Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@@H:13]2[C@@H:17]3[CH2:18][CH2:19][CH2:20][C@@H:21]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH2:40][CH2:41][C:42]([NH:44][NH2:45])=[O:43])[CH:33]=4)[N:16]3[C:15](=[O:46])[O:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[C:58](Cl)(Cl)=[O:59]>C(Cl)Cl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@@H:13]2[C@@H:17]3[CH2:18][CH2:19][CH2:20][C@@H:21]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[CH:33]=[C:34]([CH2:40][CH2:41][C:42]5[O:43][C:58](=[O:59])[NH:45][N:44]=5)[CH:35]=[CH:36][C:37]=4[O:38][CH3:39])[N:16]3[C:15](=[O:46])[O:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:48])[CH:8]=1
Reactant: COc1ccc(CCC(=O)NN)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CCC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCc2n[nH]c(=O)o2)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CCC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46600 %

Procedure:
To 3-[2′-{(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanehydrazide (10 mg, 0.015 mmol) in DCM (2 mL) was added DIPEA (5.6 mg, 0.044 mmol) and phosgene (4.30 mg, 0.44 mmol). The reaction was stirred at room temperature for 30 minutes before the reaction was directly purified by column chromatography to yield (1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2′-methoxy-5′-[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl]-4-(trifluoromethyl)biphenyl-2-yl}hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (5 mg, 6.99 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 3:1 ratio: 1H NMR (500 MHz, CDCl3) δ9.23 (s, 1H), 7.88 (s, 1H), 7.80 (s, 2H), 7.79 (s, 1H, minor rotamer), 7.65 (s, 2H, major rotamer) 7.62 (m, 1H) 7.4 (d, J=7.8 Hz, 1H, major rotamer), 7.25 (d, J=7.8 Hz, 1H, minor rotamer), 7.09 (s, 1H), 7.02 (m, 2H), 5.58 (m, 1H, minor rotamer) 5.42 (m, 1H, major rotamer), 4.19 (m, 1H), 3.85 (s, 3H, minor rotamer), 3.80 (s, 3H, major rotamer), 3.0-2.85 (m, 4H), 1.98 (m, 2H), 1.5-1.6 (m, 4H). MS ESI calc'd. for C33H27F9N3O5 [M+H]+ 716.2, found 716.3. RTA (95% HS): 942 nM
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]([O:27]CC)=[O:26])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]([OH:27])=[O:26])[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](OC1CC2C(C1)C2C(=O)O)(c1ccccc1)c1ccccc1
Reaction time: 20 h
Yield: 81.4 %

