Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([C:31]3[O:32]C=CC=3)[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].I([O-])(=O)(=O)=[O:44].[Na+].C1(C)C=CC=CC=1>ClC(Cl)(Cl)Cl.C(#N)C.O.[Ru](Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([C:31]([OH:44])=[O:32])[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3ccco3)n(-c3ccccc3)n2)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 1 h

Procedure:
To a vigorously stirred mixture of 320 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-furan-2-yl-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2 ml of tetrachloromethane, 2 ml of acetonitrile and 3 ml of water, 531 mg of sodium periodate and 1 mg of ruthenium(III)chloride was added at RT. After 1 h, 20 ml of toluene was added and the solvents were removed under reduced pressure. The crude product was used in the subsequent reaction. Yield: 314 mg.
Reaction SMILES: CC(C)(NC[CH2:9][CH2:10][NH:11][C:12]([CH3:18])([CH3:17])[C:13](=[N:15][OH:16])[CH3:14])C(=NN)C.[NH2:20]CCN>CO.O>[NH2:20][CH2:9][CH2:10][NH:11][C:12]([CH3:17])([CH3:18])[C:13](=[N:15][OH:16])[CH3:14]
Reactant: NCCN
Reactant: CC(=NN)C(C)(C)NCCCNC(C)(C)C(C)=NO
Solvent: CO
Solvent: O
Product: CC(=NO)C(C)(C)NCCN
Reaction time: 8 h

Procedure:
A solution of Compound A from Example 1 (10 g, 73.8 mmol) was added dropwise to a stirred solution of 1,2-diaminoethane (25 g, 416.7 mmol) in methanol (10 mL}at 0° C. After the addition was complete, the mixture was left overnight at room temperature with stirring. Removal of the methanol in vacuo gave a light yellow oil which was dissolved in water. The pH of the solution was adjusted to about 11. The solvent was removed under vacuum, and the residue was extracted with ethyl acetate. Evaporaticn of the organic phase gave a light yellow semi-solid which on crystallization with ether gave the product as a crystalline solid. Yield: 5.89 g (50%); mp. 65°-67° C. 1H NMR {CDCl3) δ 1.22[s, 6H, C(CH3)2 ], 1.87[s, 3H, C(=N)CH3 ], 2.49(t, 2H, CH2NH2) and 2.88(m, 2H, NHCH2). MS:(M+H)+ =160.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1.Cl.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:21][C:5]1[CH:4]=[N:3][CH:2]=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CCO
Product: CC(C)NC(=O)C1CCC(Nc2ccncc2N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (100 mg, 0.293 mmol) and conc. HCl (0.072 mL, 0.880 mmol) in EtOH (3.0 mL) under nitrogen was added Pd/C (10% wt) (156 mg, 0.147 mmol) and ammonium formate (185 mg, 2.93 mmol), and the mixture was stirred at RT for 30 minutes. The mixture was filtered through a pad of Celite® brand filter aid and evaporated. The residue was diluted with 10% IPA in DCM, and washed with 1 N NaOH and then with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and the solvent was removed to afford 4-(3-aminopyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide as an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([CH2:14][N:15]2[C@@H:19]([CH3:20])[C@@H:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=3)[O:17][C:16]2=[O:32])=[N:4][C:5]([N:8]2[CH2:11][C:10]([F:13])([F:12])[CH2:9]2)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([C@H:47]2[CH2:52][CH2:51][C@H:50]([C:53]([O:55][CH3:56])=[O:54])[CH2:49][CH2:48]2)=[CH:43][C:42]=1B1OC(C)(C)C(C)(C)O1>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C1COCC1>[F:12][C:10]1([F:13])[CH2:11][N:8]([C:5]2[N:4]=[C:3]([CH2:14][N:15]3[C@@H:19]([CH3:20])[C@@H:18]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=4)[O:17][C:16]3=[O:32])[C:2]([C:46]3[CH:45]=[C:44]([C@H:47]4[CH2:48][CH2:49][C@H:50]([C:53]([O:55][CH3:56])=[O:54])[CH2:51][CH2:52]4)[CH:43]=[CH:42][C:41]=3[O:40][CH3:39])=[CH:7][CH:6]=2)[CH2:9]1
Reactant: C[C@H]1[C@@H](c2cc(F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ccc1Br
Reactant: COc1ccc([C@H]2CC[C@H](C(=O)OC)CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc([C@H]2CC[C@H](C(=O)OC)CC2)cc1-c1ccc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
(4S,5R)-3-{[3-bromo-6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methyl}-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (530.8 mg, 1.012 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (66.0 mg, 0.101 mmol), potassium carbonate (1.519 ml, 3.04 mmol), methyl trans-4-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclohexanecarboxylate (INTERMEDIATE 7) (436 mg, 1.164 mmol) and THF (6 ml) were sealed in a reaction vessel and placed in a 90° C. oil bath for 4 hrs. LCMS indicated complete consumption of the starting material and formation of the desired product. Volatiles were removed under reduced pressure. The resulting pot residue was worked up with brine/ethyl acetate. The combined extracts were dried over Na2SO4, filtered and evaporated to afford a dark mixture. This mixture was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated in vacuo to afford a brown solid foam of 507 mg as the titled compound. LCMS calc.=691.25. found=692.49 (M+1)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10](=[O:42])[NH:11][CH2:12][C@H:13]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[C:18]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[C:29]([Cl:41])[CH:28]=1)=[N:19][CH:20]=[N:21]2)[CH3:14])C)(C)(C)C>FC(F)(F)C(O)=O>[Cl:41][C:29]1[CH:28]=[C:27]([NH:26][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[CH:25][C:16]=3[O:15][C@H:13]([CH3:14])[CH2:12][NH:11][C:10](=[O:42])[CH2:9][NH:7][CH3:6])[N:21]=[CH:20][N:19]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1
Reactant: C[C@H](CNC(=O)CN(C)C(=O)OC(C)(C)C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 14.4 %

