Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[OH:2][C:3]1[C:10]([OH:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[OH-].[Na+].[CH3:15]OS(OC)(=O)=O.Cl>O>[OH:2][C:3]1[C:10]([OH:11])=[C:9]([O:12][CH3:15])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1ccc(O)c(O)c1O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: COc1ccc(C=O)c(O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a vigorously stirred solution of sodium boratedecahydrate (borax, 30 g) in 600 mL of water was added 2,3,4-trihydroxy-benzaldehyde (5 g, 32.4 mmol). The yellow solution was stirred at room temperature for 30 min followed by dropwise and simultaneous addition (over 30 min) of sodium hydroxide (4.0 g, 100 mmol) in water (50 mL) and dimethylsulfate (9.45 mL, 100 mmol). Vigorous stirring was continued overnight and conc. hydrochloric acid was added to pH 1. After stirring for an additional 30 min the mixture was extracted with chloroform (5×300 ml). The organic layer was once washed with brine, dried and evaporated to yield a slightly yellowish solid which on crystallization from ethyl acetate-hexane afforded slightly yellowish colored needles (3.9 g, 72%), mp 116°-17° C.: (lit. 118°-119° C.), IR (film) 3374, 1646, 1505, 1461, 1443, 1278, 1210, 1106, 636 cm-1 ; 1H-NMR 3.987 (3H, s, OCH3), 5,466 (1H, brs, OH-3, D2O exchanged) 6.617 (1H, d, JAB =8.62, H-5), 7.147 (1H, d, JBA =8.62 HZ, H-6, 9,757 (1H, S, CHO) 11,113 (1H, brs, OH-2, D2O exchanged); and HREIMS (m/z, 168.0419 (M, 100%; calcd 168.0423 for C8H8O4).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].[Na+].[I-].C([O-])([O-])=O.[K+].[K+].[CH2:24]([O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH:25]=[CH2:26]>O.CCOC(C)=O.CC#N>[CH2:24]([O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:15])[CH2:30][CH2:29]1)[CH:25]=[CH2:26]
Reactant: O=c1ccc2ccccc2n1CCCCl
Reactant: C=CCOC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC1CCN(CCCn2c(=O)ccc3ccccc32)CC1
Temperature: 40 °C
Reaction time: 72 h
Yield: 71.5 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-1H-quinolin-2-one (0.130 g, 0.6 mmol), NaI (0.225 g, 1.5 mmol), K2CO3 (0.210 g, 1.5 mmol), 4-allyloxypiperidine (0.085 g, 0.60 mmol) and dry CH3CN (1 mL). The mixture was shaken at 40° C. for 72 h and then poured onto The compound EtOAc (25 mL) and water (15 mL). The water phase was extracted (2×25 mL) and the combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 4:1) followed by cation-exchange CC to yield the title compound (0.140 g, 70%). 1H NMR (CD3OD) δ 7.81 (d, J=9.6 Hz, 1H), 7.64-7.55 (m, 3H), 7.27-7.21 (m, 1H), 6.61 (d, J=9.6 Hz, 1H), 5.93-5.82 (m, 1H), 5.27-5.20 (m, 1H), 5.13-5.07 (m, 1H), 4.33-4.26 (m, 2H), 3.40-3.28 (m, 2H), 2.76-2.67 (m, 2H), 2.47-2.39 (m, 2H), 2.18-2.08 (m, 1H), 1.93-1.80 (m, 4H), 1.61-1.50 (m, 2H); 13C NMR (CD3OD) δ 162.9, 140.3, 139.0, 135.5, 131.1, 129.2, 122.6, 121.3, 120.4, 115.5, 114.7, 74.2, 68.7, 55.3, 51.0, 40.6, 30.9, 24.9.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])C.NC1C=CC([F:18])=CC=1S.CI>>[CH3:1][S:3][C:4]1[CH:10]=[C:9]([F:18])[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Nc1ccc(F)cc1S
Reactant: CCSc1ccccc1N
Solvent: CI
Product: CSc1cc(F)ccc1N

Procedure:
Under conditions similar to those used for the preparation of 2-(ethylthio)aniline in Example 2, 2-amino-5-fluorothiophenol was alkylated with methyl iodide to give 2-methylthio-4-fluoroaniline.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[CH2:16][CH2:17][C@@:11]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:12]([OH:18])[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:30]Br.C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH2:3]([N:10]1[C@@H:15]2[CH2:16][CH2:17][C@@:11]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:12]([O:18][CH2:30][C:29]1[CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=1)[CH2:13][CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 127 %