Procedure:
To a solution of ethyl 3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylate (70.0 g, 171 mmol) in ethanol (400 mL) was slowly added a solution of sodium hydroxide (20.56 g, 513.94 mmol) in water (100 mL). After 20 h, the reaction mixture was concentrated and the resulting residue was diluted with water (200 mL). The aqueous solution was adjusted to pH=3 by dropwise addition of 3 M aqueous hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (2×200 mL). The combined organics were washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylic acid as a yellow solid (53 g). To an ice-cooled suspension of crude acid in dichloromethane (600 mL) was added carbonyldiimidazole (25.5 g, 158 mmol). After 2 h, N, O-dimethylhydroxylamine hydrochloride (32 g, 0.33 mmol) was added. After 3 h, the reaction mixture was filtered and the filtrate was concentrated. Purified by flash column chromatography (6:1 petroleum ether/ethyl acetate) afforded 3-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylbicyclo[3.1.0]hexane-6-carboxamide (37 g, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.63-7.61 (m, 4H), 7.42-7.33 (m, 6H), 4.33-4.31 (m, 1H), 3.74 (s, 2H), 3.57 (s, 1H), 3.21 (s, 2H), 3.10 (s, 1H), 2.21-2.18 (m, 1H), 2.00-1.80 (m, 6H), 1.06-1.01 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][N:17](C(OC(C)(C)C)=O)[CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2.[ClH:49]>C(Cl)Cl.CO>[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2.[ClH:49].[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2
Reactant: Cc1ccc(C(=O)Nc2ccc(Oc3cc4cnn(C)c4cc3-c3cnn(C(=O)OC(C)(C)C)c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C(=O)Nc2ccc(Oc3cc4cnn(C)c4cc3-c3cn[nH]c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (423.9 g, 649.50 mmol) is dissolved in DCM (4.24 L). HCl in MeOH (5.74 N, 799.99 mL, 4.59 mol) is added and the solution is heated at 30° C. for 1 hour. Then the reaction mixture is heated to 45° C. and DCM (1.5 L) is added. After two hours, the solution is heated to 50° C. and DCM (2 L) is added. After 3 hours, DCM (2 L) is added followed by HCl in MeOH (4.5 N, 721.67 mL, 3.25 mol). After another 45 min, DCM (1 L), HCl in MeOH (4.5 N, 288.67 mL, 1.30 mol), and MeOH (1.5 L) are added. The reaction solution is then heated to 60° C. After 4 hours, MeOH (2 L) is added and 10 min later DCM (1 L) is added followed by HCl in MeOH (4.5 N, 200 mL). After 5 hours, the reaction is complete. The reaction mixture is concentrated to about ⅓ volume. MeOH (2 L) is added and the solution is concentrated to a thick slurry. Again, MeOH (2 L) is added and the mixture is concentrated to a thick slurry. The slurry is cooled to about 10-15° C. and then filtered. The solids are washed with MeOH. The solids are placed in a 55° C. vacuum oven for 2 days to give the desired product N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (377 g, 92.8%). MS (m/z): 551.0 (M−H).
Reaction SMILES: Br/[C:2](/[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[C:3](\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)/[CH2:4][CH3:5].[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:19]([C:21]1[CH:26]=[CH:25][C:24](/[C:2](/[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:3](\[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)/[CH2:4][CH3:5])=[CH:23][CH:22]=1)=[O:20]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC/C(=C(/Br)c1ccc(F)cc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC/C(=C(\c1ccc(F)cc1)c1ccc(C=O)cc1)c1ccccc1
Yield: 92.6 %

Procedure:
To a solution of the bromide 3 (2.0 g, 6.54 mmol) in DME (30 mL) was added 4-formylbenzene boronic acid (1.37 g, 9.11 mmol), tetrakis(triphenylphosphine)palladium(0) (800 mg, 0.7 mmol), and 2N aqueous sodium carbonate(4.8 mL, 9.6 mmol). After refluxing overnight the solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 5% EtOAc/hexanes) to give the aldehyde (4) as a white solid (2.0 g, 92%): 1 H NMR (CDCl3) δ 9.83 (m, 1 H), 7.52 (d, J=8.4 Hz, 2 H), 7.15 (m, 11 H), 2.49 (q, J=7.3 Hz, 2 H), 0.94 (t, J=7.3 Hz, 3 H); APcI m/z: 372 (M+H+CH3CN+, 100%).
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[CH2:9]([N:12]([CH:19]([OH:34])[C@H:20]1[O:26][C@:24]([CH2:27][CH:28]([CH3:30])[CH3:29])([OH:25])[C@H:23]([OH:31])[C@@H:22]([OH:32])[C@@H:21]1[OH:33])[C:13](=[O:18])[NH:14][CH2:15][CH2:16][Cl:17])[CH2:10][CH3:11].O1CCOCC1.S(=O)(=O)(O)O>CO>[CH2:9]([N:12]([CH:19]([OH:34])[C@H:20]1[O:26][C@:24]([CH2:27][CH:28]([CH3:29])[CH3:30])([OH:25])[C@H:23]([OH:31])[C@@H:22]([OH:32])[C@@H:21]1[OH:33])[C:13](=[O:18])[N:14]([CH2:15][CH2:16][Cl:17])[N:1]=[O:2])[CH2:10][CH3:11]
Reactant: CC(C)CCON=O
Reactant: CCCN(C(=O)NCCCl)C(O)[C@H]1O[C@@](O)(CC(C)C)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1COCCO1
Product: CCCN(C(=O)N(CCCl)N=O)C(O)[C@H]1O[C@@](O)(CC(C)C)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 68.4 %