Procedure:
[((R)-2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)phenylamino]quinazolin-5-yloxy}propylcarbamoyl)methyl]methylcarbamic acid tert-butyl ester (obtained as described in Example 123, 0.50 g) was stirred in trifluoroacetic acid (5 ml) for 20 hours. Volatile material was removed by evaporation and the residue was purified by chromatography, eluting with aqueous ammonia (0.880), methanol, DCM (1:10:90). Evaporation of the appropriate fractions gave the title compound as a solid (60 mg, 15%); (DMSO-d6 @ 373k) 1.47-1.50 (d, 3H), 2.20 (s, 3H), 3.10 (s, 2H), 3.45-3.55 (q, 1H), 3.55-3.65 (q, 1H), 4.85-5.00 (m, 1H), 5.25 (s, 2H), 7.15-7.25 (q, 2H), 7.25-7.30 (m, 2H), 7.55-7.65 (t, 1H), 7.70-7.80 (m, 2H), 8.20 (s, 1H), 8.50 (s, 1H), 8.55-8.60 (d, 1H), 9.85-9.95 (bs, 1H); Mass spectrum MH+ 507.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:4][CH2:5][CH3:6].FC(C(F)(F)F)(C(F)(F)F)C(OC)=[O:17].C([Mg]Br)C>>[F:1][C:2]([F:12])([F:13])[C:3]([F:11])([C:7]([F:8])([F:9])[F:10])[CH:4]([OH:17])[CH2:5][CH3:6]
Reactant: CCCC(F)(C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C(F)(C(F)(F)F)C(F)(F)F
Agent: CC[Mg]Br
Product: CCC(O)C(F)(C(F)(F)F)C(F)(F)F

Procedure:
1,1,1,2-Tetrafluoro-2-(trifluoromethyl)-pentane ((CF3)2CFCH2CH2CH3) may be prepared by reacting methyl perfluoroisobutyrate with ethyl magnesium bromide followed by hydrolysis to give 1,1,1,2-tetrafluoro-2-(trifluoromethyl)-3-pentanol. The pentanol is converted to 4,5,5,5-tetrafluoro-4-(trifluoromethyl)-2-pentene by dehydration with phosphorous pentoxide and the double bond saturated by hydrogenation over a palladium on carbon catalyst.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.S(O)(O)(=O)=O.[CH3:18][C@H:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:27][C@@H:19]([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: C[C@H](N)Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN[C@@H](C)Cc2ccccc2)cc1OC
Reaction time: 16 h
Yield: 65.7 %

