
Product: Cn1cc(CS(C)=O)c(=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of the above 1-methyl-3-methylthiomethyl-4-quinolone (4.86 g.) in dichloromethane (220 ml.) at -20° was added a solution of 3-chloroperbenzoic acid (85%, 4.86 g.) in dichloromethane (220 ml.) during 1 hour. The solution was allowed to warm to room temperature and extracted with saturated aqueous sodium bicarbonate until free of per-acid. The organic phase was dried over anhydrous magnesium sulphate and evaporated to give a solid product. The product was crystallised from acetone to give the novel 1-methyl-3-methylsulphinylmethyl-4-quinolone, m.p. 93°-95°.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41]C(Br)(Br)Br>C1COCC1>[Br:41][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCBr
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A solution 3-(2-hydroxyethyl)-2-(triethylsilyl)-1H-indole-5-carbonitrile (0.873 g; 2.91 mmol) in THF (6 mL) was added to a solution of triphenylphosphine (1.52 g; 5.81 mmol) and perbromomethane (1.93 g; 5.81 mmol) in THF (30 mL) pre-stirred for 30 minutes. The resulting mixture was stirred at room temperature overnight, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 40% ethyl acetate in heptane) to yield 0.906 g (86%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][CH2:24]Br.O>CN(C=O)C>[Br:22][CH2:23][CH2:24][O:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: COc1cccc2c(O)ccc(C=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(OCCBr)ccc(C=O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (1 g, 5 mmol) was dissolved in DMF (15 mL). To this mixture potassium carbonate (3.4 g, 25 mmol) and 1,2-dibromoethane (4 mL, 50 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water. (150 mL) was added and the resulting mixture was extracted with ethyl acetate (3×90 mL). The combined organic extracts were washed with saturated sodium chloride (100 mL), dried (MgSO4) and evaporated in vacuo to afford 1.13 g (74%) of 4-(2-bromoethoxy)-8-methoxynaphthalene-1-carbaldehyde.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[CH:30][C:31]([F:40])=[C:32]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:33]=2)[CH2:24][CH2:23]1>>[F:40][C:31]1[CH:30]=[CH:29][C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:27][CH2:26]2)=[CH:33][C:32]=1[NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38]
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)ccc1F

Procedure:
Example 51 was prepared from 2,2-diphenylpropanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.27–8.13 (m, 1H), 8.04 (s, 1H), 7.62 (s, 1H), 7.50–7.39 (m, 1H), 7.39–7.16 (m, 7H), 7.12–6.90 (m, 2H), 6.79–6.60 (br, 1H), 4.94–4.61 (br, 1H), 3.60–3.22 (m, 4H), 2.89–2.76 (m, 2H), 2.76–2.55 (m, 4H), 2.55–2.34 (m, 3H), 2.14–1.82 (m, 3H), 2.00 (s, 3H), 1.26 (d, 6H, J=6.4 Hz); ESMS m/e: 530.4 (M+H)+; Anal. Calc. for (HCl salt) C33H41ClFN3O2.0.24CHCl3.0.96H2O: C, 65.23; H, 7.11; N, 6.86. Found: C, 64.96; H, 7.36; N, 6.87.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([OH:41])=[O:40].S(=O)(=O)(O)O.[CH3:47]O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:16][CH2:17]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([O:41][CH3:47])=[O:40]
Reactant: COc1cccc(N2CCN(C3=Nc4c(F)cccc4C(CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Yield: 75.2 %

Procedure:
(±)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid (54 g) is dissolved in methanol (540 g), then concentrated sulphuric acid (7.85 ml) is added. The mixture is stirred under reflux for 26 h, then cooled and concentrated in vacuo to ca. one third of the original volume. Water (150 ml) and dichloromethane (150 ml) are added, then the phases are separated. The organic phase is extracted with saturated sodium hydrogencarbonate solution (two times 140 ml), dried over sodium sulphate and concentrated to give a foamy residue. This is dissolved twice in succession in ethanol (150 ml each) and concentrated, and subsequently dried for 18 h in vacuo using entraining nitrogen. A total of 41.6 g of methyl {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate are thus obtained as an amorphous solid, corresponding to 75.2% of theory.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][CH2:9]Br.[CH:11]12[NH:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][CH:13]([NH:19][C:20]1[C:21]([CH3:29])=[C:22]3[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]3)[CH2:12]2>CN(C)C=O>[CH2:9]([N:18]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH2:12][CH:13]([NH:19][C:20]1[C:21]([CH3:29])=[C:22]3[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]3)[CH2:14]2)[CH2:8][CH3:7]
Reactant: CCCBr
Reactant: Cc1c(NC2CC3CCC(C2)N3)ccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1C2CCC1CC(Nc1ccc3[nH]ncc3c1C)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.7 %

