Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)S(OC1CCC2C(=CC(OC)=CC=2)C=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48])CCC>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH2:8][C:9]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=1[N+:47]([O-:49])=[O:48])=[CH:10]2
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1[N+](=O)[O-]
Agent: COc1ccc2c(c1)C=C(OS(=O)(=O)C(F)(F)F)CC2
Product: COc1ccc2c(c1)C=C(c1ccc(OC)cc1[N+](=O)[O-])CC2

Procedure:
Synthesized from 7-methoxy-2-tetralone according to an analogous synthetic method to Preparation Example 82 described above, 7-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (3.5 g) and tributyl(4-methoxy-2-nitrophenyl)tin (18 g) were used according to an analogous synthetic method to Preparation Example 77 to provide the title compound (1.9 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[CH3:35][O:36][C:37]1[C:42]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[CH3:33][CH:32]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:40]4[CH:41]=[C:42]([NH:43][S:44]([CH3:47])(=[O:45])=[O:46])[C:37]([O:36][CH3:35])=[N:38][CH:39]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][CH:23]=2)[CH2:31][CH2:30]1)[CH3:34]
Reactant: CC(C)N1CCN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3ncc(CN4CCN(C(C)C)CC4)o3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 120 °C
Reaction time: 3 h
Yield: 10.5 %

Procedure:
To a solution of 6-chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (200 mg, 0.400 mmol) and N-[2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methanesulfonamide (171 mg, 0.520 mmol) in 1,4-dioxane (2 ml) was added chloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.2 mg, 0.020 mmol), potassium phosphate tribasic (255 mg, 1.20 mmol) and water (0.2 ml). The reaction mixture was heated and stirred at 120° C. under microwave irradiation for 3 h. The reaction mixture was filtered through a silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous extracted with further dichloromethane (2×2 ml). The combined organics were concentrated under a stream of nitrogen and the residue dissolved in MeOH:DMSO (2 ml, 1:1, v/v) and purified by MDAP (method A) in 2 injections. The appropriate fractions were combined and concentrated and the residue dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and further purified by MDAP (method B). The appropriate fractions were basified to pH 7 with saturated sodium bicarbonate solution and extracted with dichloromethane (2×20 ml). The combined organics were dried (hydrophobic frit) and concentrated to give the title compound as a white solid (22 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:36](=[O:46])[N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[N:4][N:5]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])=[CH:10][C:9]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:6]=1[CH3:7].[OH-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[C:3]([C:36](=[O:46])[N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])=[N:4][N:5]([C:8]2[CH:23]=[CH:22][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To benzyl 4-(4-bromo-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (55 mg, 0.080 mmol) in THF (1.0 mL) was added 1N aq. NaOH solution (802 μL, 0.80 mmol). The resulting biphasic mixture was stirred vigorously at room temperature for 2.5 h, then acidified with 1N aq. HCl solution (pH=3) and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (46 mg, 96%) as a clear, colorless oil. MS(ESI+) m/z 597.3 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CCO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33](=[O:1])[NH2:34])[CH:28]=2)[C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(C#N)c2)c2ccc3[nH]ccc3c2)CC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(C(N)=O)c2)c2ccc3[nH]ccc3c2)CC1

Procedure:
A solution of NaOH (54 mg, 1.35 mmol) in water (0.2 mL) was added to a solution of 4-[(3-cyano-benzyl)-(1H-indol-5-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (115 mg, 0.27 mmol) (prepared as described in Example 2 Step 1) in EtOH (10 mL). The reaction mixture was heated at reflux for 16 hours, the solvent was evaporated and the residue was purified by flash chromatography (0% to 25% of MeOH in DCM) to give 4-[(3-carbamoyl-benzyl)-(1H-indol-5-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester. This material was dissolved in DCM (5 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred for 16 hours, it was then evaporated under reduced pressure and the residue was basified by addition of an aqueous solution of NH4OH. The crude material was purified first by flash chromatography and then by preparative HPLC (Agilent Technologies Zorbax SB-Phenyl column (21.2 mm inner diameter by 100 mm length, 7 micron particle size), water (0.1% TFA added)/acetonitrile 75/25 gradient to 5/95 over 10 minutes at 20 ml/min flow rate) to give the desired 3-{[(1H-indol-5-yl)-piperidin-4-yl-amino]-methyl}-benzamide trifluoroacetate, MS=349 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.FC(F)(F)C(O)=O.