Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16].C(Cl)Cl>C(OCC)C>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:16]
Reactant: CCOC(CBr)OCC
Reactant: C1=Cc2ccccc2C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(CC1C=Cc2ccccc21)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of n-butyllithium (20.0 mL, 1.6 M, 32.2 mmol) in hexanes was added dropwise to a cooled (0° C.) solution of indene (5.35 g, 32.2 mmol) in 50 mL of diethyl ether. The reaction solution turned yellow and was warmed to 25° C. for 30 minutes. This yellow solution was added dropwise to a cooled (0° C.) solution of bromoacetaldehyde diethylacetal (5.00 mL, 32.2 mmol) in 50 mL of diethyl ether. The reaction mixture turned bright red after warming to 25° C. and was stirred for 12 hours, during which time it darkened to brown. The solvent was then removed in vacuo leaving brown oil. Methylene chloride (100 mL) was added to give a cloudy white mixture which was extracted with deionized water (3×100 mL). The brown organic layer was dried over Na2SO4 and then solids were separated by filtration. Solvent was removed from the filtrate in vacuo resulting in brown oil. Yield: 5.48 g, 23.5 mmol (85%). 1H NMR (CDCl3, 600 MHz): δ 7.43 (d, 3JHH=7.2 Hz, 1H, H4), 7.35 (d, 3JHH=7.8 Hz, 1H, H7), 7.25 (t, 3JHH=7.2 Hz, 1H, H5), 7.19 (t, 3JHH=7.2 Hz, 1H, H6), 6.80 (dd, 1H, H2), 6.61 (dd, 1H, H3), 4.68 (m, 1H, CH), 3.69 (dm, 2H, OCH2CH3), 3.56 (m, 1H, H1), 3.52 (dm, 2H, OCH2CH3), 2.22 (m, 1H, CH2), 1.71 (m, 1H, CH2), 1.24 (t, 3JHH=7.2 Hz, 3H, OCH2CH3), 1.19 (t, 3JHH=7.2 Hz, 3H, OCH2CH3). 13C{1H} NMR (CDCl3, 150.8 MHz): 147.51 (s, C7a), 144.13 (s, C3a), 139.13 (s, C3), 130.79 (s, C2), 126.56 (s, C5), 124.73 (s, C6), 123.00 (s, C4), 121.05 (s, C7), 102.10 (s, CH), 61.44 (s, OCH2CH3), 61.23 (s, OCH2CH3), 46.66 (s, C1), 35.51 (s, CH2), 15.38 (s, OCH2CH3). MS (ES) m/z (assignment, relative intensity): 255.2 (C15H20O2Na, [M+Na]+, 100%). Anal. Calcd. for C15H20O2: C, 77.54; H, 8.68. Found: C, 77.34; H, 8.76.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:14]2[N:15]=[C:16]([NH:19][CH:20]([CH3:22])[CH3:21])[S:17][CH:18]=2)[N:3]=1.ClC1N=C(O[CH:37]2[CH2:54][CH:53]3[N:39]([C:40](=[O:60])[N:41]([CH3:59])[CH2:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH:47][CH:48]4[C:50]([C:56]([OH:58])=[O:57])([NH:51][C:52]3=[O:55])[CH2:49]4)[CH2:38]2)C2C(C=1)=CC(OC)=CC=2>>[CH:20]([NH:19][C:16]1[S:17][CH:18]=[C:14]([C:4]2[N:3]=[C:2]([O:1][CH:37]3[CH2:54][CH:53]4[N:39]([C:40](=[O:60])[N:41]([CH3:59])[CH2:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH:47][CH:48]5[C:50]([C:56]([OH:58])=[O:57])([NH:51][C:52]4=[O:55])[CH2:49]5)[CH2:38]3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:15]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: COc1ccc2c(O)nc(-c3csc(NC(C)C)n3)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3csc(NC(C)C)n3)cc2c1

Procedure:
The title product 71 was prepared from 1-hydroxy-3-(2-isopropylaminothiazol-4-yl)-6-methoxyisoquinoline following the same procedures described for the preparation of 17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42, Example 10): m/z=649 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:7]([NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])=[O:8])=[N+:2]=[N-:3].O.O=[C:32]1O[C@H:37]([C@H](CO)O)[C:35]([O-])=[C:33]1[OH:34].[Na+]>CC(O)(C)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:33]([C:35]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[C:6]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:27])=[O:28])[CH2:23][CH2:24][CH3:25])[CH:21]=2)[C:7]([NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[O:8])[CH:37]=1)(=[O:34])[CH3:32]
Reactant: CCCN(c1cc(N=[N+]=[N-])cc(C(=O)N[C@H](C)c2ccc(F)cc2)c1)S(C)(=O)=O
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(C(C)=O)nn2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 1025.5 %