Procedure:
Potassium carbonate (122 mg, 0.883 mmol) and then n-propyl bromide (40 μl, 0.440 mmol) were added to a solution of the N-(8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (74 mg, 0.289 mmol) obtained in Example 501 in N,N-dimethylformamide (2 ml), and the resulting mixture was stirred at room temperature for 15 hours. After the solid was removed by filtration, the solvent was distilled off under reduced pressure as an azeotrope with toluene. The residue was purified by a silica gel column chromatography (chloroform/methanol/triethylamine=100/1/5) and then a preparative thin-layer chromatography (200×200×0.5 mm, 2 plates, eluent: chloroform/methanol/triethylamine=100/5/5) to obtain N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (36 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(O)c1cccnc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(Cl)ccc2C1c1cccnc1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
rac-6-Chloro-3-hydroxy-3-pyridin-3-yl-1,3-dihydro-indol-2-one (0.27 g, 1.0 mmol) (from Example 39a supra) was suspended in a mixture of triethylsilane (0.49 mL, 3.0 mmol) (Aldrich) and trifluoroacetic acid (1.77 g, 15.0 mmol) (Aldrich) and heated in an 78° C. oil bath for overweekend. After cooling to room temperature, the mixture was diluted with ethyl acetate and treated with solid sodium carbonate (1.0 g). After stirring for 30 minutes, mixture was extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated to obtain rac-6-chloro-3-pyridin-3-yl-1,3-dihydro-indol-2-one (Yield 0.1 g, 40%) as yellow oil and carried out for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:21])[NH:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:6][N:5]=[C:4]([C:22]([OH:24])=O)[N:3]=1.Cl.[NH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][NH:26][C:22]([C:4]1[N:3]=[C:2]([OH:1])[C:7]([C:8](=[O:21])[NH:9][CH2:10][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][CH:20]=2)=[CH:6][N:5]=1)=[O:24])[CH3:32]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ncc(C(=O)NCc2cccc3ccccc23)c(O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CNC(=O)c1ncc(C(=O)NCc2cccc3ccccc23)c(O)n1
Temperature: 0 °C
Yield: 10.5 %

Procedure:
The mixture of step D product, 2-20-e, (2.5 g, 7.7 mmol), ethyl 2-aminoacetate hydrochloride (1.29 g, 9.3 mmol), TBTU (2.98 g, 9.3 mmol), DIPEA (2.0 g, 15.5 mmol) in DMSO (20 mL) and stirred at the ambient temperature overnight. Then the reaction mixture was added ice-water (40 mL), extracted with DCM (30 mL×2). The organic phase was concentrated to give a residue, which was purified by column chromatography with DCM:MeOH=150:1 to obtain 2-20 (330 mg, 11%). 1H NMR (300 MHz, DMSO-d6): δ 1.18-1.22 (t, J=6 Hz, 3H), 4.0-4.02 (d, J=6 Hz, 2H), 4.11-4.14 (q, J=6.0 Hz, 2H), 5.0-5.02 (d, J=6.0 Hz, 1H), 7.48-7.57 (m, 4H), 7.87 (m, 3H), 8.55 (br s, 1H), 9.48 (m, 1H), 9.87 (br s, 1H), 13.54 (br s, 1H). LC-MS: (M+H)+ 409.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH3:10][O:11]C=O>[Co]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]=[O:11])=[CH:4][N:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COC=O
Agent: [Co]
Product: NCc1ccc(Cl)nc1
Product: O=CNCc1ccc(Cl)nc1

Procedure:
30 g of 91.7% pure 2-chloro-5-cyanopyridine were hydrogenated in 100 ml of methylformate using 7 g of Raney cobalt analogously to Example 2. 2-Chloro-5-(formylaminomethyl)pyridine was obtained in a yield of 92.6% of theory, in addition to 2.9% of theory of 2-chloro-5-(aminomethyl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][CH2:22][S:23]([O-:26])(=O)=[O:24])[O:12]1.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)[Cl:45].CN(C)C=O.S(Cl)(Cl)=O>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][CH2:22][S:23]([Cl:45])(=[O:26])=[O:24])[O:12]1
Reactant: ClCCl
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(=O)(=O)[O-])O[C@H]2n1cnc2c(Cl)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(=O)(=O)Cl)O[C@H]2n1cnc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 78.1 %

