Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([CH:17]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[OH:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]#[N:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH2:37][CH3:38]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]4)[C:15]([CH:17]([CH:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[O:18][CH2:37][CH3:38])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]#[N:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(C(O)C3CCCC3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1)C1CCCC1
Temperature: 0 °C

Procedure:
4-(5-chloropyridin-3-yl)-2-(cyclopentyl(hydroxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (240 mg, 0.517 mmol) was dissolved in THF (5.2 mL) and cooled to 0° C. in a flask under nitrogen before adding sodium hydride (41.4 mg, 1.034 mmol). Upon cessation of gas evolution, iodoethane (0.125 μL, 1.552 mmol) was added, and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with sat. aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/0-40% EtOAc) to afford racemic 4-(5-chloropyridin-3-yl)-2-(cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. The racemic material was then purified by chiral supercritical fluid chromatography (Chiralpak IC, 21×250 mm, 2-Propanol +0.25% Dimethyl Ethyl Amine in CO2) to afford 4-(5-chloropyridin-3-yl)-2-(R)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile and 4-(5-chloropyridin-3-yl)-2-((S)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. 1H NMR (600 MHz, CD3OD) δ 8.78 (d, J=2.3, 1H), 8.75 (d, J=1.5, 1H), 8.29 (t, J=2.0, 1H), 8.24 (s, 1H), 4.65 (d, J=8.5, 1H), 4.08-3.97 (m, 2H), 3.59-3.34 (m, 2H), 2.65-2.54 (m, 1H), 1.88-1.77 (m, 1H), 1.73-1.54 (m, 6H), 1.49 (d, J=13.2, 2H), 1.30-1.25 (m, 1H), 1.17 (t, J=7.0, 3H), 1.15-1.08 (m, 1H), 1.01-0.95 (m, 1H), 0.91-0.76 (m, 4H), 0.75 (d, J=6.6, 3H), 0.56-0.45 (m, 2H). MS ESI calc'd. for C28H34ClN5O [M+H]+ 492. found 492.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4].C1(OC2C=CC=CC=2)C=CC=CC=1>CCOCC>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1OC)C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(OC)cccc2c1=O

Procedure:
Ethyl 2-butyryl-3-(2-methoxyphenylamino)acrylate (15.50 g, 0.053 mol) was added in portions to boiling diphenyl ether (400 ml) and the mixture heated under reflux for 1.5 hours. After cooling, the solution was diluted with ether and petroleum ether, filtered, and the solid washed with petroleum ether to give 3-butyryl-8-methoxy-4-(1H)-quinolone as light grey crystals (13.46 g, 63.1%, m.p. 200°-202°.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:37]2[CH2:36][CH2:35][N:34]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=3)[CH2:39][CH2:38]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)c(OC)c(OC)c3)CC2)c(OC)nc1C
Yield: 52 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[C@H:13]([CH:25]([CH3:26])[CH3:27])[NH2:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 103.8 %

Procedure:
N-[(Phenylmethoxy)carbonyl]-L-valyl-L-proline tert-butyl ester (905 g) was dissolved in ethanol (4 litres) and 10% palladium on carbon (20 g) was added. The reaction mixture was shaken under a hydrogen atmosphere (50 psi) for 12 hours and then the catalyst was removed by filtration through diatomaceous earth. The filtrate was concentrated under vacuum and the residue twice re-evaporated from toluene (1 litre) to give L-Valyl-L-Proline tert-butyl ester as an oil (628 g); TLC, Rf =0.2, acetone:hexane (20:80); MS: m/z=271(M+1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]([F:29])([F:28])[C:5]([F:27])([F:26])[O:6][C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[O:9][C:10]([F:21])([F:20])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[CH2:32]([C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)=[N:44][CH:45]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:32]([C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:10]([O:9][C:8]([F:22])([F:23])[C:7]([F:24])([F:25])[O:6][C:5]([F:26])([F:27])[C:4]([F:28])([F:29])[O:3][C:2]([F:1])([F:31])[F:30])([F:21])[F:20])=[CH:48][CH:47]=2)=[N:42][CH:41]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)COCCCCCCBr
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 6-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromohexane (85 g, 0.155 mol; prepared from 1,6-dibromohexane (500 g, 0.7 mol), 10 2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol (150 g, 0.37 mol), and potassium t-butoxide (412 mL of 1M solution in t-butanol)) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (45 g, 0. 162 mol). The crude product was further purified by recrystallization from heptane and subsequently dried in a vacuum oven (yield of 93.0 g).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(=O)c(O)c(CO)o1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Yield: 80 %

