Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH2:12]([O:15][C:16](Cl)=[O:17])[CH:13]=[CH2:14].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(NC(C2CC2)=O)C1)=O)CCC>>[CH2:12]([O:15][C:16]([NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1)=[O:17])[CH:13]=[CH2:14]
Reactant: NC1CNc2ccccc2C1
Reactant: C=CCOC(=O)Cl
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(NC(=O)C2CC2)Cc2ccccc21)NC(=O)OC(C)(C)C
Product: C=CCOC(=O)NC1CNc2ccccc2C1

Procedure:
In a manner analogous to that described in Example 109b) from 1.0 g of 1.0 g of 3(R,S)-amino-1,2,3,4-tetrahydroquinoline and 0.75 ml of allylchloroformate: Rf (P)=0.81; MS: M+ =232.
Reaction SMILES: O=[CH:2][C:3](=[CH2:5])[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([NH2:17])[C:10](=[C:14]([Cl:16])[CH:15]=1)[C:11]([OH:13])=[O:12].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].S(=O)(=O)(O)O>O>[Cl:6][C:7]1[CH:15]=[C:14]([Cl:16])[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:8]=1[CH:2]=[C:3]([CH3:5])[CH:4]=[N:17]2
Reactant: Nc1cc(Cl)cc(Cl)c1C(=O)O
Reactant: C=C(C)C=O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Cc1cnc2c(C(=O)O)c(Cl)cc(Cl)c2c1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
14 g of methacrolein were added dropwise, at l00? C, to a solution of 20.6 g os 4,6-dichloroanthranilic acid and 19 g of sodium m-nitrobenzenesulfonate in 200 g of 57% strength sulfuric acid. The mixture was stirred for 1 hour at 130° C., after which it was diluted with 450 g of water and filtered under suction while hot. The pH was brought to 2-3 with concentrated sodium hydroxide solution, while cooling with ice. The precipitated solid was filtered off under suction, washed with water and dried.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1[F:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:12][C:10]1[N:11]=[C:3]2[C:2]([O:1][CH2:19][C:20]3[C:21]([F:28])=[CH:22][CH:23]=[C:24]([F:27])[C:25]=3[F:26])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]2[C:9]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Fc1ccc(F)c(CBr)c1F
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)ccc(F)c3F)cc(C)cn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
3.00 g (12.81 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 17A, 3.27 g (14.1 mmol) of 2-(bromomethyl)-1,3,4-trifluorobenzene and 9.18 g (28.17 mmol) of caesium carbonate were initially charged in 183 ml of dry DMF and heated for 30 min in an oil bath warmed to 60° C. About 1.8 l of water were added to the reaction mi×ture, the mixture was stirred for 30 min and the solid was filtered off, washed with water and dried under reduced pressure. This gave 5.07 g of the title compound (99% of theory; purity about 96%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]1([F:35])[CH2:31][CH:30]1[C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:30]5[CH2:31][C:29]5([F:35])[F:28])=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CC1(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CC1(F)F

Procedure:
The title compound, white solid (99 mg, 91%), MS (ISP) m/z=435.3 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2,2-difluoro-cyclopropane-carboxylic acid.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:29][NH:30][S:31]([CH2:34][CH2:35][CH2:36]Cl)(=[O:33])=[O:32])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:3])[CH3:2].C(SCC(OC)CNS(CCC[I:65])(=O)=O)CCCCCCCCCCCCCCC>>[C:1]([NH:4][CH:5]([CH2:29][NH:30][S:31]([CH2:34][CH2:35][CH2:36][I:65])(=[O:33])=[O:32])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)NC(C)=O

Procedure:
2-acetamido-3-(3-chloropropylsulfonylamino)-1-octadecylcarbamoyloxypropane IIIg1 is allowed to react and worked up by the same procedure as described in (5). m.p. 101°-102° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Br)c4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-bromophenyl)-5-oxopentyl]-4-piperidinyl]phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 572.0 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12](Br)[C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:30]2[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]2)[C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)c2occc2c1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(CO[Si](C)(C)C(C)(C)C)cc3ccoc23)CC1
Yield: 62.7 %

