Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:30])[CH2:10][C:11]1[CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH:12]=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].ClCCl>CN(C=O)C.CO.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].C(OCC)(=O)C>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH:40]=[C:41]([C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=3)[CH:12]=[C:11]([CH2:10][C:9]([O:8][CH3:7])=[O:30])[CH:20]=2)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)c2cc(F)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2cc(F)ccc2c1
Yield: 54.2 %

Procedure:
Anhydrous potassium carbonate (0.40 g, 2.9 mmol) was added to a stirred solution of compound (6-fluoro-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 0.37 g, 1 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.30 g, 0.97 mmol) in dry DMF-MeOH (4:1, 5 mL) in a pressure tube. The mixture was deoxygenated by bubbling with argon for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (available from Sigma-Aldrich; 80 mg, 0.1 mmol) was added under argon. The mixture was heated at reflux for 12 h and then cooled. Ethyl acetate (20 mL) was added and the mixture was filtered through a pad of celite. The celite was washed with ethyl acetate and the combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), using 5% ethyl acetate/hexanes as eluent, to give 4-(7-fluoro-3-methoxycarbonylmethyl-naphthalen-1-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.21 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.78 (dd, J=6.6, 4.4 Hz, 1H), 7.64 (s, 1H), 7.51 (dd, J=7.1, 1.1 Hz, 1H), 7.21-7.26 (m, 2H), 5.77 (s, 1H), 4.12 (s, 2H), 3.70-3.76 (m, 7H), 2.45-2.50 (m, 2H), 1.52 (m, 9H); MS cald. for C23H27FNO4 [(M+H)+] 400, obsd. 400.2.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:35]=[CH:36][CH:37]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[C:23]([F:33])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11]C1=O)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:35]=[CH:36][CH:37]=1)[CH2:8][NH:9][C@@H:17]1[C@@H:12]([OH:11])[C@H:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])=[C:23]([F:33])[CH:22]=2)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCNc1ccc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1F
Solvent: Cc1ccccc1
Product: CN(C)CCNc1ccc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc1F

Procedure:
The title compound was prepared in analogous manner as described for example 1o) from (3aR*,7S*,7aS*)-3-(3-tert-butyl-benzyl)-7-[4-(2-dimethylamino-ethylamino)-3-fluoro-benzyl]-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one to yield a sticky oil: TLC (toluene-ETA 85:15) Rf=0.20; HPLC RtA=1.51 min; ESIMS [M+H]+=506; 1H-NMR (600 MHz, DMSO-d6): δ 7.35 (s, 1H), 7.24 (m, 2H), 7.13 (d, 1H), 6.85 (d, 1H), 6.78 (d, 1H), 6.65 (t, 1H), 5.65 (d, 1H), 4.92 (m, 1H), 3.80 (d, 1H), 3.62 (d, 1H), 3.37 (m, 1H), 3.10 (m, 3H), 2.95 (m, 3H), 2.78 (m, 1H), 2.63 (m, 1H), 2.45 (t, 2H), 2.37 (m, 1H), 2.15 (s, 6H), 1.98 (m, 1H), 1.25 (s, 9H).
Reaction SMILES: N1CCCC1.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1.[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20]>CO>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[CH:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[C:15]2=[O:18])=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)CC2
Temperature: 25 °C
Yield: 71 %

Procedure:
2.5 mL (30.1 mmol) of pyrrolidine were added to a room temperature (about 25° C.) solution of 5.30 g (30.1 mmol) of 7-methoxy-1-tetraione and 4.55 g (30.1 mmol) of 3-nitrobenzaldehyde in 25 mL methanol. The reaction flask was fitted with a soxhlet extractor containing a thimble filled with 3 Å molecular sieves and a reflux condenser was placed on top of the soxhlet extractor. The reaction mixture was heated to reflux under N2 for 18 hours, cooled to room temperature and filtered. The precipitate was washed twice with CH3OH, and then dried on the funnel for 24 hours to yield 6.62 g of light tan powder. (71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]([NH2:12])=[S:11].[CH2:13](Br)[CH2:14][CH3:15]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10](=[NH:12])[S:11][CH2:13][CH2:14][CH3:15]
Reactant: CCCBr
Reactant: NC(=S)NCc1ccccc1Cl
Solvent: CC#N
Product: CCCSC(=N)NCc1ccccc1Cl
Yield: 78 %

