Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:21][N:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[N:25]([CH3:31])[C:23]1=[S:24].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:31][N:25]1[C:26](=[O:27])[CH:28]([C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:17]=[CH:18][C:3]([C:2]([F:19])([F:20])[F:1])=[CH:4][CH:5]=3)=[CH:9][CH:10]=2)=[O:16])[C:29](=[O:30])[N:22]([CH3:21])[C:23]1=[S:24]
Reactant: O=C=Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CN1C(=O)CC(=O)N(C)C1=S
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)C(=O)N(C)C1=S

Procedure:
4-(4'-Trifluoromethylphenoxy)phenyl isocyanate (3.7 g.) was added to a stirred mixture of 1,3-dimethyl-2-thiobarbituric acid (2.3 g.) and triethylamine (1.7 ml.) in dry benzene (30 ml.). The mixture was refluxed for 12 hours. The mixture was evaporated in vacuo. Diethyl ether (10 ml.) was added to the gummy residue and the mixture was acidified with 1N hydrochloric acid. The mixture was filtered and the solid was washed with water and then ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].C([Sn](CCCC)(CCCC)[C:27]([O:29]CC)=[CH2:28])CCC>O1CCOCC1.[Pd](Cl)Cl.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>[C:27]([C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18])(=[O:29])[CH3:28]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
Bis(triphenylphosphine) palladium (II) chloride (12.78 mg, 0.02 mmol) was added to a stirred mixture of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (215 mg, 0.61 mmol) and tributyl(1-ethoxyvinyl)stannane (0.226 mL, 0.67 mmol) in 1,4-dioxane (5 mL) and the mixture was purged with nitrogen. The resulting mixture was stirred at 100° C. for 3 hrs. HCl2N (0.5 mL) was added and the reaction mixture was stirred at 50° C. for 25 minutes then allowed to cool to room temperature and concentrated under vacuum. The product was diluted with diethyl ether and pentane to afford a solid, which was collected by filtration and washed with ether/pentane to give 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 104%) as a beige solid. Mass Spectrum: M+H+ 318.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>COCCOC>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc(Cl)cc1Br
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: Cn1cc(Cl)cc(Br)c1=O
Yield: 74.6 %

Procedure:
A mixture of 3-bromo-5-chloro-1H-2-pyridone (930 mg, 4.46 mmol), potassium carbonate (1.25 g, 9.1 mmol) and iodomethane (2.8 mL, 45 mmol) in 10 mL of DME was heated to reflux for 18 hr. The mixture was filtered hot and concentrated. The residue was recrystallized from ethyl acetate to give 3-bromo-5-chloro-1-methyl-2-pyridone (740 mg, 74%), mp 162-163° C. HRMS (C6H5BrClNO): Obs. Mass 220.9249. Calcd. Mass 220.9243 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:68]=[CH:67][C:33]([CH2:34][O:35][C:36]([C:38]2[CH:39]=[C:40]([C:44]([C:46]3[N:47]=[CH:48][N:49]4[CH:53]=[C:52]([Sn](CCCC)(CCCC)CCCC)[S:51][C:50]=34)=[O:45])[CH:41]=[N:42][CH:43]=2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:52]3[S:51][C:50]4=[C:46]([C:44]([C:40]5[CH:41]=[N:42][CH:43]=[C:38]([C:36]([O:35][CH2:34][C:33]6[CH:67]=[CH:68][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=6)=[O:37])[CH:39]=5)=[O:45])[N:47]=[CH:48][N:49]4[CH:53]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(C(=O)OCc4ccc([N+](=O)[O-])cc4)c3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(C(=O)OCc6ccc([N+](=O)[O-])cc6)c5)c4s3)[C@H](C)[C@H]12
Yield: 47.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(4-nitrobenzyloxycarbonyl)pyridin-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (97.2 mg) was prepared in the same manner as in step a) of Example 1, except that 98 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 198 mg of 7-[5-(4-nitrobenzyloxycarbonyl)pyridin-3-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[O:14])[C:6]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([OH:26])[CH2:5]2.C=O.O.[C:37]1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][N:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)=[O:14])[CH2:37][O:26][C:6]1([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[CH2:5]2
Reactant: O=C(NN=C1c2ccc(Cl)cc2CC1(O)c1ccc(Cl)cc1)Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1COC2(c3ccc(Cl)cc3)Cc3cc(Cl)ccc3C2=N1
Yield: 172.8 %