Procedure:
A solution of 3,4-dimethoxybenzaldehyde (1.06 g, 6.4 mmol), (S)-1-methyl-2-phenylethylamine sulfate (1.18 g, 6.4 mmol) and triethylamine (0.89 ml, 6.4 mmol) in 1,2-dichloroethane (50 ml) was stirred at room temperature under argon for 15 min. Sodium triacetoxyborohydride (2.97 g, 14 mmol) was added over 5 min. then stirring was continued for a further 16 h. The reaction mixture was diluted with MDC (50 ml) then washed with saturated aqueous K2CO3. The aqueous phase was extracted with MDC and the combined organics washed with brine. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0–100% EtOAc-pentane) to afford the title compound as a colourless oil (1.20 g, 67%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:11][CH3:12])=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][Cl:14])=[CH:19][CH:20]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CCC(=O)c1ccc2occc2c1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2occc2c1
Yield: 79.8 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(benzofuran-5-yl)propan-1-one (250 mg, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (794 mg, 2.0 eq) to give 480 mg desired product (80%, Z/E=1/1).
Reaction SMILES: [N:1]1([C:5]([C:7]2[O:11][C:10]([S:12]([NH:15][C:16]3[CH:21]=[C:20]([O:22][C@H:23]([CH3:45])[CH2:24][O:25]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:19]=[C:18]([S:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:49]=4[F:55])[N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC)C=CC=CC=1.O>CO>[N:1]1([C:5]([C:7]2[O:11][C:10]([S:12]([NH:15][C:16]3[CH:21]=[C:20]([O:22][C@H:23]([CH3:45])[CH2:24][OH:25])[N:19]=[C:18]([S:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:49]=4[F:55])[N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(C(=O)N3CCC3)o2)nc(SCc2cccc(F)c2F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: COc1ccccc1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccc(C(=O)N3CCC3)o2)nc(SCc2cccc(F)c2F)n1

Procedure:
To a solution of 5-(azetidin-1-ylcarbonyl)-N-{2-[(2,3-difluorobenzyl)thio]-6-[(1R)-1-methyl-2-(triphenylmethyloxy)ethoxy]pyrimidin-4-yl}furan-2-sulfonamide (the product of step iv) (0.24 g) in methanol (5 mL) was added para-toluenesulfonic acid hydrate (58 mg) and anisole (0.34 mL). After stirring at room temperature for 2d, H2O (5 mL) was added and the mixture extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered and evaporated to dryness in vacuo. The resulting crude solid was purified by reverse phase HPLC (50% to 5% gradient of 0.1% aqueous ammonium acetate in acetonitrile as eluent) to give the title compound as a white solid. Yield: 10 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])=[C:18]([O:28][CH3:29])[CH:17]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[C:32]([NH:39][CH2:40][C:41](O)=[O:42])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(N=C=NC(C)C)(C)C>C(Cl)Cl>[C:35]([O:34][C:32]([NH:39][CH2:40][C:41]([O:27][C:24]([CH3:26])([CH3:25])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[C:12](=[O:30])[C:11]3[S:31][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:9][C:10]=3[CH:15]=[N:14]2)=[CH:17][C:18]=1[O:28][CH3:29])=[O:42])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc(-n2ncc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: COc1cc(-n2ncc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)CNC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-chlorophenyl)-6-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)thieno[2,3-d]pyridazin-7(6H)-one (100 mg, 0.219 mmol) that was prepared in Example 9,4-(pyrrolidin-1-yl)pyridine (32.4 mg, 0.219 mmol) and boc-glycine (192 mg, 1.094 mmol) in CH2Cl2 (10 ml) was added N,N′-diisopropylcarbodiimide (0.170 ml, 1.094 mmol). The mixture was stirred at reflux for 1 hours and then at RT for 18 hours. LC-MS analysis revealed desired product as well as the imide resulting from condensation with a second Boc-glycine. The later product was cleaved to regenerate desired product by addition of hydrazine (0.343 ml, 10.94 mmol) was added and the stirring at RT for 30 min. The reaction was diluted with a solution of saturated NaHCO3 (15 ml) and extracted with CH2Cl2 (20 ml). The CH2Cl2 extracts were dried over Na2SO4 and concentrated. The crude product was purified by ISCO chromatography on two silica gel column (2×12 g) employing a 10 min gradient ranging from hexane to 100% ethyl acetate to elute 1-(4-(2-(4-chlorophenyl)-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)-2-methoxyphenoxy)-2-methylpropan-2-yl 2-(tert-butoxycarbonylamino)acetate (130 mg, 0.212 mmol, 97% yield) as light brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(CC=Cc2ccccc2)c(O)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCCc2ccccc2)c(O)c(C(C)(C)C)c1

