Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=2[C:13]=1[O:14][CH3:15].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=3[C:13]=2[O:14][CH3:15])=[N:18][CH:19]=1
Reactant: COc1c(N)ccc2c1CCC(=O)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2OC)CCC(=O)CC3)ncc1Cl

Procedure:
The title compound was prepared from 2-amino-1-methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner as Example 179. Product was isolated as an off-white solid (12 mg, 20%). LCMS (m/e) 466 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.68 (d, 1H, J=8.8 Hz), 8.17 (d, 1H, J=8.34 Hz), 8.13 (s, 1H), 7.50 (m, 2H), 7.42 (s, 1H), 7.11 (t, 1H), 6.96 (d, 1H, J=8.34 Hz), 6.23 (broad s, 1H), 3.76 (s, 3H), 3.04 (d, 3H, J=4.8 Hz), 3.01 (m, 2H), 2.89 (m, 2H), 2.62 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20](CC4C=CC(OC)=CC=4)[CH2:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:39][CH3:40])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2].C(O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([O:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:20][CH2:19]3)[CH2:17][CH2:18]2)=[O:12])=[CH:7][C:6]=1[O:39][CH3:40])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2CC3(CCN(C(=O)c4ccc(OC(C)C)c(OC)c4)CC3)OCC2c2ccccc2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(C(=O)N2CCC3(CC2)CNC(c2ccccc2)CO3)ccc1OC(C)C
Temperature: 65 °C

Procedure:
To (4-isopropoxy-3-methoxy-phenyl)-[8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone (175 mg, 0.32 mmol), Pd(OH)2 (129 mg, 0.9186 mmol) and ammonium formate (405 mg, 6.43 mmol) was added ethanol. The reaction mixture was then heated at 65° C. for 16 hours. The reaction mixture was filtered, the solvent evaporated and the residue was purified by silica gel column chromatography using 0 to 60% EtOAc in hexanes as eluent to give (4-isopropoxy-3-methoxy-phenyl)-(9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)methanone. ESI-MS m/z calc. 424.5. found 425.5 (M+1)1; Retention time: 1.28 minutes (3 min run).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])(=O)=O.OB(O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[C:25]1([C:7]2[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Reactant: OB(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A mixture of dimethyl 5-(trifluoromethylsulfonyloxy)isophthalate (2.3 g), dihydroxy-phenylborane (1.23 g) and triethylamine (2.0 4 g) in N,N-dimethylformamide (30 ml) was heated at 100° C. and stirred for 3 hours under nitrogen. After evaporating the solvent, the residue was dissolved in a mixture of dichlomethane (100 ml) and water. The organic layer was successively washed with aqueous 10% sodium carbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from hexane to afford dimethyl 5-phenylisophthalate (1.07 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][C:12]=2[C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:25][C:21]1[CH:20]=[C:19]([NH:18][C:17]([C:12]2[N:13]=[C:14]([CH3:16])[S:15][C:11]=2[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=2)=[O:26])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc(Nc2sc(C)nc2C(=O)Nc2cccc(Cl)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(Nc2cccc(CO)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107 %

Procedure:
A solution of 3-[4-(3-chloro-phenylcarbamoyl)-2-methyl-thiazol-5-ylamino]-benzoic acid methyl ester (0.02 g, 0.05 mmol) in THF (1.00 ml) was treated at room temperature with lithium aluminium hydride (0.008 g, 0.20 mmol) and stirred at room temperature for 30 min. The reaction mixture was quenched with a drop of 5N NaOH and sodium sulphate. The solids were filtered and the mother liquor evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate) to yield the title compound (0.02 g, 90%) as a light brown gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].[CH3:11][C:12]1[N:16]([CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[C:15]2[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=2[N:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:16]2[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]=[C:12]2[CH3:11])=[CH:26][CH:25]=1
Reactant: Cc1nc2ccccc2n1Cc1ccc(C(=O)O)cc1
Reactant: NCCc1ccccc1F
Product: Cc1nc2ccccc2n1Cc1ccc(C(=O)NCCc2ccccc2F)cc1