Procedure:
Isoamyl nitrite (4 ml) was dropped into a solution of the above synthesized 3-n-propyl-3-(isobutyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (3.47 g, 9.06 mmol) in a mixture of methanol (50 ml), dioxane (150 ml), and 10% sulfuric acid (50 ml), with well stirring at 0° to 5° C. After stirring for further 3 hours to complete reaction, which was confirmed by TLC, the reaction mixture was vacuum-concentrated at 25° C. and crystallized from ethanol and water, giving 2.55 g of 3-n-propyl-3-(isobutyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea; yield 68.4%, m.p. 58°-60° C., [α]D20 +71.7° (C 1.0, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][C:3]=1[CH:12]([CH2:15][OH:16])[C:13]#[N:14].C(#N)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].OS(O)(=O)=O>O>[C:20]([O:16][CH2:15][CH:12]([C:3]1[CH:4]=[C:5]([O:8][CH:9]([F:11])[F:10])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:13]#[N:14])(=[O:22])[CH3:21]
Reactant: N#CC(CO)c1cc(OC(F)F)ccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: CC(=O)OCC(C#N)c1cc(OC(F)F)ccc1Cl
Yield: 80.4 %

Procedure:
A 5 mL screw-capped test tube was charged with 250 mg (1.00 mmol) of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile, 0.4 mL of acetonitrile and 122 μL (1.3 mmol) of acetic anhydride. This mixture was stirred briefly with a melting point capillary having the tip wetted with conc. H2SO4 to give an immediate exotherm. After 15 minutes the mixture was diluted with water and extracted with butyl chloride. The extract was washed with water 3 times, dried (Na2SO4), and stripped of solvent under high vacuum to give 233 mg (96%) of the desired ester product, i.e., 3-acetoxy-2-(2-chloro-5-(difluoromethoxy)phenyl)propanenitrile, as a colorless oil.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].C([O-])([O-])=O.[K+].[K+].[Br-].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>CC(C)=O>[CH2:16]([N:4]1[C:5](=[O:6])[CH2:7][S:1][C:2]1=[S:3])[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: O=C1CSC(=S)N1
Reactant: CC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1C(=O)CSC1=S)c1ccccc1

Procedure:
Reagents: Rhodanine (133 mg, 1 mmol), K2CO3 (excess) and acetophenone bromide (199 mg, 1 mmol) in 25 ml of acetone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)=[C:5]([NH2:19])[CH:4]=1)#[N:2].[CH2:20](OC=C(C#N)C#N)C>C(O)CC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[CH:13]4)[CH:20]=[N:19][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC=C(C#N)C#N
Reactant: N#Cc1ccc(Nc2ccc3[nH]ccc3c2)c(N)c1
Solvent: CCCO
Product: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Yield: 94 %

Procedure:
5-(4-Cyano-2-nitrophenylamino)-1H-indole (0.56 g, 2.0 mmoles) was reduced by catalytic hydrogenation, to form 5-(4-cyano-2-aminophenylamino)-1H-indole (0.50 g, 2.0 mmole). The 5-(4-cyano-2-aminophenylamino)-1H-indole was cyclized using ethoxymethylenemalononitrile (0.49 g, 2.0 mmoles) in propanol, and the cyclization reaction was heated for 24 hours. Column chromatography using ethyl acetate/hexanes [1:1] afforded the title compound (94%) as a yellow solid. Mp, 263.0°-264.0° C.; 13C NMR (DMSO-d6) δ147.2, 143.5, 137.5, 135.8, 128.5, 128.1, 127.3, 127.0, 125.3, 120.2, 118.2, 116.7, 113.1, 112.6, 104.8, 102.2; HRMS calculated for C16H10N4 258.0904, found 258.0904. Analytical calculated for C16H10N4 : C, 74.40; H, 3.90; N, 21.69. Found: C, 74.20; H, 3.92; N, 21.69.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C@@H:8]([CH2:20]O)[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:47]I>>[C:1]([O:5][C:6](=[O:22])[CH2:7][C@@H:8]([CH2:20][I:47])[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CI)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-benzyloxycarbonyl-3(S)-hydroxymethyl -β-alanine tert-butyl ester (2.0 g), triphenylphosphine (1.87 g), imidazole (0.66 g) and I2 (1-80 g) was stirred for 30 minutes at room temperature. The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% (EtOAc/n-hexane) to give N-benzyloxycarbonyl-3(S)-iodomethyl-β-alanine tert-butyl ester (1.8 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]([CH:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]([CH:12]2[CH2:17][CH2:16][S:15](=[O:32])[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CN(C(=O)C1CCSCC1)c1ccc(OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C(=O)C1CCS(=O)CC1)c1ccc(OC)cc1