Procedure:
To a solution of 0.15 g (0.36 mmol) 3-azido-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide in 2 mL t-BuOH was added 1 mL water and 0.004 g (0.018 mmol) copper(II) sulfate hydrate and 0.007 g (0.036 mmol) sodium ascorbate. The heterogeneous reaction mixture was stirred at rt for 24 h, then diluted w. 75 mL EtOAc, washed with 50 mL water, 50 mL brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (40 g silica gel cartridge 20-100% EtAOc/hex over 15 min) afforded 0.18 g (100%) 3-(4-acetyl-1H-1,2,3-triazol-1-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl) (propyl)amino]benzamide as a foam. 1H NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.11 (br t, J=1.83 Hz, 1H), 7.93 (t, J=2.02 Hz, 1H), 7.89 (br t, J=1.64 Hz, 1H), 7.38 (m, 2H) 7.06 (m, 2H), 6.52 (br d, J=7.50 Hz, 1H), 5.32 (quint, J=7.15 Hz, 1H), 3.74 (t, J=7.14 Hz, 2H), 2.93 (s, 3H), 2.76 (s, 3H), 1.64 (d, J=6.96 Hz, 3H), 1.54 (m, 2H), 0.93 (t, J=7.32 Hz, 3H). LCMS [M+H]+=488.1
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:43]=[CH:42][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[F:41])=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[F:41][C:32]1[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:31]=1[NH:30][C:28]([C:27]1[CH:42]=[CH:43][C:24]([N:19]2[CH2:18][CH2:17][N:16]([C:13]3[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=3)[CH2:21][CH2:20]2)=[N:25][CH:26]=1)=[O:29]
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1F)c1ccc(Cl)nc1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C(F)(F)F)cc4F)cn3)CC2)cc1

Procedure:
4-{4-[5-(2-Fluoro-4-trifluoromethyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(2-fluoro-4-trifluoromethyl-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C24H20N4O3F4 [M+H]+: 489.1545. Found: 489.1543.
Reaction SMILES: C(OC(=O)NCC1C=CC2N(CCC(C)C)C(CN3C4C(=CC=CC=4)C(=O)N(C4CC4)C3=O)=NC=2C=1)(C)(C)C.[CH:40]([C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][N:43]=1)=[CH2:41].[C:51]([O:55][C:56]([NH:58][CH2:59][C:60]1[CH:81]=[CH:80][C:63]2[N:64]([CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74](=[O:79])[C:75]([CH3:78])([CH3:77])[CH3:76])[C:65]([CH2:67]Cl)=[N:66][C:62]=2[CH:61]=1)=[O:57])([CH3:54])([CH3:53])[CH3:52].Cl>>[C:51]([O:55][C:56]([NH:58][CH2:59][C:60]1[CH:81]=[CH:80][C:63]2[N:64]([CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74](=[O:79])[C:75]([CH3:78])([CH3:77])[CH3:76])[C:65]([CH2:67][N:44]3[C:45]4[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:42]([CH:40]=[CH2:41])=[N:43]3)=[N:66][C:62]=2[CH:61]=1)=[O:57])([CH3:54])([CH3:52])[CH3:53]
Reactant: C=Cc1n[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(CCl)n2CCCCOC(=O)C(C)(C)C
Agent: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Product: C=Cc1nn(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCOC(=O)C(C)(C)C)c2ccccc12
Yield: 71 %