Procedure:
Beginning with 0.51 gm (1.5 mMol) 5-(tert-butyldimethylsilyloxymethyl)-7-bromobenzofuran and 0.30 gm (1.6 mMol) 1-tert-butoxycarbonylpiperazine, 0.42 gm (63%) of the desired compound were prepared essentially as described in GENERAL PROCEDURE II.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=2)[C@@H:59]([C@H:69](O)[CH3:70])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:63]=[CH:64][C:65]([Cl:68])=[CH:66][CH:67]=2)[C@@H:59]([C@@H:69]([O:27][C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][N:25]=2)[CH3:70])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: Oc1ccc(F)cn1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(F)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (0.914 g, 2.74 mmol) in THF (15 mL) at 0° C. were added 5-fluoro-pyridin-2-ol (0.215 g, 1.90 mmol) and then DBAD (0.47 g, 2.02 mmol). After 5 minutes was added (R)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol (0.40 g, 1.26 mmol; described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 0.315 g (44%) of the title compound as a colorless oil. ES-MS m/e: 411.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C:14]([NH:16][CH3:17])=O)[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14][NH:16][CH3:17])[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2
Reactant: CNC(=O)CC(c1ccccc1)c1cc(OC)c2cc[nH]c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccccc1)c1cc(OC)c2cc[nH]c2c1

Procedure:
[3-(4-Methoxy-1H-indol-6-yl)-3-phenyl-propyl]-methyl-amine CL was prepared from 3-(4-methoxy-1H-indol-6-yl)-N-methyl-3-phenyl-propionamide using the procedure described above for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=295.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:35])[CH3:34]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([CH2:21][NH:35][CH2:33][CH3:34])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CN(Cc3ccccc3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 81 %

Procedure:
Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester (2.0 g, 0.004 mmol) were dissolved in 2.0 M solution of EtNH2 in THF (14 mL) in an autoclave and heated to 80° C. over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, heptane/ethyl acetate 1:1) to yield the title compound (1.2 g, 81%) as a yellow oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[C:14]=2O)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH:20]1([C:18]2[O:19][C:14]3[C:15]4[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=4[CH:11]=[CH:12][C:13]=3[N:17]=2)[CH2:22][CH2:21]1
Reactant: CC(=O)NCCC1CCc2ccc(NC(=O)C3CC3)c(O)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC(=O)NCCC1CCc2ccc3nc(C4CC4)oc3c21
Yield: 69.6 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}cyclopropanecarboxamide (119 mg, 0.369 mmol) and pyridinium p-toluenesulfonate (18.5 mg, 0.074 mmol) were heated under reflux in xylene (3.7 mL) for 5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (73 mg, yield 70%).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:8]=2)[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (312 mg, 0.6902 mmol) was dissolved in a mixed solution of acetonitrile (15 ml) and water (5 ml) and after adding thereto ammonium cerium(IV) nitrate (hereinafter simply referred to as “CAN”) (946 mg, 1.7262 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (187 mg, 0.4431 mmol, 64%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][CH:9]([OH:11])[CH3:10].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:11][CH:9]([CH3:10])[CH2:8][O:7][CH3:6])(=[O:4])=[O:3]
Reactant: COCC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (2.86 ml, 36.9 mmol) was added dropwise to an ice-cooled solution of 1-methoxy-2-propanol (3 ml, 30.7 mmol) and triethylamine (10.27 ml, 73.7 mmol) in dichloromethane (150 ml), and the reaction stirred at room temperature for 18 hours. The mixture was washed with water, then 2M hydrochloric acid, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a yellow oil, 5.24 g.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[N:15]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:13]=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[C:9]=1[C:10]#[N:11].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O.C(OCC)(=O)C>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:12]2[C:9]([C:10]#[N:11])=[C:8]([Cl:7])[N:15]=[C:14]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:13]=2)=[CH:26][CH:25]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1c(-c2ccc(O)cc2)cc(C2CCCC2)nc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)cc(C2CCCC2)nc1Cl
Reaction time: 16 h
Yield: 85.7 %