Procedure:
A mixture of 0.30 g (0.0006 moles) of the product obtained in Step D, 0.36 g (0.012 moles) of paraformaldehyde, 50 mg of p-toluene sulfonic acid monohydrate and 30 mL of acetonitrile was refluxed for 1 hour. The resulting mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated to give an oil that was chromatographed on silica gel using 4:1 hexanes-ethyl acetate to give 0.23 g of an oil that solidified on standing, melting point, 213°-214° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:19][CH2:20][OH:21]>CN(C=O)C>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:19][CH2:20][OH:21])[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: OCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCN(CCO)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
1-Methylhomopiperazine (2.00 g, 17.5 mmol) and DIPEA (3.0 mL, 18.4 mmol) were dissolved in DMF (25 mL). 2-bromethanol (1.3 mL, 18.4 mmol) was added slowly over 5 minutes. The reaction mixture was stirred at 100° C. for 2 hours and then at room temperature for 48 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (−300 mL) and then washed sequentially with 1M aq Na2CO3 solution (5×200 mL), dried (MgSO4) and concentrated in vacuo to give 2-(4-methylhomopiperazin-1-yl)ethanol (2.77 g, 100%) as a brown oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH2:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:12])[F:10])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:27])[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(N)nc12
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(NC(=O)C3CC3)nc12

Procedure:
Cyclopropanecarboxylic acid [8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-amide was prepared from 8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl-amine (0.07 g, 0.2 mmol) and cyclopropanecarbonyl chloride (0.021 mL, 0.23 mmol) in a manner analogous to Example 240b. Product was isolated as a foam (0.063 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.61 (d, J=6.7 Hz, 1H), 7.76-7.66 (m, 2H), 7.60-7.50 (m, 1H), 7.51-7.45 (m, 1H), 7.13-7.06 (m, 1H), 3.86 (s, 3H), 1.56 (m, 1H), 1.19-1.14 (m, 2H), 1.01-0.95 (m, 2H), MS=377 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[NH2:24][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:6][CH:7]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1ccc(C(=O)CC(C)C)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(C(N)CC(C)C)cc1
Temperature: 60 °C

Procedure:
A mixture of 4-(3-Methyl-butyryl)-benzoic acid ethyl ester (2000 mg, 8.536 mM), ammonium acetate (6580 mg, 85.4 mM) and sodium cyanoborohydride (1070 mg, 17.1 mmol) in methanol (17.1 mL) was heated to 60° C. for 6 h. The reaction was cooled, quenched with NH4Cl solution (10 mL). MeOH was removed under reduced pressure. The aqueous solution was extracted with EtOAc (3×30 mL). The organic solution was separated, dried (Na2SO4) and concentrated. The crude material was separated by a 40 g HC silica gel column with 0-15% MeOH in DCM. The desired product was collected as colorless oily material (1560 mg, 77.7%). 1H NMR (500 MHz, CDCl3) δ ppm 0.91 (dd, J=13.66, 6.59 Hz, 6H) 1.40 (t, J=7.07 Hz, 3H) 1.84-1.99 (m, 3H) 4.27-4.42 (m, 3H) 6.36 (br. s., 2H) 7.51 (d, J=8.05 Hz, 2H) 8.05 (d, J=8.05 Hz, 2H). GC: m/z 235.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[OH:7].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][O:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccccn1