Procedure:
The title compound was prepared in analogy to example 1c, but using 2-(2-fluoro-phenyl)-ethylamine and 4-(2-methyl-benzoimidazol-1-ylmethyl)-benzoic acid as coupling components. MS (ISP): 388.2 ((M+H)+.).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[CH3:5])[CH3:2].CC(C)([O-])C.[K+].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(OC(=O)C)C>C1COCC1.O>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:3]([CH2:1][CH3:2])[C:4](=[O:6])[CH3:5])=[CH:16][CH:15]=1
Reactant: CCNC(C)=O
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(Cc1ccc(Br)cc1)C(C)=O
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
0.568 mL N-ethylacetamide was dissolved in 20 mL THF. 0.67 g Potassium tert-butoxide was added and the mixture stirred for 20 min at 50° C. Then 1 g of 4-bromobenzylbromide dissolved in 5 mL THF was added and the suspension stirred for 2 h at 50° C. After cooling, ethylacetate and water were added and the organic phase extracted with water (1×), dried and the solvent distilled off. The product was purified via FCC (cyclohexane/ethylacetate: 90/10→50/50) to yield 830 mg N-(4-bromobenzyl)-N-ethylacetamide as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O.[N:17]([O-:19])=[O:18].[Na+]>O>[CH3:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([OH:9])=[C:5]([N+:17]([O-:19])=[O:18])[CH:6]=1
Reactant: Cc1ccc(O)cc1C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(O)c([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
To 3,4-dimethylphenol(12.1 g, 0.1 mol), trifluoroacetic acid(250 ml) was added, and in water bath sodium nitrite(12.4 g, 0.18 mol) was added slowly. The resulting mixture was stirred at room temperature for 14 hours and concentrated under the reduced pressure to remove trifluoroacetic acid, followed by addition of water(150 ml), extracted with ether and purified by column chromatography to obtain the titled compound.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.S(Cl)([Cl:46])=O>ClC(Cl)C>[Cl:46][CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCCl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (1400 mg, 2.381 mmol) and thionyl chloride (1.738 mL, 23.81 mmol) in dichloroethane (15 mL) was heated to 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure to provide the desired product as a brown solid (1.3 g, 90%), which was taken to the next step without further purification. LCMS: m/e 606.48 (M+H)+, 2.46 min (method 5).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Cl:24])=[CH:10][N:11]2[S:14]([C:17]2[CH:22]=[CH:21][C:20](C)=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)=O.[CH3:25]C(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:24][C:9]1[C:8]2[C:12](=[CH:13][C:5]([CH2:3][OH:2])=[CH:6][CH:7]=2)[N:11]([S:14]([C:17]2([CH3:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH2:18]2)(=[O:15])=[O:16])[CH:10]=1
Reactant: COC(=O)c1ccc2c(Cl)cn(S(=O)(=O)c3ccc(C)cc3)c2c1
Reactant: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC1(S(=O)(=O)n2cc(Cl)c3ccc(CO)cc32)C=CC=CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-(toluene-4-sulfonyl)-1H-Indole-6-carboxylic acid methyl ester (3.10 g, 8.53 mmol) in 50 mL of toluene at −78° C. is added DIBAL (13.8 mL of a 1.5M solution in toluene, 20.8 mmol) dropwise. The mixture is stirred at −78° C. for 2 h, then warmed to room temperature and stirred for 2 hours. The reaction mixture is quenched by the addition of MeOH and washed with saturated disodium tartrate solution. The aqueuos layer is extracted with Et2O. The combined organics are washed with saturated disodium tartrate solution, water and saturated NaCl solution. The organic phase is then dried over anhydrous MgSO4, filtered and concentrated to give the title compound (2.88 g). The crude product is used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.01 (s, 1H), 7.79 (d, 2H), 7.56 (s, 1H), 7.53 (d, 1H), 7.31 (d, 1H), 7.25 (d, 2H), 4.84 (s, 2H), 2.37 (s, 3H), 1.88 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][C:38]1=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23]([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])[N:22]=1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(N2CCCC2=O)n1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and pyrrolidin-2-one (2.0 equiv.) in dioxane (0.10M) was added cesium carbonate (1.0 equiv.) and the allowed to stir at 120° C. for 24 hours. LCMS analysis indicated formation of the desired product. The volatiles were removed in vacuo. The crude material was purified via preparative reverse phase HPLC. Upon lyophilization of the pure fractions, N-(4-methyl-3-(6-morpholino-2-(2-oxopyrrolidin-1-yl)pyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide was isolated as the TFA salt in 12% yield. LCMS (m/z) (M+H)=526.3, Rt=0.83 min. 1H NMR (400 MHz, <cd3od>) δ ppm 2.25 (quin, J=7.73 Hz, 2H) 2.47 (s, 3H) 2.81 (t, J=8.02 Hz, 2H) 3.82-3.87 (m, 8H) 4.15 (t, J=7.43 Hz, 2H) 7.03 (s, 1H) 7.47 (d, J=8.61 Hz, 1H) 7.71 (dd, J=8.41, 2.15 Hz, 1H) 7.75 (t, J=7.83 Hz, 1H) 7.92 (d, J=7.83 Hz, 1H) 8.11 (d, J=2.35 Hz, 1H) 8.22 (d, J=7.83 Hz, 1H) 8.27 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH3:19])=[O:4].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]=1[CH2:19][Br:20])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(=O)n(Cc2ccccc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(=O)n(Cc2ccccc2)c1CBr
Yield: 69.3 %