Procedure:
Sodium hydride (60% in oil, 90 mg, 2.25 mmol) was washed twice with THF and treated with a solution of (1R,2R,5R)-8-benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 53; 79 mg, 0.25 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (350 mg, 1.14 mmol), 18-crown-6 (110 mg, 0.41 mmol) in THF (5 ml). The reaction mixture was stirred at room temperature for 24 hours, quenched with saturated aqueous NH4Cl and extracted into diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (165 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Cl.Br[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>O.C1(P(CCCC[Pd-](Cl)Cl)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: Brc1ccncc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd-](Cl)CCCCP(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)Oc1ccc(-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-(trifluoromethoxy)benzene boronic acid (2 g, 9.7 mmol), 4-bromopyridine hydrochloride (2.83 g, 14.5 mmol), diphenylphosphinobutylpalladium (II) dichloride (100 mg), dimethoxyethane (50 ml) and a 2M sodium carbonate solution (30 ml) were stirred at 85° C. for 2 hours. The solution was allowed to cool to ambient temperature diluted with water (100 ml), and extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulphate. Removal of the solvents in vacuo gave an oil which was chromatographed on silica in 30% ethyl acetate/hexane giving the title compound as an oil (1.86 g, 80%). 1H NMR (250 MHz, CDCl3) δ 8.72-8.70 (2H, d, J=6.2 Hz), 7.69-7.63 (2H, d, J=9.6 Hz), 7.49-7.47 (2H, d, J=6.2 Hz), and 7.36-7.32 (2H, d, J=9.6 Hz). m/z (ES+) 240 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:8]([C:7]1[C:2]([C:16]2[CH:17]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:11])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1cccc(-c2ncccc2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 41.4 %