[C:34]([O:38][C:39]([NH:41][C@H:42]([C:49](O)=[O:50])[C:43]([CH3:48])([CH3:47])[C:44]([OH:46])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:34]([O:38][C:39]([NH:41][C@H:42]([C:49]([N:12]1[CH2:13][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:10][C@H:11]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:50])[C:43]([CH3:48])([CH3:47])[C:44]([OH:46])=[O:45])=[O:40])([CH3:36])([CH3:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C(=O)O
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 1.00 g, 2.80 mmol, 1 equiv) in a 4:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred for 30 minutes, then concentrated. The residue was dried via benzene azeotrope (1×50 mL), then dissolved in DMF (30 mL). N-(tert-butoxycarbonyl)-3,3-dimethylaspartic acid (29-3, 1.08 g, 4.20 mmol, 1.50 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.805 g, 4.20 mmol, 1.50 equiv), 1-hydroxy-7-azabenzotriazole (0.571 g, 4.20 mmol, 1.50 equiv) and triethylamine (2.73 mL, 19.6 mmol, 7.00 equiv) were added, and the resulting mixture was stirred at 23° C. for 20 hours. The reaction mixture was partitioned between water, acidified to pH 2, and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography through silica gel (hexane initially, grading to 100% EtOAc) followed by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide (3S)-3-[(tert-butoxycarbonyl)amino]4-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2,2-dimethyl-4-oxobutanoic acid (29-4) as a white foam. 1H NMR (500 M CDCl3) major rotamer: δ 7.28 (m, 5H), 7.05 (m, 3H), 6.40 (s, 1H), 5.89 (br s, 1H), 5.74 (d, 1H, J=10.2 Hz), 5.17 (d, 1H, J=14.2 Hz), 4.93 (ddd, 1H, J=13.9, 4.4, 1.7 Hz), 4.62 (d, 1H, J=10.2 Hz), 1.45 (s, 9H), 1.30 (s, 3H), 1.05 (s, 3H). LRMS m/z (M+H) 501.5 found, 501.2 required.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:20]([O:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26](F)[C:25]=1[N+:33]([O-:35])=[O:34])[CH:21]=[CH2:22]>C1COCC1.C(OCC)(=O)C>[CH2:20]([O:23][C:24]1[C:25]([N+:33]([O-:35])=[O:34])=[C:26]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[C:27]([F:31])=[C:28]([F:30])[CH:29]=1)[CH:21]=[CH2:22]
Reactant: Nc1ccc(I)cc1F
Reactant: C=CCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of 2-fluoro-4-iodo-phenylamine (1.1 g, 4.6 mmol) in THF (50 mL) was dropwise added LHMDS solution (6.0 mL, 6.0 mmol, 1 M in THF) at −78° C. After stirring for 1 h at −78° C., a solution of 1-allyloxy-3,4,5-trifluoro-2-nitrobenzene (1.2 g, 5.1 mmol) in THF (10 mL) was dropwise added into the reaction mixture. The reaction mixture was stirred at −78° C. for additional 1 h and brought to room temperature and stirred for 16 h. The progress of reaction was monitored by 1H NMR. After completion, the solvent was removed under reduced pressure. The residue obtained was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was triturated with hexane to yield (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine as a yellow solid (900 mg). 1H-NMR (400 MHz, CDCl3): δ 4.62 (2H, d, J=4.8), 5.33-5.36 (1H, d, J=10), 5.48 (1H, d, J=17.2), 5.98-6.02 (1H, m), 6.22 (1H, dd, J=2.4, 9.6), 6.36 (1H, dd, J=2, 10.4), 7.04-7.08 (1H, m), 7.45-7.52 (2H, m), 7.79 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9](O)(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:3]1([CH2:2][NH:1][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NCC1CCCCC1
Reactant: CCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCC(=O)NCC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of aminomethylcyclohexane (0.34 g, 3.0 mmol) in methylene chloride (30 mL) was added heptanoic acid (0.39 g, 3 mmol) and DMAP (0.37 g, 3.0 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.57 g, 3.0 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (100 mL), and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL) and brine (75 mL), and dried over Na2SO4. Concentration in vacuo afforded 0.62 g (92%) of an oil, which then crystallised.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([CH:11]=O)=[O:10].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([OH:10])[CH2:11][NH:17][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: O=CC(=O)c1cc(O)ccc1Cl
Reactant: CC(C)(C)N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NCC(O)c1cc(O)ccc1Cl