Procedure:
A mixture of 1-benzyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.64 g, 10.3 mmol), N-bromosuccinimide (2.01 g, 11.3 mmol), and benzoyl peroxide (250 mg, 1.03 mmol) in CCl4 (100 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-40% EtOAc/hexanes) to give 2.4 g of the title compound as a viscous oil. MS: (+) m/z 335.92, 337.89 (M+1, 79/81Br)
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([NH:12][C:13]([CH3:32])([C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[C:19]([CH3:30])[CH:18]=2)[CH3:14])=[O:11])=[CH:7][CH:6]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[C:4]([C:5]1[S:9][C:8]([C:10]([NH:12][C:13]([CH3:32])([C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[C:19]([CH3:30])[CH:18]=2)[CH3:14])=[O:11])=[CH:7][CH:6]=1)#[CH:3]
Reactant: Cc1cc(NC(=O)C(C)(C)NC(=O)c2ccc(C#C[Si](C)(C)C)s2)ccc1N1CCOCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccc(C(=O)NC(C)(C)C(=O)Nc2ccc(N3CCOCC3=O)c(C)c2)s1
Reaction time: 2 h

Procedure:
A mixture of 0.81 g (1.63 mmol) of 5-(2-trimethylsilylethynyl)-N-{1-methyl-1-[3-methyl-4-(3-oxomorpholin-4-yl)phenylcarbamoyl]ethyl}thiophene-2-carboxamide and 0.57 g (1.79 mmol) of tetrabutylammonium fluoride trihydrate in 30 ml of methylene chloride is stirred for 2 h and then the organic phase is washed 3× with water, dried with sodium sulphate, filtered and concentrated in vac. The crude product is purified by chromatography (silica gel, methylene chloride→methylene chloride:ethanol 25:1).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([F:10])=[CH:5][C:3]=1[NH2:4].C([Li])(CC)C.[I:16]I>C1COCC1>[F:1][C:2]1[C:8]([F:9])=[C:7]([I:16])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc(F)cc(F)c1F
Reactant: II
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Nc1cc(F)c(I)c(F)c1F
Temperature: 20 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a stirred solution of 2,3,5-trifluoro aniline (2.0 g, 13.605 mmol, 1.0 eq) in dry THF (40 mL) at −78° C., was added sec-butyl lithium (10.88 mL, 13.6 mmol, 1.0 eq) over 30 minutes. Stirring was continued at −78° C. for 2 h. A solution of iodine (4.14 g, 16.32 mmol, 1.2 eq) was added dropwise and reaction was slowly warmed to 20° C. over 1 hour (h). The reaction was quenched with 10% aq. Na2S2O3 solution and extracted with methyl tert-butyl ether (MTBE) (3×50 mL). The combined organic extract was washed with saturated (sat.) brine solution, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product was column purified over silica using 0-10% EtOAc with hexanes as eluent to afford 2,3,5-trifluoro-4-iodoaniline (1.3 g, 35%) as pink solid: 1H NMR (400 MHz, CDCl3) δ 6.43-6.39 (m, 1H), 3.99 (brs, 2H); ESIMS m/z 274 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[H-].[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C=O)C>[F:1][C:2]([F:12])([C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9])[CH2:3][O:4][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,2,3,3,4,4,4-heptafluorobutanol (5.7 g, 28.5 mmol) in DMF (100 mL) was stirred and cooled to −5° C. as sodium hydride (0.72 g, 30 mmol) was added. After 1 h at −5° C., the reaction was treated with 4-fluoronitrobenzene (4.1 g, 29 mmol). The reaction was allowed to warm to ambient temperature, concentrated, and slurried in methylene chloride (200 mL). The slurry was washed with an 1 N aqueous potassium hydroxide solution (2×) and brine solution, dried over basic alumina, treated with charcoal, filtered, and concentrated to give 4-(2′,2′,3′,3′,4′,4′,4′-heptafluorobutanoxy)nitrobenzene.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:28]=[N+:29]=[N-:30].[Na+]>CC(C)=O.O>[N:28]([C:12]([C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][CH:10]=1)=[O:14])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cnnn1-c1ccccc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1cnnn1-c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17.7 %