Procedure:
The procedure for the preparation of [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester was followed starting with 3-vinyl-1H-indazole (140 mg, 0.970 mmol) and 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-chloromethyl-benzoimidazol-1-yl]-butyl ester; HCl salt (474 mg, 0.614 mmol). After quenching with water, a gum formed. The water was decanted and the residue partitioned between diethyl ether and water. The layers were separated and the aqueous phase extracted with diethyl ether (2×40 mL). The combined organic phases were washed with water (twice), brine, and dried (MgSO4). Purification by flash chromatography (eluent hexane-acetone 2:3) afforded 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-(3-vinyl-indazol-1-ylmethyl)-benzoimidazol-1-yl]-butyl ester (386 mg, 71%) as a colorless foam:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH:5]=[C:6]([O:30][CH3:31])[C:7]=1[O:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:5]=[C:6]([O:30][CH3:31])[C:7]=1[O:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)[N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCC[C@H](Oc1c(Cl)cc(CCC(=O)OCC)cc1OC)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC[C@H](Oc1c(Cl)cc(CCC(=O)O)cc1OC)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirring solution of ethyl 3-{3-chloro-5-(methyloxy)-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoate (118 mg, 0.20 mmol) in THF (3 mL) and MeOH (3 mL) at ambient temperature was added NaOH (2N, 3 mL) and the mixture stirred for 2 h and then left to stand overnight. HCl (2N, 3 mL) was then added and the mixture reduced under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 20:1 to 0:1) to give the title compound (94 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH2:12][CH2:13][NH2:14])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[CH:17]1([C:20](Cl)=O)[CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([CH2:20][NH:14][CH2:13][CH2:12][C:10]2[O:9][C:8]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:11]=2)[CH2:19][CH2:18]1
Reactant: COc1cccc2cc(CCN)oc12
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cccc2cc(CCNCC3CC3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a mixture of 10.27 g of 7-methoxy-3-benzofuranethylamine, 60 ml of methylene chloride, and 60 ml of 15% aqueous sodium hydroxide solution was added, with cooling, 8 ml of cyclopropanecarbonyl chloride. The mixture was stirred at room temperature overnight; an additional 2 ml of cyclopropanecarbonyl chloride added after two hours. The solvent was removed from the dried organic layer and the residue heated under reflux with 3.5 g of lithium aluminum hydride in tetrahydrofuran for 6 hours. Water (3.5 ml), 15% aqueous sodium hydroxide solution (3.5 ml) and finally water (10.5 ml) were added with cooling, and the mixture filtered. Removal of the solvent and short-path distillation of the residue (bath to 170°, 1 micron pressure) gave 11.74 g (90% yield) of N-cyclopropylmethyl-7-methoxy-3-benzofuranethylamine; nmr spectrum (in CDCl3): τ2.6 (s, 1); 2.8-3.4 (m, 3); 6.1 (s, 3); 7.1-7.4 (m, 4 ); 7.6 (d, J=6.5 Hz, 2) and 8.1-10.2 (m, 6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=[O:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([Cl:19])[CH:21]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C(NCC1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 15 h
Yield: 97.5 %

Procedure:
To a stirred solution of Intermediate 9 (0.05 g) was added a solution of 3,4-dichlorobenzoyl chloride (42.7 mg) in N,N-dimethylformamide (7 ml). The mixture was stirred at 22° C. for 15 h before the solvent was evaporated in vacuo. The residue was purified by eluting through a 1 g silica solid phase extraction cartridge (Varian Bondelut), eluting sequentially with dichloromethane, ether, ethyl acetate, acetone, acetonitrile and methanol, to give the title compound as a white solid (0.080 g). LC/MS (System A) Rt 3.10 min, Mass Spectrum m/z 442 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[C:7](=[O:12])[C:6]=12.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[C:7](=[O:12])[C:6]=12)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(C)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 8-hydroxy-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (25.0 g, 104.9 mmol) in DMF (500 mL), potassium carbonate (58 g, 420 mmol) and benzyl bromide (14.9 mL, 126 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate concentrated under vacuum. The residue was partitioned between dichloromethane and brine. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate to give titled material.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:19][CH2:20][CH2:21][OH:22].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>CO>[CH3:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]([C:5]2[CH:17]=[CH:18][C:2]3[N:1]=[C:28]([C:27]4[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=4)[N:19]([CH2:20][CH2:21][OH:22])[C:3]=3[CH:4]=2)=[O:7])[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(NCCO)c2)cc1C
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4ccc(Cl)cc4)n(CCO)c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-amino-N-(3,4-dimethyl-phenyl)-3-(2-hydroxy-ethylamino)-benzamide (0.1 mL in 0.2 M DMSO solution), 4-chlorobenzaldehyde (0.1 mL in 0.2 M toluene solution) and FeCl3 (0.05 mL in 0.02 M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-(4-chlorophenyl)-3-(2-hydroxy-ethyl)-3H-benzoimidazole-5-carboxylicacid (3,4-dimethylphenyl)-amide: MS (m/z) 420 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc(Br)ccc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-4-bromo-phenyl)-phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.72 (s, 3H), 6.75 (d, 2H, J=8.8 Hz), 7.19-7.26 (m, 2H), 7.37-7.43 (m, 4H), 7.57 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.96 (s, 1H), 10.09 (s, 1H). MS: m/z 447.9 (M++1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][O:16][CH:17]([CH3:19])[CH3:18].[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([OH:30])=[CH:24][C:23]=2[O:22]1>CC(C)=O>[CH:17]([O:16][CH2:15][CH2:14][C:13]([CH3:20])=[CH:12][CH2:11][CH2:10][O:30][C:25]1[CH:26]=[CH:27][C:28]2[O:29][CH2:21][O:22][C:23]=2[CH:24]=1)([CH3:19])[CH3:18]
Reactant: CC(=CCCBr)CCOC(C)C
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=CCCOc1ccc2c(c1)OCO2)CCOC(C)C