Procedure:
Sodium hydroxide (4.84 g, 121 mmol, 1.1 eq.) dissolved in 10 ml distilled water was added to 100 ml methanol containing 2-hydroxymethyl-3-hydroxy-6-methyl-pyran-4(1H)-one (17.2 g, 110 mmol, 1 eq.) and heated to reflux. Benzyl bromide (20.7 g, 121 mmol, 1 eq.) was added dropwise over 30minutes and then refluxed overnight The reaction mixture was concentrated in vacuo, the residue taken up into 300 ml dichioromethane and the inorganic salts filtered off. The dichloromethane layer was washed with 2×100 ml 5% w/v sodium hydroxide solution, 100 ml water, dried (Na2SO4), and concentrated in vacuo to yield the crude product as a yellow crystalline solid. Recrystallisation from CH2Cl2/Pet. ether 40/60 afforded the title product in 80% yield (21.6 g) as a white crystalline solid. m p. 115-116° C. [lit 114-116° C. Tilbrook (1995)].
Reaction SMILES: [C:1]1([C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:12]([C:13]3[C:18]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[CH:17][CH:16]=[C:15]([F:26])[CH:14]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:39]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:33]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:8]2[C:12]([C:13]3[C:18]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][Br:39])=[CH:21][CH:20]=4)=[CH:17][CH:16]=[C:15]([F:26])[CH:14]=3)=[N:11][N:10]=[N:9]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(-c2ccc(F)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2ccc(CBr)cc2)c(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 3 h

Procedure:
To a solution of N-Triphenylmethyl-5-(4-fluoro-4'-methyl-biphen-2-yl)tetrazole (454.4 mg; 0.9161 mmol) in dry CCl4 (8 mL) was added N-bromosuccinimide (179.2 mg; 1.1 eq) and a catalytic amount of AIBN. The reaction was heated to reflux (105°-115°) under N2. After 3 hrs. the reaction was cooled and filtered through a cotton plugged pipet to remove the succinimide formed. The solvent was removed and replaced by EtOAc/Et2O. The reaction was washed with 1N NaOH and brine. The organic solution was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford the product. The crude product was used in the next reaction.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH3:19]>>[N+:1]([CH:4]=[C:5]([NH2:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: N
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Product: Cc1nc[nH]c1CSCCNC(N)=C[N+](=O)[O-]

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene (see Example 2(i)) with ammonia by the procedure of Example 2(ii) yields, after recrystallisation from methanol, the title compound, m.p. 193°-195° C.
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[C:30](O)[CH:31]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[C:28]([CH:27]=1)[O:5][CH2:4][C@@H:2]1[CH2:1][O:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: OC[C@@H]1CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OC[C@@H]1CO1
Yield: 70.7 %

Procedure:
In a flask was added (R)-glycidol (0.994 g, 13.4 mmole) and triphenylphosphine (3.52 g, 13.4 mmole) and THF (20 ml, dried over molecular sieves), and 5-fluoro-2-nitrophenol (2.10 g, 13.4 mmole). The mixture was stirred until a homogeneous solution was obtained. The solution was cooled in an ice bath and diethylazodicarboxylate (DEAD, 2.11 ml, 13.4 mmole) was added dropwise over a few minutes. After completed addition, the flask was allowed to reach room temperature and stirred for an additional 2 hours. The solvent was removed in vaccuo and to the residue was added chloroform (5-10 ml). The precipitate (PPh3O) was removed by filtration and the solid was washed with an additional amount of chloroform (5-10 ml). The filtrate was added to a flash column (SiO2, Heptane:Ethyl acetate 4:1), and purified to give 2.02 g (71%) of the sub-title compound as a crystalline material after concentration of pure fractions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.[O:22]=[C:23]1[CH:28]([N:29]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:29]([CH:28]1[CH2:27][CH2:26][C:25](=[O:45])[NH:24][C:23]1=[O:22])[C:10]2=[O:12]
Reactant: O=C(O)c1cccc(NCc2cccc(Cl)c2)c1C(=O)O
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CCOCC
Product: O=C1CCC(N2C(=O)c3cccc(NCc4cccc(Cl)c4)c3C2=O)C(=O)N1
Yield: 89 %