Procedure:
To a solution of 1-phenyl-1H-1,2,3-triazole-5-carboxylic acid (500 mg, 2.64 mmol) in a mixture of acetone (10 mL) and water (5 mL) was added triethylamine (0.55 mL, 3.96 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (573 mg, 5.28 mmol) was then added and the resulting mixture was stirred for 1.5 hours at 0° C. To the mixture was added sodium azide (0.844 g, 13.0 mmol), and the mixture was stirred for another 1.5 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give desired product (100 mg, 18%). 1HNMR (CDCl3) (δ) 8.30 (s, 1H), 7.57 (t, 3H), 7.51 (d, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:20][C:19]3([CH3:22])[CH2:21][CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18]3)=[O:13])=[CH:8][CH:7]=1)=[O:4].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC(C)=O.CC#N>[N:25]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[CH2:20][C:19]4([CH3:22])[CH2:21][CH:15]3[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18]4)=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)CCl)cc2)C1
Reactant: C1CCNCC1
Solvent: CC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)CN3CCCCC3)cc2)C1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
A solution of 2-chloro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acetamide (40 mg, 0.115 mmol) in acetone (250 μl) was added to a mixture of piperidine (17.1 μl, 0.173 mmol) and DIPEA (40 μl, 0.229 mmol) in MeCN (250 μl). The resulting reaction mixture was heated and stirred in a microwave oven for 10 min. at 100° C. After cooling to room temperature the volatiles were removed in vacuo and the residue purified on a prep. Gilson HPLC. Pure fractions were collected, evaporated in vauco and dried at 50° C. for 16 hours affording 43.8 mg (75%) of the title compounds as a TFA salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.C(O)=O>[Pd].C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1
Reactant: CS(=O)(=O)c1cc(F)cc(C2=CCNCC2)c1
Agent: [Pd]
Solvent: O=CO
Solvent: CC(C)O
Product: CS(=O)(=O)c1cc(F)cc(C2CCNCC2)c1
Reaction time: 24 h
Yield: 81.7 %

Procedure:
A mixture of 4-[3-fluoro-5-(methylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine (2.02 g, 7.9 mmol), palladium on carbon (0.56 g) and formic acid (1.9 ml) in isopropyl alcohol (60 ml) was hydrogenated at 50 psi for 24 h under hydrogen. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness to give 1.66 g of crude product. MS m/z (relative intensity, 70 eV) 257 (M+, bp), 256 (80), 133 (21), 69 (25) 56 (99).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=1[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]([C:30]2[N:31]=[C:32]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[N:33]([CH3:36])[C:34]=2[CH3:35])=O)[CH2:22][CH2:21]1>O1CCCC1>[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=1[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:30]2[N:31]=[C:32]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:41][CH:42]=3)[N:33]([CH3:36])[C:34]=2[CH3:35])[CH2:22][CH2:21]1
Reactant: COc1ccc(CN2CCN(CCC(=O)c3nc(-c4ccc(C(F)(F)F)cc4)n(C)c3C)CC2)c(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCN(CCCc3nc(-c4ccc(C(F)(F)F)cc4)n(C)c3C)CC2)c(OC)c1OC
Temperature: 0 °C
Yield: 20.5 %

Procedure:
A solution of lithium aluminum hydride (0.6 g) and 1-(2,3,4-trimethoxyphenyl)methyl-4-[(2-(4-trifluoromethylphenyl)-1,5-dimethylimidazol-4-yl)-3-oxoprop-1-yl]piperazine (2 g) in 50 ml of tetrahydrofuran was refluxed for 48 hours Excess reagent was hydrolysed by cooling the mixture to 0° C. and adding wet tetrahydrofuran dropwise. The mixture was filtered, the solid washed with a mixture of 1:1 ethanol/isopropanol, solvent evaporated from the filtrate, and the residue flash-chromatographed on silica gel, eluting with 2% methanol in dichloromethane, to yield 400 mg of 1-(2,3,4-trimethoxyphenyl)methyl-4-[(2-(4-trifluoromethylphenyl)-1,5-dimethylimidazol-4-yl)prop-1-yl]piperazine, which was converted to its hydrochloride salt, m.p. 212° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][CH2:2][CH2:3][S:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCSc1ccc(CCC(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCc1ccc(SCCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-[4-(2-aminoethylthio)phenyl]propionic acid (0.8 g), triethylamine (1.6 ml) and methylene chloride (50 ml) was added 4-chlorophenylsulfonyl chloride (0.79 g), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 3% hydrochloric acid and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave a residue, which was then crystallized from ethyl acetate--n-hexane to give 3-{4-[2-(4-chlorophenylsulfonylamino)ethylthio]phenyl}propionic acid (Compound No. 52) (1.07 g)