Procedure:
4,6-Di-t-butyl-2-cinnamylphenol (11.0 g., prepared as described in Example 1) was hydrogenated at room temperature and pressure in tetrahydrofuran (100 ml.) in the presence of 5% palladium on charcoal. The reaction was allowed to proceed until uptake of hydrogen ceased. The mixture was filtered and the filtrate evaporated to an oil. Distillation of the oil gave the desired compound as a colorless oil, b.p. 186°-187°C. at 0.5 mm. Hg. The nmr spectrum at 100 MHz in CDCl3 exhibited absorbances as follows: a singlet (9 protons) at δ 1.30, a singlet (9 protons) at δ 1.43, a multiplet (2 protons) at δ 1.85-204, a multiplet (4 protons) at δ 2.50-2.80, a singlet (1 proton) at δ 4.58, a doublet (1 proton) at δ 6.99 (J = coupling constant = 2.0 Hz), and a multiplet (6 protons) at δ 7.13-7.36.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1)(=[O:12])=[O:11])([O-])=O>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc(SC(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1S(=O)(=O)Nc1cccc(SC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.9 %

Procedure:
A solution of 2-nitro-N-{3-[(trifluoromethyl)sulfanyl]phenyl}benzenesulfonamide (605 mg, 1.6 mmol) in ethanol/H2O (4:1, 50 mL total reaction volume) was added to a suspension of 10% palladium on charcoal (50 mg) in ethanol/H2O (4:1) and the mixture stirred at rt under an atmosphere of H2 for approximately 2 d. After this time further 10% palladium on charcoal (75 mg) was added and the reaction mixture stirred under an atmosphere of H2 at rt for 3 h. Filtration and concentration in vacuo yielded the title compound (455 mg, 1.31 mmol).
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([NH2:15])=[CH:8][C:9]=2[C:10]([CH3:14])([CH3:13])[CH2:11][CH:12]=1)[CH3:2].Br[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([NH:15][C:7]2[CH:6]=[CH:5][C:4]3[C:3]([CH2:1][CH3:2])=[CH:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=3[CH:8]=2)=[CH:18][CH:19]=1)[CH3:25]
Reactant: CCC1=CCC(C)(C)c2cc(N)ccc21
Reactant: CCOC(=O)c1ccc(Br)cc1
Product: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CC=C3CC)cc1