Procedure:
To a suspension of 2-chloro-3-nitropyridine (792 mg), 3-aminophenylboronic acid (1.01 g) and tetrakis(triphenylphosphine)-palladium (289 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (6.5 ml). The mixture was stirred at 80° C. for 7 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. Methanol was added to the residue. The precipitate was collected by filtration and dried under reduced pressure to give 3-(3-nitropyridin-2-yl)-aniline (445 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:17](Cl)[CH:18]1[O:22][CH2:21][CH2:20][CH2:19]1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:19][CH2:20][CH2:21][O:22]3)[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: ClCC1CCCO1
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Product: CS(=O)(=O)c1cccc(C2CCN(CC3CCCO3)CC2)c1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)piperidine and tetrahydrofurfuryl chloride, the titled compound was recovered by the procedure described in Example 1. MS m/z (relative intensity, 70 eV) 323 (M+, 1), 252 (bp), 129 (9), 115 (6), 70 (17). Rf=0.3 (MeOH, 0.03 (EtOAc).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54](O)(=[O:63])[C@@H:55]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[OH:56].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:54](=[O:63])[C@@H:55]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[OH:56])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SC(Sc2c[nH]nn2)C(c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2[C@H](NC(=O)[C@H](O)c3ccccc3)C(=O)N12
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg : 1.06 mMol.) and D-(-)-mandelic acid (242 mg 1.59 mMol.) in dichloromethane (4 ml) is added dicyclohexylcarbodiimide (328 mg : 1.59 mMol.}, and the mixture is stirred under ice cooling for 1 hour. The reaction mixture is concentrated, diluted with ethyl acetate, and filtered to remove solid. The filtrate is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by Lobar column chromatography (toluene : ethyl acetate=2:1) to give 7β-D-mandelamido-3-(trityl-1,2,3-triazol-4-ylthiomethylthio) -3-cephem- 4-carboxylic acid diphenylmethyl ester (466 mg) as yellow foam. Yield : 50%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH2:30][C@@H:31]([C:33](OC)=[O:34])[N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:37])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH2:30][C@@H:31]([CH2:33][OH:34])[N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C(=O)OC)CO3)[nH]2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](CO)CO3)[nH]2)c1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
Methyl (4S)-2-[5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazole-4-carboxylate (1.76 g, 3.32 mmol) synthesized in Example (86b) was dissolved in tetrahydrofuran (30 mL), and lithium aluminum hydride (0.25 g, 6.65 mmol) was added at 0° C. After stirring for 30 minutes under nitrogen atmosphere, water (0.25 mL), a 5N aqueous sodium hydroxide solution (0.25 mL) and water (0.75 mL) were added in this order, and stirring was carried out for 10 minutes. Ethyl acetate (100 mL) was added followed by stirring for 5 minutes, and subsequently drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (1.15 g, 69%) as a white powder.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.[C:22]1([CH2:28][C:29]([NH:31][CH:32]2[C:57](=[O:58])[N:34]3[CH:35]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[O:42])[CH:36]([CH2:39][OH:40])[CH2:37][S:38][C@H:33]23)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>CS(C)=O.C1C=CC=CC=1>[C:22]1([CH2:28][C:29]([NH:31][CH:32]2[C:57](=[O:58])[N:34]3[CH:35]([C:41]([O:43][CH:44]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)=[O:42])[CH:36]([CH:39]=[O:40])[CH2:37][S:38][C@H:33]23)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=CC1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
Dicyclohexylcarbodiimide (1.8 g.) and pyridine (0.23 g.) were added to a solution of diphenylmethyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (1.5 g.) in dimethylsulfoxide (7 ml.) and benzene (15 ml.). To the solution was added trifluoroacetic acid (0.17 g.) and the mixture was stirred at room temperature overnight. After filtration, the filtrate was poured in a mixture of ethyl acetate (100 ml.) and water (100 ml.). The solution was adjusted to pH 3.0, and the ethyl acetate layer was separated, washed with aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The insoluble substance was removed by filtration and the filtrate was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and methylene chloride. The eluate was concentrated in vacuo to give diphenylmethyl 7-(2-phenylacetamido)-3-formylcepham-4-carboxylate (0.6 g.).
Reaction SMILES: S(C)C.[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][C@H:10]([C:15]([NH:17][C@H:18]([CH2:22][N:23]3[CH2:28][CH2:27][C@:26]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=4)([CH3:29])[C@@H:25]([CH3:37])[CH2:24]3)[CH:19]([CH3:21])[CH3:20])=O)[NH:11][CH2:12]2)=[CH:7][CH:6]=1.Cl.CCOCC>C1COCC1.CO>[OH:36][C:32]1[CH:31]=[C:30]([C@:26]2([CH3:29])[CH2:27][CH2:28][N:23]([CH2:22][C@@H:18]([NH:17][CH2:15][C@H:10]3[CH2:9][C:8]4[C:13](=[CH:14][C:5]([OH:4])=[CH:6][CH:7]=4)[CH2:12][NH:11]3)[CH:19]([CH3:21])[CH3:20])[CH2:24][C@@H:25]2[CH3:37])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)[C@@H](CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1)NC(=O)[C@H]1Cc2ccc(O)cc2CN1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)[C@@H](CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1)NC[C@H]1Cc2ccc(O)cc2CN1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 2M BH3.SMe2 in THF (0.495 mL 0.99 mmol) was added drop-wise to a −20° C.-solution of 14 (46 mg, 0.099 mmol) in 5 mL of dry THF. The reaction refluxed overnight. It was again cooled to −20° C. and 0.647 mL of MeOH was added. Contents stirred at room temperature for one hour. At room temperature, 1M HCl in ether (0.142 mL, 0.142 mmol) was added, and stirred for 30 minutes. The solvent was then removed under reduced pressure. The oil was then dissolved in 3:1 CH2Cl2:THF. Then, enough sat'd NaHCO3 was added to increase the pH to 10. The organic layer was separated and set aside. The aqueous layer was extracted five times with 3:1 CH2Cl2:THF. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure, yielding a yellowish foam. The crude product (0.03 g) was purified by silica preparative thin layer chromatography using a solvent gradient, starting with 25% (CHCl3:MeOH:NH4OH, 80:18:2) in CHCl3 then 40%, and finally 65%. This afforded 0.006 g of (3R)-3-{[((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)amino]methyl}-1,2,3,4-tetrahydro-7-isoquinolinol (19). 1H-NMR (MeOH): 7.12(t, J=5.1 Hz, 1H), 6.90 (d, J=4.1 Hz, 1H), 6.8(d, J=3.9 Hz, 1H), 6.76 (d, J=1.1 Hz, 1h), 6.61 (dd, J=5.8,2.2 Hz, 2H), 6.48 (d, J=1.2 Hz, 1H), 2.88-2.43 (m, 16H), 2.4-1.8 (m, 2H), 1.67 (d, J=13 Hz, 1H), 1.34 (s, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 0.81 (d, J=3.4 Hz, 3H). LRMS (ES) m/z 452.3 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([CH3:14])=[C:4]([S:15]([NH:18][CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])(=[O:17])=[O:16])[CH:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]=1[C:50]([CH3:53])([CH3:52])[CH3:51])(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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:50]([C:36]1[CH:37]=[C:38]([C:2]2[N:6]([CH2:7][CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:5]([CH3:14])=[C:4]([S:15]([NH:18][CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])(=[O:17])=[O:16])[CH:3]=2)[CH:39]=[CH:40][C:35]=1[S:32](=[O:33])(=[O:34])[NH:31][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:53])([CH3:51])[CH3:52]
Reactant: COC(=O)C(C)(C)CNS(=O)(=O)c1cc(Br)n(CC2CCCCC2)c1C
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)CNS(=O)(=O)c1cc(-c2ccc(S(=O)(=O)NC(C)(C)C)c(C(C)(C)C)c2)n(CC2CCCCC2)c1C
Temperature: 100 °C
Yield: 44.2 %