Procedure:
A chloroform solution of ethyl [(4-methoxyphenyl)-(tetrahydrothiopyran-4-carbonyl)amino]acetate was stirred by adding 3-chloroperbenzoic acid (>65%; MCPBA). Sodium bicarbonate aqueous solution was added to the reaction mixture, the organic layer was separated, washed and dried, and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained crude product by SCG, ethyl [(4-methoxyphenyl)-(1-oxo-tetrahydrothiopyran-4-carbonyl)amino]acetate (pale brown foam) was obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[O:15][C:16]3[C:17](=[C:19]([C:23]([OH:25])=O)[CH:20]=[CH:21][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl.[NH2:28][C@H:29]1[CH:34]2[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]2)[CH2:30]1>>[N:31]12[CH2:30][CH:29]([NH:28][C:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:16]4[O:15][C:14]([N:11]5[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][C@@H:12]5[C:16]5[CH:17]=[CH:19][CH:20]=[CH:21][CH:22]=5)=[N:18][C:17]=34)=[O:25])[CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(C(=O)O)cccc3o2)CC1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: CN1CCN(c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)[C@@H](c2ccccc2)C1

Procedure:
Following general procedure GP-C1, a mixture of 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(4-methyl-2-phenylpiperazin-1-yl)benzoxazole-4-carboxamide which was converted to the dihydrochloride salt following general procedure GP-D1 and isolated as a mixture of diastereomers. 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[NH2:6].C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[C:28]([N+:35]([O-:37])=[O:36])[CH:27]=1>C(Cl)Cl>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:31])=[C:28]([N+:35]([O-:37])=[O:36])[CH:27]=1
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccc(Cl)cc2[N+](=O)[O-])ccc1OCCN1CCCC1
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]aniline (43 mmol, 10.0 g) in DCM was added triethylamine (52 mmol, 5.2 g) and 4-chloro-2-nitrobenzoyl chloride (9.5 g, 43 mmol). The solution was stirred overnight. The reaction mixture was extracted with 2N HCl. The resulting acidic aqueous solution was made basic by adding 2N NaOH. The combined basic aqueous solution was extracted with DCM. The organic phase was washed with brine, dried and concentrated giving the title compound (11.5 g, 69%). 1H NMR (DMSO-D6): δ 1.66 (4H, m), 2.49 (4H, m), 2.75 (2H, t, J=6.0 Hz), 3.72 (3H, s), 4.00 (2H, t, J=6.0 Hz), 6.94 (1H, d, J=8.6 Hz), 7.14 (1H, d, J=8.6 Hz), 7.79 (1H, d, J=8.1 Hz), 7.94 (1H, d, J=8.1 Hz), 8.23 (1H, s), 10.55 (1H, s). LCMS m/z=420 (m+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[F:28][CH:29]([F:38])[O:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH:29]([F:38])[F:28])=[CH:32][CH:33]=3)=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc(COc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 80 °C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
A degassed mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylic acid methyl ester (119) (200 mg, 0.54 mmoles), 4-difluoromethoxy-1-iodo-benzene (175 mg, 0.65 mmoles), 2M aqueous cesium carbonate (0.81 ml) and), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20 mg) in 1,4-dioxan (10 ml), under an argon atmosphere was heated at 80° C. for 20 h. Further quantities of 4-difluoromethoxy-1-iodo-benzene (87.5 mg, 0.0.27 mmoles) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (10 mg) were added and heating at 80° C. was continued for 4 hours. After cooling, the mixture was concentrated. The residue was dissolved in dichloromethane and washed with water and brine, and dried. The solvent was evaporated and the residue was purified by flash chromatography using petrol (40–60°)/diethyl ether 9:1v/v as eluent to afford compound 128(120 mg) as a wax. LC/MS System A; Rt=4.14 mins.
Reaction SMILES: C(OC([NH:11][C:12]1([CH3:35])[CH2:17][CH2:16][N:15]([C:18](=[O:34])[C@:19]([C@@H:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)=O)C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:11][C:12]1([CH3:35])[CH2:17][CH2:16][N:15]([C:18](=[O:34])[C@:19]([C@@H:27]2[CH2:31][CH2:30][C:29]([F:32])([F:33])[CH2:28]2)([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(N)CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of 568 mg of 4-benzyloxycarbonylamino-1-{(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetyl}-4-methylpiperidine in a mixture of 10 ml of methanol and 5 ml of ethyl acetate, 200 mg of 10% palladium-carbon catalyst was added, followed by stirring for 18 hours under a hydrogen atmosphere. After filtering the catalyst off, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 1M hydrochloric acid and washed with diethyl ether. After basifying with 4N sodium hydroxide, the aqueous layer was extracted with chloroform, and dried over anhydrous magnesium sulfate to give 320 mg of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH:8]([CH3:15])[N:9]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:1][C:2]1[N:18]=[CH:17][C:5]2[N:6]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7](=[O:16])[CH:8]([CH3:15])[N:9]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]=2[CH:3]=1
Reactant: CC(C)CCN1c2cc(Cl)ncc2NC(=O)C1C
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCN1c2cc(Cl)ncc2N(c2ccccc2)C(=O)C1C
Temperature: 25 °C
Reaction time: 30 h
Yield: 49 %