Procedure:
A mixture of 1-(2-chlorophenyl)methyl thiourea (3 g, 14.9 mmol) and propylbromide (13.5 g, 110 mmol) in acetonitrile (20 mL) was refluxed for 5 hours. The solvent was evaporated, the residue was dissolved in 200 mL of 50% water/ether and acidified with 48% hydrobromic acid solution. The two phases were separated, the aqueous layer was washed with ether and then the aqueous layer was basified with 10% sodium carbonate solution. The liberated product was extracted with diethyl ether, washed with water and brine, dried and concentrated to give 1-(2-chlorophenyl)methyl-2-propyl-2-thiopseudourea (2.82 g, 78%); mp 112°-114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.F[C:10](F)(F)C(O)=O>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[CH2:10])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=Nc1ccc(Br)cn1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a suspension of 2-amino-5-bromopyridine (2.34 g, 13.5 mmol) and p-formaldehyde (3.0 g) in toluene (50 mL) was added trifluoroacetic acid (0.1 mL) and the reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature, filtered through a pad of diatomaceous earth and concentrated in vacuo. The residue was triturated in methanol to afford 5-bromo-N-methylenepyridin-2-amine as a colorless solid in 34% yield (0.849 g): 1H NMR (300 MHz, CDCl3) δ8.13 (s, 1H), 7.48 (dd, J=8.9, 2.4 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H), 5.51 (s, 2H); MS (ES+) m/z 184.9 (M+1), 186.9 (M+1).
Reaction SMILES: O[CH:2]([C:9]1[C:10]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:11]=2[S:12][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([BH3-])#N.[Na+].ClCCl>[I-].[Zn+2].[I-].CO>[CH2:2]([C:9]1[C:10]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:11]=2[S:12][CH:13]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CCc2c(C(O)c3ccccc3)csc2C1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1CCc2c(Cc3ccccc3)csc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
A mixture of 8.3 g of 3-(α-hydroxybenzyl)-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 12.5 g of zinc iodide, 2.0 g of sodium cyanoborohydride and 150 ml of dichloromethane was stirred at room temperature for 3 hours. After adding methanol to the reaction solution, insoluble matters were filtered off. The solvent was removed, and the residue was subjected to silica gel column chromatography and eluted with hexane and then with hexane/ethyl acetate (10:1), to give 5.9 g of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccc([N+](=O)[O-])cc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 4-nitrobenzoyl chloride (72 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:50]/[O:51][CH:52]([CH3:54])[CH3:53])/[C:27]([NH:29][C@@H:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[N:43]([NH2:44])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NC1SC=C(/C(=N/OC)/C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(NC(C)C)N=NN=4)CS[C@H]23)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:50]/[O:51][CH:52]([CH3:54])[CH3:53])/[C:27]([NH:29][C@@H:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[N:43]([NH2:44])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CC(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC(C)C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CC(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(N)n1
Yield: 41.5 %

Procedure:
A solution of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-isopropoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.90 g, 3.7 mmol) in 80% formic acid (12 ml) was treated in a manner similar to that described in Example 6, (d) to give pale brown powder of 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-isopropoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (0.83 g, 41.5%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[CH3:22].O>CN1CCCC1>[CH3:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:4][O:3][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH3:22])[CH:10]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1ccnc(CO)c1
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccnc(COc2ccc([N+](=O)[O-])cc2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
n-Butyllithium (24 ml of a 1.6 N solution in hexanes, 38.4 mmol) was added to a stirred solution of 2,4-lutidine (4.28 g, 40 mmol) in tetrahydrofuran (70 ml) at −70° C. under an inert atmosphere. After 1 hour, air was bubbled through (for 1 hour), methanol (50 ml) was added and the reaction allowed to warm to ambient temperature. The reaction mixture was filtered and then evaporated in vacuo. Purification of the crude product by flash chromatography on silica gel, eluting with ethyl acetate, yielded 2-(hydroxymethyl)-4-picoline (700 mg, 14% yield) as a white solid. b) Sodium hydride (150 mg of an 80% dispersion in mineral oil, 5.00 mmol) was added to a stirred solution of 2-(hydroxymethyl)-4-picoline (590 mg, 5.00 mmol) in N-methylpyrrolidine (20 ml) at ambient temperature. 2-Fluoro-5-nitrotoluene (775 mg, 5.00 mmol) was added, the reaction was stirred for 18 hours at ambient temperature and the reaction was poured into water (60 ml). Collection of the yellow solid which precipitated, followed by drying in vacuo, yielded 2-((4-methyl-2-pyridyl)methoxy)-5-nitrotoluene (900 mg, 70% yield) as a yellow solid. c) 5% Platinum on carbon (50 mg) was added to a solution of 2-((4-methyl-2-pyridyl)methoxy)-5-nitrotoluene (750 mg, 2.91 mmol) in ethanol (150 ml) and the solution was stirred for 2 hours at ambient temperature under an atmosphere of hydrogen. Filtration of the reaction mixture, followed by solvent evaporation in vacuo, yielded 3-methyl-4-((4-methyl-2-pyridyl)methoxy)aniline (420 mg, 63% yield) as a yellow gum.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH:12](Br)[C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2].C(#N)C.[N+]1([O-:27])C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[O:27])[C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1nc(C(Br)C(=O)OC)ns1
Reactant: [O-][n+]1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Nc1nc(C(=O)C(=O)OC)ns1
Yield: 93.6 %