Procedure:
3-(3-Chloro-benzylamino)-phthalic acid (4.8 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was slurried in diethyl ether (30 ml) for 18 h and filtered to give 1.42 g (89%) of product as a yellow solid: mp 207-209° C.; 1H NMR (DMSO-d6) δ 11.11 (s, 1H), 7.55-7.28 (m, 6H), 7.03 (d, J=7.0 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H), 5.08 (dd, J=5.4 and 12.4 Hz, 1H), 4.58 (d, J=6.3 Hz, 2H), 2.98-2.83 (m, 1H), 2.64-2.46 (m, 2H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.56, 169.84, 168.59, 167.11, 145.76, 141.68, 136.01, 133.10, 132.16, 130.25, 126.83, 126.68, 125.48, 117.40, 110.81, 109.74, 48.54, 41.54, 44.80, 30.87, 22.05; Anal. Calcd. For C20H16ClN3O4: C, 60.38; H, 4.05; N, 10.56. Found: C, 60.22; H, 4.05; N, 10.38.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@@H:13]3[CH2:15][C@@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.[NH2:19][CH:20]([CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH2:21][OH:22]>>[OH:22][CH2:21][CH:20]([NH:19][C:16]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:15][C@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Reactant: NC(CO)C1CCOCC1
Product: O=C(NC(CO)C1CCOCC1)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using Intermediate 2 and 2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol. LCMS m/z=370.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46-0.50 (m, 1H), 1.26 (td, J=7.8 and 4.6 Hz, 1H), 1.42-1.54 (m, 2H), 1.72 (d, J=12.6 Hz, 2H), 1.98-2.09 (m, 1H), 2.27-2.34 (m, 1H), 2.51 (bs, 1H), 2.73-2.79 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.4 and 6.1 Hz, 1H), 3.36-3.45 (m, 2H), 3.82-3.89 (m, 3H), 4.01 (dd, J=11.2 and 4.0 Hz, 2H), 7.11 (d, J=7.6 Hz, 1H), 8.42 (dd, J=2.5 and 1.5 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N+:3]=1[O-:10].[OH-:11].[Na+].Cl>>[OH:10][N:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]1=[O:11]
Reactant: [OH-]
Reactant: COc1cc[n+]([O-])c(Cl)c1
Agent: Cl
Agent: [Na+]
Product: COc1ccn(O)c(=O)c1
Yield: 20 %

Procedure:
2-Chloro-4-methoxypyridine-1-oxide (3.3 g) is dissolved in 10% w/v aqueous NaOH (33 ml) and the mixture is heated on a steam bath for 3.5 hours when it is cooled and acidified with concentrated HCl to a pH of 2.5 to yield white crystals. Recrystallisation of these from water gives 1-hydroxy-4-methoxypyrid-2-one (0.75 g, 20%), m.p. 174°-175° C., δ(D2O) 5.9 (s, 1H), 6.00 (q, 1H), 7.5 (d, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12](=[O:23])(=[O:22])[C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)(=O)C.C1COCC1.C([O-])([O-])=O.[K+].[K+].Cl>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12](=[O:23])(=[O:22])[C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C2=CC(=O)c3ccccc3S2(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C=C(c2ccc(O)cc2)S(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a solution of 2-(4-acetoxy-phenyl)-1,1-dioxo-1H-1λ6-thiochromen-4-one (260 mg, 0.79 mmol) in MeOH:THF (5 mL: 5 mL), K2CO3 (133 mg, 0.95 mmol) was added and stirred for 2 h at rt Then the reaction mixture was neutralized by dilute HCl and extracted by EtOAc, the combined organic layer was washed with water, brine, dried and concentrated to give a crude product, which was purified by column chromatography using 50% EtOAc in hexane, to give 134 mg (59%) of 2-(4-hydroxy-phenyl)-1,1-dioxo-1H-1λ6-thiochromen-4-one. MS (ES) m/z: 286.05 (M), 285.01 (M−1); Mp. 222-224° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:4]1.[C:18](=O)([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](=[O:29])[NH:27][CH3:28])[CH:22]=1.C(N(CC)C(C)C)(C)C>>[CH3:28][NH:27][C:26]([C:23]1[CH:22]=[C:21]([CH2:20][O:19][C:18]([NH:1][CH2:2][CH:3]2[CH2:4][C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]3)[CH2:6]2)=[O:30])[O:25][N:24]=1)=[O:29]
Reactant: CNC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(CN)C2)C1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(COC(=O)NCC2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)on1