Procedure:
To a stirred solution of 7-chloro-2-methyl-1-(3-methylbutyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one (103 mg, 0.38 mmol) in dichloromethane (7 mL) was added triethylamine (0.53 mL, 3.8 mmol), cupric acetate (140 mg, 0.77 mmol) and phenylboronic acid (94 mg, 0.77 mmol) followed by 4 Å molecular sieves (2.0 g). The reaction mixture was stirred for 30 h at rt with an air balloon. It was then filtered over celite to remove inorganic material, the organic phase was washed with aqueous sodium carbonate, dried with Na2SO4, and the solvent was removed under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluent: 40% ethyl acetate in hexane) to give the desired product (Yield: 49%). 1HNMR (CDCl3, 300 MHz) δ 1.07-1.18 (m, 6H), 1.47 (d, J=6.6 Hz, 3H), 1.69-1.86 (m, 4H), 3.18-3.26 (m, 1H), 3.48-3.58 (m, 1H), 4.32 (q, J=6.9 Hz, 1H), 6.62 (s, 1H), 6.87-7.05 (m, 1H), 7.27-7.35 (m, 2H), 7.39 (s, 1H), 7.53-7.65 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+].O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20][OH:21])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CSc1nccc(CC(=O)c2ccc(F)cc2)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CSc1nccc(CC(=NO)c2ccc(F)cc2)n1
Reaction time: 24 h
Yield: 498.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone (91.49 g,48 mmol) in acetonitrile (1.8 L) was added hydroxylamine hydrochloride (121 g, 91.7 mol) and sodium acetate (139 g, 1.7 mol). The reaction was stirred for 24 hours before 100 mL of water was added. The reaction was stirred for 24 hours. The mixture was filtered through a glass frit and the filtrate partitioned between dichloromethane and water. The layers were separated and the aqueous phase extracted with dichloromethane (2×500 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (300 mL), washed with brine (300 mL), dried over magnesium sulfate, filtered and concentrated. The residue was recrystalized from dichloromethane and hexanes to yield 66.4 g (69%) of 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone oxime. 1H NMR (CDCl3): δ 8.75 (m, 1H), 8.42 (d, 1H), 7.75 (dd, 2H), 7.09 (t, 2H), 6.98 (d, 1H), 4.29 (s, 2H), 2.54 (s, 3H). MS m/z 278 (M+1).