Procedure:
Cesium carbonate (39.3 mg, 0.120 mmol) was added to a solution of 2-chloro-6-cyclopentyl-4-(4-hydroxyphenyl)nicotinonitrile (18 mg, 0.060 mmol) and benzyl bromide (0.014 mL, 0.120 mmol) in DMSO (1 mL). After 16 h at room temperature, the mixture was diluted with ethyl acetate (80 mL), washed with saturated sodium bicarbonate (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-15% ethyl acetate in hexanes, gave 4-(4-(benzyloxy)phenyl)-2-chloro-6-cyclopentylnicotinonitrile as a white solid (20 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.50-7.74 (2H, m), 7.30-7.48 (5H, m), 7.19 (1H, s), 7.00-7.15 (2H, m), 5.13 (2H, s), 3.10-3.34 (1H, m), 2.00-2.32 (2H, m), 1.64-1.95 (6H, m), MS (ES+) m/z: 389 (M+H); LC retention time: 4.431 min (analytical HPLC Method A).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=2)=[N:4][NH:3]1.C(N(CC)CC)C.C(OC([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[N:36]1([C:19]([C:17]2[N:18]=[C:13]([CH2:12][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2](=[O:1])[NH:3][N:4]=3)[CH:14]=[CH:15][CH:16]=2)=[O:21])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)n1)N1CCNCC1
Reaction time: 18 h
Yield: 59.8 %

Procedure:
A mixture of 6-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-pyridine-2-carboxylic acid (ivb)(0.3 g, 1.1 mmol), triethylamine (0.3 ml, 2.1 mmol), tert-butyl-1-piperazine carboxylate (0.23 g, 1.3 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.5 g, 1.3 mmol) in dimethylformamide (10 ml) was stirred for 18 hours. The reaction mixture was precipitated on the addition of water (50 ml) and air-dried. The white precipitate was dissolved in ethanol (3 ml) and 12 M hydrochloric acid (6 ml) was added to the solution and the reaction was stirred for 30 minutes. The reaction was then concentrated in vacuo, redissolved in water (10 ml) and washed with dichloromethane (2×10 ml). The aqueous layer was basified with ammonium hydroxide and extracted into dichloromethane (2×10 ml). The combined organic layers was dried with MgSO4, filtered and evaporated to yield the expected product (va) as a pink solid (0.23 g, 73%). m/z [M+1]+ 250 (96% purity)
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:16][CH:17]=2)=[N:1]1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(OCc3ccccc3)cc2)=N1
Reaction time: 48 h
Yield: 90 %

Procedure:
To a stirred and cooled (0° C.) mixture of 4.5 parts of 2-amino-2-methyl-1-propanol and 180 parts of dichloromethane were added portionwise 4.93 parts of 4-(phenylmethoxy) benzoyl chloride. Upon complete addition, stirring was continued for 48 hours at room temperature. The precipitate was filtered off and the filtrate was evaporated. The residue was stirred in 2,2'-oxybispropane. The precipitated product was filtered off and stirred in 9.6 parts of thionyl chloride during 1 hour. After evaporation, the residue was taken up in a sodium hydroxide solution 10%, crushed ice and methylbenzene. The separated organic layer was washed with water, dried, filtered and evaporated, yielding 5 parts (90%) of 4,5-dihydro-4,4-dimethyl-2-[4-(phenylmethoxy)phenyl]oxazole as a residue (int. 1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].[CH3:22][C:23](C)([O-:25])[CH3:24].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH:23]1[CH2:24][O:25]1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccccc1CCCCc1ccc2ccccc2c1
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1ccc(OCC2CO2)c(CCCCc2ccc3ccccc3c2)c1
Yield: 84 %