Procedure:
The process is performed according to the procedure described in Example 1, step 1.1. Starting with 0.22 g (0.92 mmol) of tert-butyl 2-aminomethyl-6-azaspiro[3.4]octane-6-carboxylate (isomer 2a), described in Example 8 (step 8.2.), 0.294 g (0.92 mmol) of 3-(methylcarbamoyl)isoxazol-5-ylmethyl 4-nitrophenyl carbonate, obtained in step 4.1., 0.236 g (1.83 mmol) of N,N-diisopropylethylamine and 0.011 g (0.09 mmol) of N,N-dimethylaminopyridine, and after purification by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 0.310 g of pure product is thus obtained in the form of an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH:17]([C:19](O)=[O:20])[CH3:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH:17]([C:19](=[O:20])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C(=O)O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccccc1
Product: CC(C(=O)Nc1ccccc1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 41 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-(1-carboxyethyl)-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (more polar) (100 mg, 0.28 mmol) and aniline (28 μL, 0.31 mmol) to give 50 mg of the title compound (41%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ11.92 (s, 1H), 9.46 (s, 1H), 7.32 (d, 2H, J=8 Hz), 7.23 (t, 1H, J=8 Hz), 7.21 (s, 1H), 7.19 (s, 1H), 6.99 (t, 1H, J=8 Hz), 5.13 (bd, 1H, J=9 Hz), 2.73~2.99 (m, 2H), 2.59 (qd, 1H, J=9, 7 Hz), 2.28 (dm, 1H, J=13.5 Hz), 1.72~1.92 (m, 1H), 1.13 (d, 3H, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2([OH:21])[CH2:20][N:17]([CH:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: Cc1ccccc1
Product: OC1(c2ccc(F)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-fluorophenylmagnesium bromide (7.0 mL, 1 .OM (Et2O)) in toluene (20 mL) at −78° C. under argon, was added, dropwise, a solution of 1-diphenylmethyl-3-azetidinone (3) (1.4 g) in toluene (30 mL) over 30 minutes. The mixture was stirred for 4 hours at −78° C. then warmed to room temperature and partitioned between aqueous ammonium chloride solution (50 mL) and diethyl ether (3×20 mL). The combined organic fractions were washed (water, brine), dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (20% ethyl acetate, hexane) gave 3-(4-fluorophenyl)-1-diphenylmethyl-3-azetidinol (15) (1.82 g). To a stirred solution of the free base (1.82 g) in ether (5 mL) was added dropwise a solution of oxalic acid (0.49 g) in acetone (1 mL). The mixture was stirred for 5 minutes then filtered to give the oxalate salt hemihydrate (2.23 g), m.p. 75° C. (acetone). Found: C, 66.71; H. 5.34; N, 3.04. C24H22FNOs.0.5H2O requires C, 66.67; H, 5.32; N, 3.17%.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH3:17])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:6]=1[F:13].[H][H]>C(OCC)(=O)C.[C].[Pd]>[OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:6]=1[F:13]
Reactant: [H][H]
Reactant: CCCCC(O)C#Cc1ccc(F)c(F)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC(O)CCc1ccc(F)c(F)c1F
Yield: 91.4 %

Procedure:
In 730 mL of ethyl acetate, 183 g of 1-(3-hydroxy-1-heptynyl)-2,3,4-trifluorobenzene was dissolved, and 9 g of 5% palladium carbon (50% in water) was added. Then, the mixutre was stirred for 6 hours at a hydrogen pressure of 0.4 MPa. After the catalyst was removed by filtration (using cellulose), the solvent was evaporated under a reduced pressure to obtain 170 g of 1-(3-hydroxyheptyl)-2,3,4-trifluorobenzene as a light yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[O:31][CH3:32])([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccccc1Br
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: COc1ccccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 43 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 2-bromoanisole, the hydrochloride salt of the title compound was formed in 43% yield as a white solid, mp 290-293 C. elemental
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:17][S:18][C:19]1[CH:20]=[C:21]([NH:25][CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([OH:29])=[O:28])[CH:22]=[CH:23][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:28][C:27](=[O:29])[CH:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([S:18][CH3:17])[CH:20]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:47]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CSc1cccc(NC(C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CSc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
PS-DCC (602 mg, 0.80 mmol, loading: 1.33 mmol/g) is suspended in dry THF (15 mL). (3-Methylsulfanyl-phenylamino)-phenyl-acetic acid hydrochloride (I51) (124 mg, 0.40 mmol), HOBT (123 mg, 0.80 mmol), and (R)-quinuclidin-3-ol (153 mg, 1.20 mmol) are added and the suspension is shaken at RT overnight (16 hours). PS-DCC is filtered off, washed with THF and the filtrate is evaporated. The resulting residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated to afford the title compound as a brown oil (153 mg, quantitative yield, mixture of diastereoisomers).