Procedure:
2.35 g (0.017 mol) of potassium carbonate and 50 mg of potassium iodide are added to a solution of 4.0 g (0.017 mol) of 1-bromo-6-isopropoxy-4-methyl-3-hexene and 2.35 g (0.017 mol) of 3,4-methylendioxy-phenol in 120 cc of acetone. The suspension is boiled under reflux during the course of 20 hours, is then filtered and liberated from acetone in a vacuum. The residue is taken up in ether, washed with water and saturated salt solution, dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate 9:1. Thus the cis/trans isomeric mixture of the 5-(6-isopropoxy-4-methyl methyl-3-hexenyloxy)-1,3-benzodioxol is obtained as colourless oil. nD20 = 1.5111.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:9])[NH:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)C=O>C1(C)C=CC=CC=1>[CH2:10]([N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCCCN1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1CCCCN1Cc1ccccc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
To a suspension of sodium hydride (80%, 3.3 g, 0.11 mol) in dry toluene (250 ml) under argon, was added dropwise a solution of δ-valerolactam (9.9 g, 0.10 mol) in toluene (50 ml). When the addition was complete, the mixture was heated under reflux for 1 h, then cooled to ambient temperature. A solution of benzyl bromide (13 ml, 18.8 g, 0.11 mol) in toluene (50 ml) containing dimethyl formamide (1 ml) was then added dropwise over 15 minutes. The resulting mixture was heated under reflux for 4 h. On cooling, the mixture was filtered and the filtrate was dried (Na2SO4) and evaporated in vacuo to give an oil. Bulb-to-bulb distillation gave the title compound (D26) as a yellow oil (8.0 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[OH-].[K+].O>CS(C)=O>[N:17]1([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:7]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1N1CCCCC1
Temperature: 90 °C
Yield: 91.8 %

Procedure:
To 1-(5-chloro-2-nitro-phenyl)-piperidine (184 mg, 0.760 mmol, as prepared in Example 3, step (a)) and imidazole (67.8 mg, 0.99 mmol) in 3 mL of DMSO was added KOH (64 mg, 1.1 mmol). The reaction was heated to 90° C. overnight. The dark solution was poured into 40 mL of water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo to give 190 mg (92%) of the title compound as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C14H16N4O2, 273.1 (M+H), found 273.1.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([C:35]1([CH3:34])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H](Cc1ccccc1)CN1CCC(c2cc(F)ccc2OC)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)C2(C)CCCCC2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-methyl-amine (0.12 g. 0.33 mmole) and triethylamine (0.10 mL, 0.74 mmole) in dichloromethane (10 mL) was cooled to 0° C. To the solution, 1-methyl-1-cyclohexanecarboxylic acid chloride (93 mg, 0.58 mmole) in a minimal amount of dichloromethane was added. The resulting mixture was stirred at 0° C. overnight. The solvent was evaporated and the residue dissolved in EtOAc (50 mL) and water (50 mL). The layers were separated, the organics washed with water (2×50 mL) and brine and dried over Na2SO4, filtered and concentrated. Flash chromatography (elution with 1:3 EtOAc-hexane) gave 0.14 g (88% yield) of 1-methyl-cyclohexanecarboxylic acid {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-methylamide. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid. m.p. 160-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12]
Reactant: CC(C)(C)N
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-methylbenzene-1-sulfonyl chloride (1.50 g) in dichloromethane (10 ml) at 0° C. was added tert-butylamine (1.5 ml). The reaction mixture was allowed to warm to and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with 1N HCl and with sat. aq. NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated to give 1.20 g 4-bromo-N-tert-butyl-3-methylbenzenesulfonamide as a white solid.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH2:9]1[CH2:11][CH:10]1[CH2:12][NH2:13].[CH3:14][C:15]1[N:16]=[C:17]([N:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[C:24]2=[O:40])[S:18][C:19]=1[C:20](O)=[O:21]>>[CH:10]1([CH2:12][NH:13][C:20]([C:19]2[S:18][C:17]([N:23]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=4)[C:24]3=[O:40])=[N:16][C:15]=2[CH3:14])=[O:21])[CH2:11][CH2:9]1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCC1CC1
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCC1CC1
Yield: 15 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 2-cyclopropylmethylamine to react with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a white powder in 15% yield: mp 184-186° C.: 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 5.70 (s, 1H), 4.48 (s, 2H), 4.08 (t, J=8.4 Hz, 2H), 3.46 (t, J=8.4 Hz, 2H), 3.24-3.20 (m, 2H), 2.58 (s, 3H), 1.03-0.92 (m, 1H), 0.55-0.44 (m, 2H), 0.29-0.27 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.3, 156.9, 155.5, 152.7, 148.9, 134.4, 129.7, 121.4, 120.4, 117.6, 47.3, 44.8, 42.0, 41.8, 17.1, 10.6, 3.5: MS (ES+) m/z 455.3 (M+1).