Procedure:
Into a 1 L round bottom flask equipped with mechanical stirring and reflux condenser was charged methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)-bromoacetate (50.0 g, 0.154 mol, 1.0 eq.) followed by acetonitrile (500 mL). To the clear light yellow solution was charged pyridine N-oxide (37.0 g, 0.385 mol, 2.5 eq) and the reaction mixture was heated to reflux and maintained there for three hours until reaction completion was determined by proton NMR analysis. The solution was cooled and the acetonitrile was removed by rotary evaporation to give a thin yellow oil. The oil was dissolved in dichloromethane (500 mL) and the organic was washed once with brine (1×200 mL). The brine solution was extracted several times with dichloromethane (5×100 mL) and the organic layers were combined and dried with sodium sulfate, filtered and the solvent evaporated to give a clear slightly yellow oil which solidified upon standing at room temperature. The solid was dried under high vacuum to give 37.36 grams of the title compound. 1H NMR (CDCl3) δ 1.40 (t, 3H); 4.06 (s, 3H); 4.46 (q, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:12])[C:6](=[N:10][OH:11])[C:7]([CH3:9])=[O:8].Cl[CH2:14][O:15][CH3:16].C(OCC)(=O)C>O1CCCC1>[CH3:3][O:4][C:5](=[O:12])[C:6](=[N:10][O:11][CH2:14][O:15][CH3:16])[C:7]([CH3:9])=[O:8]
Reactant: COCCl
Reactant: COC(=O)C(=NO)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCON=C(C(C)=O)C(=O)OC
Reaction time: 0.5 h

Procedure:
To a suspension of 4.13 g of 80% NaH in 50 ml of dry tetrahydrofuran are added successively at 0° 18.14 g of 2-hydroxyiminoacetoacetic acid methyl ester and 9 g of chloromethylmethylether. After 30 minutes at room temperature, the mixture is divided between 200 ml of ethyl acetate and aqueous buffer (pH 5.5). The contents of the ethyl acetate phase are bulb distilled to obtain the heading compound, m.p. 115°-120°/0.1 Torr.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CCOC(=O)c1cccc(Br)n1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cccc(-c2ccc(O)cc2)n1
Temperature: 150 °C
Yield: 69.9 %

Procedure:
To a solution of ethyl 6-bromo-2-pyridinecarboxylate (D1, 460 mg, 2.0 mmol) in dioxane (4 ml) were added 4-hydroxy-phenyl boronic acid (414 mg, 3.0 mmol), Pd(PPh3)4 (450 mg, 0.4 mmol) and potassium carbonate (420 mg, 4.0 mmol) dissolved in water (2 ml). The reaction mixture was heated in a microwave synthesizer for 15 min at 150° C. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with saturated aqueous ammonium chloride (40 ml). The resulting crude material was purified by chromatography on silica gel using ethyl acetate/cyclohexanes (1:1) to afford the title compound (340 mg, 72%); 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.05 (d, 2H), 8.0 (m, 1H), 7.80 (d, 2H), 7.05 (d, 2H), 6.80 (bt, 1H), 4.50 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1.Cl[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:23]#[N:24])[CH:14]=1)(=[O:12])=[O:11].Cl>N1C=CC=CC=1>[Cl:2][C:3]1[S:7][C:6]([NH:8][S:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:23]#[N:24])[CH:14]=2)(=[O:12])=[O:11])=[N:5][CH:4]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1C#N
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a solution of 5-chloro-1,3-thiazol-2-amine hydrochloride (1.15 g, 6.7 mmol, 3 eq) in pyridine (7.5 ml) was added methyl 4-(chlorosulfonyl)-2-cyanobenzoate (Preparation 20, 580 mg, 2.2 mmol, 1 eq) portionwise and the reaction mixture was stirred at room temperature for 1 hour. The mixture was slowly added to 6M HCl (40 ml) and the resulting precipitate was collected by filtration and triturated with MeOH to yield the title compound as a brown solid (138 mg, 0.38 mmol, 17%).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:38]4[CH2:39][CH2:40][C@@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.36 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 451 [M+H]
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][CH2:13][OH:14])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[F:1][C:2]1[C:3]([CH2:12][CH:13]=[O:14])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COc1cc(CCO)c(F)cc1C#N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1cc(CC=O)c(F)cc1C#N
Reaction time: 2 h