Procedure:
A mixture of bromide 10a (100 mg, 0.22 mmol), boronic ester P19 (106 mg, 0.27 mmol), Cs2CO3 (181 mg, 0.56 mmol) and Pd(dppf)Cl2 (50 mg) in dioxane and water (10:1, 100 mL) was heated at 100° C. overnight. The solvent was removed, diluted with water, extracted with EA (3×), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give product 10 (62 mg, 44%) as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:39])(C[Si](OC(C)C)(C)C)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:19][CH:18]=2)[C:13]1=[O:30])[CH3:11].[C:40](=O)([O-])[OH:41].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:39])([CH2:40][OH:41])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])=[CH:21][CH:22]=2)[C:13]1=[O:30])[CH3:11]
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccc(F)cc1F)[C@@H](C)n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Yield: 68.9 %

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (0.88 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 10 ml), to which 1.57 ml of 30% aqueous hydrogen peroxide and 0.128 g of sodium hydrogencarbonate were added. The mixture was heated at 70° to 80° C. for 90 minutes, cooled and extracted with 50 ml of ethyl acetate. The extract was washed with 25 ml of water, an aqueous solution of Na2S2O3 (25 ml×2) and 25 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=2:3) and recrystallized from diisopropyl ether to give 0.5 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (yield: 69%) as colorless powdery crystals.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2N=C(C)S[CH:19]=2)[N:3]=1.[CH3:21][C:22]1[S:23]C(C(OCC)=O)=C[N:26]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[I:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:14][C:15]2[S:23][C:22]([CH3:21])=[N:26][CH:19]=2)[N:3]=1
Reactant: CCOC(=O)c1cnc(C)s1
Reactant: Cc1nc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)cs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ncc(Cn2nc(I)c3c(N)cccc32)s1
Temperature: 85 °C

Procedure:
To a solution 4-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-2-methylthiazole (prepared according the method of Example 15, Steps A-D, using ethyl 2-methylthiazole-5-carboxylate) in EtOH/H2O (8 mL/2 mL) was added iron (463 mg, 8.30 mmol) and NH4Cl (44.4 mg, 0.830 mmol). The reaction mixture was heated at 85° C. for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. EtOAc/Et3N (40 mL/10 mL) was added to the residue. The mixture was heated at 85° C. for 20 minutes, cooled to 45° C., and filtered through Celite. The Celite pad was washed with MeOH (30 mL). The combined filtrate was concentrated under reduced pressure to remove EtOAc and MeOH. The aqueous suspension was extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give the product (156 mg).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>C(#N)C>[C:14]([C:12]1[CH:13]=[C:8]2[CH:7]=[CH:6][NH:5][C:9]2=[N:10][CH:11]=1)([CH3:16])=[CH2:15]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(C)(C)O)cnc21
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C=C(C)c1cnc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
To 2-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-propan-2-ol (9, 0.500 g, 1.5 mmol) in acetonitrile (10.0 mL) were added triethylsilane (1.00 mL, 6.3 mmol) and trifluoroacetic acid (0.50 mL, 6.5 mmol) under an atmosphere of nitrogen. The reaction was refluxed for 3 hours, then cooled down to room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give the compound (10, 0.200 g, 84%). MS (ESI) [M+H+]+=159.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[C:4]([F:28])[CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O)([OH:31])=[O:30].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[F:28][C:4]1[CH:3]=[C:2]([C:33]2[C:32]([C:29]([OH:31])=[O:30])=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F
Reactant: O=C(O)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccccc2C(=O)O)cc1F

Procedure:
In analogy to example 166, step 1, 5-{3-(4-bromo-2-fluoro-phenyl)-1-[(E)-hydroxyimino]-3-o-tolyl-propyl}-1-methyl-1H-pyridin-2-one (example 193, step 4) was reacted with 2-carboxyphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)-ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound containing 10% of the corresponding Z isomer as a light brown solid, MS (ESI−): m/z=483.1 [M−H]−.