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-5-hydroxyphenylglyoxal (1.85 g) in methanol (37 ml) was added a solution of tert-butylamine (3.65 g) in methanol under cooling, further the sodium borohydride (0.57 g) was added in small portions, and the reaction mixture was stirred for 3 hours. The reaction mixture was evaporated and the residue acidified with 10% HCl, and washed with ether. The aqueous layer was made alkaline with K2CO3, and extracted with ether. The extract was dried with Na2SO4 and evaporated. The residue was recrystallized from iso-propylether n-hexane to give a 2-chloro-5-hydroxy-α-(tert-butylaminomethyl)-benzylalcohol, m.p. 162° - 163° C. Hydrochloride: m.p. 245° - 248° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:15]#[N:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:15]#[N:16])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: N#CC(=C1CCN(Cc2ccccc2)CC1)c1cccs1
Agent: [Pd]
Solvent: CO
Product: N#CC(c1cccs1)C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 70 parts of α-[1-(phenylmethyl)-4-piperidinylidene]-2-thiopheneacetonitrile in 800 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. Upon the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 70 parts of 1-(phenylmethyl)-α-(2-thienyl)-4-piperidineacetonitrile as a residue.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH3:11])=[CH:4][N:3]=1.C1C[O:15][CH2:14]C1.C([Li])(C)(C)C.CN(C)C=O>O.C(OCC)(=O)C>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]=[O:15])=[N:3][CH:4]=1)[CH2:10][CH3:11]
Reactant: C1CCOC1
Reactant: CCCOc1ccc(I)nc1
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOc1ccc(C=O)nc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A mixture comprising 2-iodo-5-propoxypyridine (0.27 g, 1 mmol) and THF (10 mL) was cooled to -78° C. and then tert-butyl lithium (1.3 mL, 1.7 M in pentane, 2.1 mmol) was added dropwise to give an orange slurry. The slurry was cooled to -78° C. and stirred for 5 minutes and then anhydrous N,N-dimethylformamide (0.4 mL, 5 mmol) was added dropwise. The mixture was allowed to warm to ambient temperature, stirred 20 minutes and then poured into a mixture comprising ethyl acetate and water. The mixture was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to provide 5-propoxypyridine-2-carboxaldehyde (0.2 g, 1.3 mmol) as a dark oil. 1H-NMR (300 Mhz, CD3OD): 1.1 (t, 3H), 1.9 (m, 2H), 4.1 (t, 2H), 7.5 (m, 2H), 8.4 (m, 1H), 10.5 (s, 2H); MS (CI); Calculated for C9H11NO2, 165.2, Found (MH+): 166.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)=O.[Cl:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CO>[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][CH2:1][C:3]2[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=Cc1ccc(/C=C/C(=O)O)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(CNc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of (E)-3-(4-formylphenyl)acrylic acid 229 (1 g, 5.67 mmol) and 3-chlorobenzenamine 230 (596 L, 5.67 mmol) in THF (8 ml), dibutyltin dichloride (173 mg, 0.57 mmol) was added followed by dropwise addition of phenylsilane (697 uL, 5.67 mmol). The resulting mixture was stirred at room temperature in the nitrogen atmosphere overnight, diluted with MeOH and concentrated under reduced pressure. The solid residue was triturated with DCM to yield the title compound 231 (1.24 g, 76% yield). 1H NMR: (DMSO) δ (ppm): 7.61 (d, J=8.0 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.00 (t, J=8.0 Hz, 1H), 6.53 (t, J=2.0 Hz, 1H), 6.49-6.48 (m, 2H), 6.46 (d, J=16.0 Hz, 1H), 4.28 (bs, 2H). MS: (calc.) 287.7; (obt.) 288.1 (MH)+.
Reaction SMILES: [Na].CC1C=CC=CC=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2(C#N)[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(O)C>CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:25][CH2:24][C:19]3([O:20][CH2:21][CH2:22][O:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: N#CC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: [Na]
Solvent: CO
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h

Procedure:
To a stirred and hot (±100° C.) mixture of 101 parts of sodium and 450 parts of methylbenzene is added dropwise a solution of 189 parts of 8-(4-fluorophenyl)-1,4-dioxaspiro[4,5]decane-8-carbonitrile in 450 parts of methylbenzene and 100 parts of absolute ethanol (temperature remained at about 90° C.). Then there are added successively and dropwise 260 parts of absolute ethanol and 160 parts of methanol. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto ice-water and the product is extracted with trichloromethane. The extract is washed successively with a hydrochloric acid solution 5%, a sodium bicarbonate solution 5% and with water, dried, filtered and evaporated, yielding 167 parts of 8-(4-fluorophenyl)-1,4-dioxaspiro[4,5]decane; mp. <60° C.