Procedure:
Following a procedure similar to that described in Example 1(a), 300 mg of 2-[4-(2-naphthyl)butyl]phenol (prepared as described in Preparation 15), 122 mg of potassium t-butoxide and 301 mg of epibromohydrin were reacted in 15 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 303 mg (yield 84%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cc1cccc(Br)c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cccc(N2CCN(c3cnccc3C)C2=O)c1
Yield: 67.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 1-bromo-3-methyl-benzene (172.8 mg, 1.017 mmol), 1,4-dioxane (20 mL), copper iodide (16.13 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium phosphate (539.3 mg, 2.541 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.2% MeOH in CHCl3) afforded 153 mg of the product (67.69% yield).
Reaction SMILES: C([N:8]([CH2:22][C:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)=[N:24]O)[C@H:9]([CH2:14][CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10](OC)=[O:11])C1C=CC=CC=1.C(N(CC(C1C=C(F)C=C(F)C=1)=NO)[C@@H](CC1CCCCCC1)C(OC)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH:15]1([CH2:14][C@H:9]2[NH:8][CH2:22][CH:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[NH:24][C:10]2=[O:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: [H][H]
Reactant: COC(=O)[C@@H](CC1CCCCCC1)N(CC(=NO)c1cc(F)cc(F)c1)Cc1ccccc1
Agent: [Pd]
Agent: COC(=O)[C@H](CC1CCCCCC1)N(CC(=NO)c1cc(F)cc(F)c1)Cc1ccccc1
Solvent: CO
Product: O=C1NC(c2cc(F)cc(F)c2)CN[C@@H]1CC1CCCCCC1

Procedure:
Under a hydrogen atmosphere 5.5 g (12.0 mmol) methyl (R)-2-(benzyl-{2-(3,5-difluoro-phenyl)-2-[hydroxyimino]-ethyl}-amino)-3-cycloheptyl-propionate (this compound may be prepared analogously to the synthesis of methyl (S)-2-(benzyl-{2-(3,5-difluoro-phenyl)-2-[hydroxyimino]-ethyl}-amino)-3-cycloheptyl-propionate described herein using the corresponding (R)-configured starting component) and 0.70 g palladium on charcoal (10%) were hydrogenated in 30 ml of methanol for 3 days at 50° C. to 60° C. and 3 bar hydrogen pressure. After elimination of the catalyst the filtrate was concentrated by rotary evaporation. Purification was carried out by flash chromatography.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH2:12].[C:13](OC(=O)C)(=O)[CH3:14]>C(Cl)Cl>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:10][CH2:11][NH:12][CH:13]2[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(CCN)c1F
Solvent: ClCCl
Product: COc1ccc2c(c1F)CCNC2C
Reaction time: 2 h

Procedure:
To 500 mg (2.96 mmol) 2-(2-fluoro-3-methoxy-phenyl)-ethylamine and 622 μL (3.10 mmol) TEA in 7 mL DCM are added slowly 293 μL (3.83 mmol) acetic anhydride at 0° C. and stirring is continued for 2 h. After that time, the reaction mixture is quenched by the addition of water and extracted three times with DCM. The organic layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([OH:16])[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][C:6]=1[OH:17])C.Cl>[OH-].[Na+]>[OH:16][C:14]1[CH:15]=[C:5]([C:4]([OH:18])=[O:3])[C:6]([OH:17])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1cc(O)c(C(=O)OCC)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(O)c(C(=O)O)cc1O

Procedure:
Diethyl-1,4-cyclohexanedione-2,5-dicarboxylate is reacted with bromine in cold sulfuric acid (0°-10° C.) to provide the aromatized product, diethyl-2,5-dihydroxyterephthalate. Hydrolysis of the diethyl-2,5-dihydroxyterephthalate by refluxing in aqueous sodium hydroxide followed by acidification with HCl provides 2,5-dihydroxyterephthalic acid. The diacid may be converted to the diacid halide by reaction with thionyl halide in diethyl ether.