Procedure:
Following General Procedure L, 5-ethyl-8,8-dimethyl-7,8-dihydro-naphthalen-2-ylamine (Compound 72, 0.17 g, 0.85 mmol), was reacted with ethyl 4-bromobenzoate to give the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][CH2:25][CH2:26]Cl)=[O:23])=[CH:18][CH:17]=1)[CH3:15]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:26][CH2:25][CH2:24][C:22](=[O:23])[C:19]2[CH:18]=[CH:17][C:16]([CH2:14][CH3:15])=[CH:21][CH:20]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: CCc1ccc(C(=O)CCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1ccc(C(=O)CCCSc2nnnn2C)cc1
Reaction time: 2 h
Yield: 49 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g), potassium carbonate (2.1 g) and 3-chloropropyl 4-ethylphenyl ketone (3.2 g) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off. The filtrate is concentrated under reduced pressure and the residue is purified by cilica gel column chromatography (Kieselgel 60, eluant: benzene-ether (10:1) and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(4-ethylbenzoyl)propyl]thio-1,2,3,4-tetrazole (yield 49%) as colorless needles, m.p. 68°-69° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([NH2:12])[CH:6]=1)(=[O:3])[CH3:2].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][NH:12][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[F:11])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: CC(=O)Nc1ccc(F)c(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cc(NC(C)=O)ccc1F)C(=O)OCC
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A mixture of 1.9 g (0.0113 mol) of 4-(N-acetylamino)-2-amino-1-fluorobenzene, 2.6 ml (2.78 g/0.0129 mol) of diethyl ethoxymethylenemalonate, and 4 ml of toluene is stirred at reflux for three hours, then allowed to cool to ambient temperature. The resulting precipitate is triturated with ether to give 3.29 g (84%) of title compound:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([P:10](=[O:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.N#N>CO.[Pd]>[CH2:11]([P:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])([CH2:14][CH2:15][CH3:16])=[O:17])[CH2:12][CH3:13]
Reactant: CCCP(=O)(CCC)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CCCP(=O)(CCC)c1cccc(N)c1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A solution of (3-nitrophenyl)(dipropyl)phosphane oxide (0.801 g, 3.14 mmol) in MeOH (3 mL) was charged with Palladium 10% wt on activated carbon (0.17 g, 0.16 mmol) and subjected to 3 cycles of evacuation and N2 purging. After a fourth evacuation the flask was purged with H2. The reaction was stirred at rt over night. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and purified via column chromatography to afford 329 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 0.90 (t, J=7.33 Hz, 6H), 1.21-1.36 (m, 2H), 1.36-1.52 (m, 2H), 1.67-1.91 (m, 4H), 5.30 (s, 2H), 6.67 (dt, J=8.02, 1.17 Hz, 1H), 6.72-6.79 (m, 1H), 6.88-6.95 (m, 1H), 7.11 (td, J=7.71, 3.54 Hz, 1H).
Reaction SMILES: C(OC(=O)[O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:7]=1[Cl:16])C.C(=O)(O)[O-].[Na+]>CO.O>[Cl:16][C:7]1[CH:8]=[C:9]([F:15])[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[OH:5]
Reactant: CCOC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a solution of the product from Example 73B (0.87 g, 3.30 mmol) in methanol (20 mL) and water (1 mL) was added sodium bicarbonate (2.22 g, 26.4 mmol) and the mixture stirred at room temperature for 16 hours. The methanol was then removed under vacuum, dichloromethane (20 mL) was added to the mixture, the organic solution was washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product (0.62 g, 98%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](SC2C=CC=CC=2C)=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].S1C=CC=C1C([O-])=O.[Cu+]>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](=[O:29])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][C:2]([F:14])([F:13])[F:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: Cc1ccccc1SC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cu+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a mixture of 2-trifluoromethoxy-phenyl-boronic acid (0.307 g, 2.24 mmol, 1.5 eq.), ligand TFP (0.069 g, 0.298 mmol, 0.2 eq.), Pd2(dba)3 (0.154 g, 0.149 mmol, 0.1 eq.), copper (I) thiophene-2-carboxylate (0.426 g, 2.24 mmol, 1.5 eq.) was added a solution of p-tolylsulfanylcarbonyl-piperidine-1-carboxylic acid tert-butyl ester (0.479 g, 1.49 mmol, 1 eq.) in 15 mL of DME while purging with N2 at room temperature. After 18 h stirring at room temperature, the reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated to give an oil. This oil was purified by silica gel column chromatography (10% ethyl acetate/heptane) to give the title compound as a white solid (0.5 g, 86%). Exact mass calculated for C18H23F3N1O4 374.2. MS (ESI) m/z 274.3 [(M-100)H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[C:10]1([CH2:16][CH2:17][CH2:18][OH:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCc1ccccc1
Reactant: BrCCCCCCCBr
Product: BrCCCCCCCOCCCc1ccccc1

Procedure:
(2.05 g) from 1,7-dibromoheptane (3.83 g) and 3-phenylpropanol (1.08 ml).