Procedure:
A solution of pyridin-2-ol (1 g), tert-butyl bromoacetate (2.33 mL) and cesium carbonate (6.85 g) in DMF (20 mL) was stirred at 60° C. overnight. The reaction mixture was poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.18 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[OH:11].O[CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1.CN1CCCC1=O>[Br:18][C:14]1[CH:13]=[C:12]([CH:10]([O:11][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OC(c1cccc(Br)c1)c1nc2ccccc2[nH]1
Reactant: CN1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: Clc1ccccc1
Product: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
A mixture of 1H-benzimidazol-2-yl(3-bromophenyl)methanol (12.9 g), 4-hydroxy-1-methylpiperidine (4.86 g) and para-toluenesulfonic acid (24 g) in chlorobenzene (60 mL) and N-methylpyrrolidone (6 mL) is heated under reflux for 120 h in a Dean Stark apparatus. Solvent is removed by evaporation. To the residue is added water which is made alcaline by addition of sodium hydroxyde solution, then extracted with ethyl acetate. The pooled organic extracts are washed with water, treated with activated charcoal, dried over magnesium sulfate and concentrated under reduced pressure. The residue is triturated in diethyl ether to give 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]2[N:6]([CH:10]=[C:11]([CH3:13])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl.O>CS(C)=O>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][O:3][C:4]1[C:5]2[N:6]([CH:10]=[C:11]([CH3:13])[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cn2cccc(O)c2n1
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn2cccc(OCc3ccccc3Cl)c2n1
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (1.87 g) was added portionwise to a suspension of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (6.3 g) in dimethyl sulfoxide (63 ml) at room temperature over a period of 15 minutes. After being stirred for 30 minutes, 2-chlorobenzyl chloride (7.54 g) was added in one portion to the mixture and then the resultant mixture was stirred for 24 hours at room temperature. The mixture was poured into water and the resulting precipitate was collected by filtration. The crude product was purified by column chromatography on silica gel (30 g) with methylene chloride as an eluent to afford a solid, which was recrystallized from a mixture of diethyl ether and n-hexane to give 8-(2-chlorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (7.75 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10]CC2C=CC=CC=2)[CH:5]=[C:4]([Cl:18])[C:3]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([OH:29])=[O:28]>O1CCCC1.ClC1C=CC=CC=1Cl.[Pd]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([OH:10])[CH:5]=[C:4]([Cl:18])[C:3]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: COc1c(OCc2ccccc2)cc(Cl)c(Nc2ccccc2CC(=O)O)c1Cl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Product: COc1c(O)cc(Cl)c(Nc2ccccc2CC(=O)O)c1Cl

Procedure:
The 2-[(2,6-dichloro-3-methoxy-4-benzyloxyphenyl)amino]phenylacetic acid (10 g) from example 37 was hydrogenated with Pd-C (1 g, 5%) in tetrahydrofuran (100 ml) and 1,2-dichlorobenzene (10 ml) at normal pressure for 25 min at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated to leave the final product 2-[(2,6-dichloro-3-methoxy-4-hydroxyphenyl)amino]phenylacetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C>[Br-].[Zn+2].[Br-]>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCNC(C)=O)CCC3)cc1
Agent: [Br-]
Agent: [Zn+2]
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CCCNC(C)=O)CCC3)cc1

Procedure:
In analogy to the procedure described in example 1(e), the (3R,4R)-3-[1-(3-acetylamino-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with zinc bromide to yield the (3R,4R)-N-[3-[7-(4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl)-3,4-dihydro-2H-quinolin-1-yl]-propyl]-acetamide as a light yellow oil; MS: 616 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CS(O[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: O=Cc1cccc(O)c1Br
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1cccc(C=O)c1Br
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A mixture of 2-bromo-3-hydroxybenzaldehyde (5 g, 24.9 mmol), 3-(tert-butoxy carbonylamino)-propyl methanesulfonate (7.55 g, 30 mmol) and Cs2CO3 (24 g, 75 mmol) in DMF (60 mL) was stirred at 50° C. for 3 h and quenched with water (600 mL). The resulting mixture was extracted with EtOAc (3×60 mL) and the combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to give the product (7.2 g, yield 81%). 1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 7.53 (dd, J=7.8 Hz, 1.6 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.12 (dd, J=8.2 Hz, 1.6 Hz, 1H), 5.16 (s, 1H), 4.15 (t, J=5.9 Hz, 2H), 3.42 (m, 2H), 2.10 (m, 2H), 1.44 (s, 9H); MS (ESI) m/z=358 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:4].OO.C([O-])(O)=[O:18].[Na+]>CC(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([OH:18])=[CH:10]2)=[O:4]
Reactant: COC(=O)c1cccc2cccnc12
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cccc2cc(O)cnc12
Temperature: 85 °C
Yield: 44 %