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5]1[CH:10]=[C:9]([S:11][CH3:12])[C:8]([CH3:13])=[CH:7][C:6]=1[OH:14].[OH-].[Na+]>C(O)(=O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:12])=[O:1])[C:8]([CH3:13])=[CH:7][C:6]=1[OH:14]
Reactant: COc1cc(SC)c(C)cc1O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(S(C)=O)c(C)cc1O

Procedure:
10% v/v Aqueous hydrogen peroxide (27 ml) was added to 2-methoxy-5-methyl-4-(methylthio)phenol (1.72 g) in glacial acetic acid (15 ml). After 24 hours the acetic acid was neutralised with 2 N aqueous sodium hydroxide and the product was extracted into methylene chloride (100 ml). The organic extract was washed with 10% w/v aqueous sodium sulphite solution and water, dried (Na2SO4) and the solvent was removed in vacuo. Recrystallisation from ethanol/diethyl ether gave 2-methoxy-5-methyl-4-methylsulphinylphenol (0.16 g) as colourless crystals m.p. 166°-168° (identical to that prepared in (i) above).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(O)c(C(=O)c2ccccc2)c1
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(=O)c2ccccc2)c1
Temperature: 180 °C
Reaction time: 9 h
Yield: 8.1 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (93 mg) with 2-hydroxy-5-methoxybenzophenone (462 mg) was stirred at 180° C. for 9 hr. The reaction solution was cooled to room temperature and was purified by column chromatography on silica gel using acetone-hexane to give the title compound (14 mg, yield 8%).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[CH3:15][Mg]Br>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1
Reactant: Fc1ccc(Cc2ccsc2I)cc1
Reactant: C[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: Cc1sccc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
The 2-iodo-3-(4-fluorophenylmethyl)thiophene prepared in step 1 was taken up in ether and methylmagnesium bromide (3.0M in ether, 2.42 mL, 7.26 mmol) and dichloro [1,3-bis(diphenylphosphino)propane]nickel(II) (164 mg, 0.302 mmol) were added and the reaction mixture was stirred for 17 hours at ambient temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic phase was washed with 1N aqueous H3PO4, saturated aqueous NaHCO3, saturated aqueous Na2S2O3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (10% ethyl acetate/hexane) gave 2-methyl-3-(4-fluorophenylmethyl)thiophene (602 mg, 48%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.[Rh]>[C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2cnc3cnccc32)cc1
Agent: [Rh]
Solvent: CC(=O)O
Product: c1ccc(-n2cnc3c2CCNC3)cc1
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of Intermediate 2 (111 mg, 0.569 mmol) in AcOH (15 ml) was passed through a Rh/C catalyst cartridge on an H-Cube hydrogenation apparatus at a pressure of 80 bar and a flow rate of 1 ml/min at 100° C. The reaction was looped through the apparatus for 2 h. The crude reaction mixture was concentrated and purified on 12 g SiO2 column with 0-10% NH3/MeOH CH2Cl2 to give the desired compound (90 mg, 80%). MS (ESI): mass calcd. for C12H13N3, 199.3. m/z found, 200.2 [M+H]+.
Reaction SMILES: CN(C)C=O.Br[CH:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.[NH2:26][C:27]1[CH2:31][CH2:30][CH2:29][N:28]=1>O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:26]=[C:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Reactant: NC1=NCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3n(c2-c2ccc(OC)cc2)CCC3)cc1
Reaction time: 72 h

Procedure:
To 300 ml of dry N,N-dimethylformamide was added 30. g (0.09 mol) of 2-bromo-1,2-di(4-methoxyphenyl)ethanone and 19.5 g (0.27 mol) of 2-amino-4,5-dihydro-3H-pyrrole. The mixture was stirred for three days at 25° with the exclusion of moisture. The reaction mixture was poured into water and the aqueous suspension was extracted three times with methylene chloride. The organic extracts were combined and washed six times with water, then dried (K2CO3). The solvent was evaporated and the residue was recrystallized from chloroform-hexane and dried overnight (80° in vacuo) to give the title compound, m.p. 146°-147.5°.