Procedure:
Tetrabutyl-ammonium 2-[(3aR,4R,6R,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-ethanesulfonate (250.0 mg, 0.0003481 mol) was dissolved in methylene chloride (5.00 mL, 0.0780 mol) and N,N-dimethylformamide (100.0 μL, 0.001292 mol). Thionyl chloride (228 μL, 0.00313 mol) was added and the reaction was stirred at 0° C. for 45 minutes, concentrated in vacuo to dryness and followed by azeotroping with toluene. The residue was purified by flash chromatography (10% THF in DCM) to yield product (115 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14]CC)=O)=[CH:6]2.[CH3:18][C:19]([O-])(C)C.[K+].C1COCC1.C(OC)(=O)C=C.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:18][CH2:19][C:12](=[O:14])[C:7]3=[CH:6][C:5]=2[C:4]=1[CH3:17]
Reactant: CCOC(=O)c1cc2c(C)c(OC)ccc2[nH]1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: C=CC(=O)OC
Product: COc1ccc2c(cc3n2CCC3=O)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of ethyl 5-methoxy-4-methyl-1H-indole-2-carboxylate (712 mg, 3.05 mmol) in toluene (10 mL) was added a 1 M solution of KOtBu in THF (3.97 mL, 3.97 mmol). The reaction mixture was stirred at room temperature for 5 min, methyl acrylate (825 μL, 9.15 mmol) was added. The reaction was stirred at reflux overnight and neutralized with 1 N HCl aqueous solution. The solid was collected and divided into three microwave vial. Each was added AcOH (8 mL) and H2O (1 mL), and heated at 180° C. for 15 min under microwave irradiation. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a yellow solid (500 mg). LCMS m/z=216.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.45 (s, 3H), 3.21 (t, J=6.5 Hz, 2H), 3.68 (s, 3H), 4.40 (t, J=6.2 Hz, 2H), 6.98 (s, 1H), 7.13 (d, J=9.0 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26]Br.O>CN(C)C=O>[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26][N:12]1[C:11](=[O:20])[CH2:10][C@@:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19]
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CC=C(C)C)C(=O)C3)c1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of 4 g (14.7 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 50 ml of anhydrous dimethylformamide was added dropwise to 700 mg of a 55% suspension of sodium hydride in mineral oil in 50 ml of dimethylformamide at 70°. The reaction mixture was heated for 1 hour after the addition was complete and then cooled to 25°. 3,3-Dimethylallyl bromide (2.37 g, 15.8 mmoles) in 10 ml of dimethylformamide was added dropwise and the solution stirred overnight at 25°. After heating at 80° for 1 hour it was poured into water and extracted with ether to yield 4.74 g of N-(3,3-dimethylallyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline (oil), which was evaporatively distilled, bp 225° (0.005 mm).
Reaction SMILES: C(OC(=O)[N:7]([C:38]1[CH:39]=[N:40][C:41](Cl)=[CH:42][CH:43]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:36])[C:15]2[C:23]3[C:22]([O:24][CH3:25])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:16]=2)=[C:10]([F:37])[N:9]=1)(C)(C)C.ClCCl.[CH:49]1([Mg]Br)[CH2:51][CH2:50]1.O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:49]1([C:41]2[N:40]=[CH:39][C:38]([NH:7][C:8]3[N:9]=[C:10]([F:37])[C:11]([CH:14]([C:15]4[C:23]5[C:22]([O:24][CH3:25])=[N:21][CH:20]=[N:19][C:18]=5[N:17]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:27]([CH3:29])[CH3:28])[CH:30]([CH3:32])[CH3:31])[CH:16]=4)[OH:36])=[CH:12][CH:13]=3)=[CH:43][CH:42]=2)[CH2:51][CH2:50]1
Reactant: COc1ncnc2c1c(C(O)c1ccc(N(C(=O)OC(C)(C)C)c3ccc(Cl)nc3)nc1F)cn2[Si](C(C)C)(C(C)C)C(C)C
Reactant: Br[Mg]C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ncnc2c1c(C(O)c1ccc(Nc3ccc(C4CC4)nc3)nc1F)cn2[Si](C(C)C)(C(C)C)C(C)C
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
To (6-chloro-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (72, 105 mg, 0.160 mmol) in 3.8 mL of toluene, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (13.0 mg, 0.016 mmol) is added under an atmosphere of nitrogen. The reaction is stirred for 5 minutes, then cyclopropylmagnesium bromide (17, 1.60 mL, 1.0 M in tetrahydrofuran, 1.60 mmol) is added slowly. The reaction is heated at 65° C. for 5 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (73, 70 mg). MS (ESI) [M+H+]+=563.6.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:21]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=O)=[CH:27][CH:26]=1)([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[C:7]1[CH:8]=[CH:9][C:4]([C:3]2[N:2]([CH3:1])[C:29]([C:28]3[CH:33]=[CH:34][C:25]([C:21]([O:23][CH3:24])=[O:22])=[CH:26][CH:27]=3)=[N:31][N:32]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CNC(=O)c1ccc(C(=O)OC)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)n2C)cc1