Procedure:
To a solution of 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile (175 mg, 0.90 mmol) in dichloromethane (4 mL) was added Dess-Martin periodinane (530 mg, 1.3 mmol) at RT. The mixture stirred at roomtemperature for 2 h, then was diluted with saturated sodium bicarbonate and saturated sodium thiosulfate and stirred 30 min. The mixture was extracted with dichloromethane (3×) and the combined organics dried (MgSO4), filtered and concentrated to provide 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile which was used without further purification. LC-MS (IE, m/z): 194.2 [M+1]+.
Reaction SMILES: C(OC(N[CH:9]([OH:19])[C@H:10](C)[CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=O)(C)(C)C.CC(C)([O-])C.[K+].O.[CH3:27][N:28](C)[CH:29]=[O:30]>>[CH3:27][N:28]1[C@H:10]([CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][O:19][C:29]1=[O:30]
Reactant: C[C@H](CCc1cccs1)C(O)NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CN1C(=O)OC[C@H]1CCc1cccs1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
(2R)-t-Butoxycarbonylamino-2-methyl-4-(thiophen-2-yl)-1-butanol (15.4 g, 53.9 mmol) obtained in Example 67(b) was dissolved in N,N-dimethylformamide (200 ml), and potassium t-butoxide (9.07 g, 80.8 mmol) was added thereto in an ice bath followed by stirring for 10 minutes in an ice bath and subsequently for 40 minutes at room temperature. To the reaction solution was added water, and then the solution was extracted with ethyl acetate, and after the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=3:1-1:1) to afford the tide compound (11.5 g, 100% yield) as a white solid. The data obtained from analytical instruments were in accord with that obtained in Example 66.
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C1(C)C=CC=CC=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>>[CH3:34][O:33][C:31](=[O:32])[CH2:30][O:1][C:2]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)C1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate (480 mg, 0.0018 mol) in toluene (20 mL, 0.2 mol) was added sodium hydride (80.2 mg, 0.00200 mol) and the solution was refluxed for 1 hour. Methyl bromoacetate (0.190 mL, 0.00200 mol) was then added and the mixture continued to be stirred under reflux overnight. The reaction mixture was allowed to cool to rt and the product was extracted with EtOAc. The combined organic layers were washed with water, dried with MgSO4, and concentrated in-vacuo. LC/MS: m/z 336.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][OH:22])[C:15]=2[CH3:23])[CH2:10][CH2:9]1)=O)(C)(C)C.N1CCCCC1>>[CH2:19]([N:18]1[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH3:23])[C:16]([CH2:21][OH:22])=[N:17]1)[CH3:20]
Reactant: CCn1nc(CO)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCNCC1
Product: CCn1nc(CO)c(C)c1C1CCNCC1

Procedure:
The title compound was prepared from 1-(tert-butoxycarbonyl)-4-(1-ethyl-3-hydroxymethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine (from Step C) using a procedure analogous to that described for Piperidine 8, Step F.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][N:15]=2)[C:8](=[O:24])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([CH2:18][OH:19])=[CH:16][N:15]=2)[C:8](=[O:24])[CH:7]=1
Reactant: COC(=O)c1ccc(Cn2c(C)cc(OCc3ccc(F)cc3F)cc2=O)nc1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1Cc1ccc(CO)cn1

Procedure:
Methyl 6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinate (from preparation of step 3) (350 mg, 0.87 mmol) was added into anhydrous tetrahydrofuran (15 ml) and the solution was cooled to −78 C. Into the cold solution, was added lithium aluminum hydride (100 mg, 2.6 mmol). After the addition, the reaction mixture was warm to 0 C and continue stirring for one additional hour. Potassium hydrogen sulfate (1 N solution, 150 ml) was added slowly into the reaction mixture to quench the reaction. The resulting mixture was transferred to a separatory funnel and the product was extracted with ethyl acetate (200 ml×2). The combine ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. LC/MS, tr=1.88 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 373 (M+H)