Procedure:
To the mixture of 8-quinoline carboxylic acid (500 mg, 2.89 mmol) in THF (80 mL) was added CH2N2 in Et2O sol. [Prepared from nitrosomethylurea (1.65 g) and 50% KOH (5 mL)] at room temperature. The reaction mixture was stirred for 12 h and then concentrated to give the intermediate ester. 1H NMR (300 MHz, DMSO-d6) δ 3.92 (3H, s), 7.60-7.70 (2H, m), 7.93-7.96 (1H, m), 8.14-8.17 (1H, m), 8.44-8.48 (1H, m), 8.97-8.99 (1H, m). To a solution of the intermediate 8-Quinolinecarboxylic acid methyl ester (2.89 mmol) in AcOH (4 mL) was added 30% H2O2 (0.6 mL). The reaction mixture was heated at 85° C. for 7.5 h. The reaction mixture was treated with sat NaHCO3, and extracted six times with CHCl3. Organic layer was dried over anhydrous MgSO4, and concentrated. Crude residue was triturated with CHCl3/toluene to provide compound 97 (256 mg, 44%, in 2 steps). 1H NMR (300 MHz, DMSO-d6) δ 3.89 (3H, s), 7.52 (1H, d, J=6.9 Hz), 7.57 (1H, d, J=1.5 Hz), 7.66 (1H, dd, J=1.5, 6.9 Hz), 7.95 (1H, dd, J=1.5, 8.1 Hz), 8.63 (1H, d, J=2.7 Hz), 10.5 (1H, br s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:12][O:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: COc1ccc(B(O)O)cn1
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: Cc1ccccc1
Product: COc1ccc(-c2ncccc2C(F)(F)F)cn1
Yield: 94.8 %

Procedure:
Heat a mixture of 2-chloro-3-trifluoromethylpyridine (37 g, 0.2 mol), 2-methoxypyridine-5-boronic acid (32 g, 0.21 mol), tetrakis(triphenylphosphine)palladium(0) (9 g, 7 mmol) and 2M potassium carbonate (150 mL) in toluene (500 mL) under a nitrogen atmosphere at 90° C. for 8 hours. Cool the reaction mixture and separate the layers. Extract the aqueous layer with ethyl acetate (2×250 mL) and wash the combined organics with 4M sodium hydroxide (250 mL), water (250 mL), and brine (250 mL). Dry (MgSO4) and concentrate under reduced pressure. Purify the resulting oil by flash chromatography on silica gel (50% ether/50% hexane) to give the title compound (48.2 g, 95%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([NH:11][C@H:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[O:10])[CH:3]=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:30]([C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([NH:11][C@H:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[O:10])[CH:3]=1)#[N:31]
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F)c1c[nH]c(=O)c(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)c[nH]c1=O

Procedure:
To a solution of (S)-5-bromo-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (0.080 g, 0.170 mmol) in DMF (0.5 mL) was added zinc(II) cyanide (0.043 mL, 0.681 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol). The resulting mixture was then subjected to a microwave irradiation at 130° C. for 30 min. Then, the mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. 1H NMR (400 MHz, MeOH) δ ppm 8.63 (d, J=2.5 Hz, 1H), 8.51 (d, J=4.7 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 7.55-7.73 (m, 6H), 7.47 (dt, J=8.5, 4.4 Hz, 1H), 6.75 (s, 1H). MS (ESI pos. ion) m/z: 417.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:16][C:17]2[O:21][C:20]([C:22]([O:24]C)=[O:23])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[C:3]([CH2:16][C:17]2[O:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1ccc(Cc2cc3c(cc2C)C(C)(C)CCC3(C)C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1Cc1ccc(C(=O)O)o1)C(C)(C)CCC2(C)C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
To a solution containing methyl 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl) methyl]-2-furoate 6 (15.1 g, 44 mmol) in MeOH (175 mL) and water (175 mL), a solution of NaOH (3.53 g, 88.3 mmol) in water (29 mL) is added. The reaction mixture is stirred overnight. After completion as judged by tlc, the solution is acidified with 1M HCl to pH 2. The crude product is extracted into organic layer using ethyl acetate, and concentrated to afford 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furoic acid 7 (15.0 g, 99% yield). NMR 1.26 (s, 6H), 1.28 (s, 6H), 1.68 (s, 4H), 2.24 (s, 3H), 4.00 (s, 2H), 6.01 (d, 1H), 7.10 (s, 21), 7.23 (d, 1H).