Procedure:
A solution of N-methyl-p-carbmethoxybenzamide in chloroform was treated with phosphorus pentachloride to give E. Then E was reacted with p-carbmethoxybenzoyl hydrazine to yield dimethyl-4,4'-(4-methyl-1,2,4-triazol-3,5-diyl)dibenzoate, (F). Then IV was obtained by reacting F in a similar manner as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Na+].[I-:16].Cl.N>O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([I:16])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: [I-]
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Clc1ccc(-c2ccc(I)nn2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
20 mL ACN are added to 0.50 g (1.11 mmol) 3-(4-chlorophenyl)-6-chloropyridazine and 3.33 g (22.2 mmol) NaI before 189 μl fuming conc. HCl are added and the mixture is stirred at 80° C. for 4 h. The mixture is alkalised with aq. ammonia solution (32%) diluted with water and extracted with EtOAc. The org. phases are combined, dried with Na2SO4 and the solvent is removed in vacuo. The resulting crude product is triturated with TBME.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[Br:38][C:39]1[CH:40]=[C:41]([C@H:49](O)[CH3:50])[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.ClCCl>[C:17]1([C:11]2([C:14]([O:16][C@@H:49]([C:41]3[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:39]([Br:38])[CH:40]=3)[CH3:50])=[O:15])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: C[C@@H](O)c1cc(Br)cc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H](OC(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (3.8 g, 10.3 mmol) in a dichloromethane (5 mL) and toluene (30 mL) mixture was treated with 1,3-dicyclohexylcarbodiimide (2.96 g, 14.4 mmol) and stirred for 30 min. The suspension was cooled to 0° C. and treated with (R)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (2.79 g, 10.3 mmol) and dimethylaminopyridine (1.26 g, 10.3 mmol). The ice bath was removed and the suspension stirred at room temperature for 60 h. The reaction mixture was poured into pentane, filtered, and the solids washed several times with pentane. The filtrate was washed with 1 N hydrochloric acid (1×), water (2×), then 1 N sodium hydroxide, then brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography on silica gel (12% ethyl acetate/hexanes) gave 4.8 g (84%) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.23-7.33 (m, 6H), 7.19 (s, 1H), 5.80 (q, J=6.6 Hz, 1H), 3.82-3.97 (m, 2H), 2.97-3.09 (m, 2H), 2.44-2.53 (m, 2H), 1.76-2.01 (m, 2H), 1.42 (s, 9H), 1.40 (m, 3H). Mass spec.: 558.06 (MH)+.
Reaction SMILES: O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[C:47]3[C:42](=[CH:43][C:44]([O:48][CH2:49][O:50][CH3:51])=[CH:45][CH:46]=3)[S:41][CH2:40][C:39]2([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][O:61][CH3:62])=[CH:55][CH:54]=2)[CH3:52])=[CH:34][CH:33]=1)(C(C)(C)C)(C)C>O>[OH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[C:47]3[C:42](=[CH:43][C:44]([O:48][CH2:49][O:50][CH3:51])=[CH:45][CH:46]=3)[S:41][CH2:40][C:39]2([C:53]2[CH:54]=[CH:55][C:56]([O:59][CH2:60][O:61][CH3:62])=[CH:57][CH:58]=2)[CH3:52])=[CH:34][CH:33]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Under argon atmosphere, tetrahydrofuran solution of tetrabutylammonium fluoride (1.0M, 2.27 ml, 2.27 mmol) was added dropwise to tetrahydrofuran solution (35 ml) of (3RS,4RS)-4-(4-t-butyldimethylsilyloxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methylthiochroman (856 mg, 1.51 mmol) at 0° C. and the resulting mixture was stirred for 2 hours. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The crude product thus obtained was purified with silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 682 mg (yield: 100%) of the title compound.