Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]([C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1)=[O:37].C1C=CC2N(O)N=NC=2C=1.N=C=N.C(=O)([O-])[O-].[N-]=C=O>CN(C=O)C>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:42]([C:41]2[CH:45]=[CH:46][C:38]([C:36]([O:35][CH3:34])=[O:37])=[CH:39][CH:40]=2)=[O:43])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)cc1
Reaction time: 8 h

Procedure:
To a mixture of 13.3 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate, 6.3 mg of 4-methoxycarbonyl benzoic acid, 4.7 mg of HOBt, and 1 mL of DMF was added 100 mg of PS-Carbodiimide (Argonaut Technologies, USA) at room temperature, followed by stirring overnight. To the reaction mixture was added 50 mg of MP-Carbonate (Argonaut Technologies, USA), 50 mg of PS-Isocyanate (Argonaut Technologies, USA), and 0.5 mL of DMF at room temperature, followed by stirring for 4 hours, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain methyl 4-{[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}benzoate as a crude product. To a solution of the obtained crude product in 0.5 mL of 1,4-dioxane solution was added 0.5 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure to obtain methyl 4-{[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}benzoate as a crude product. To a solution of the obtained crude product in 0.5 mL of THF were added 0.5 mL of methanol and 0.5 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. To the reaction mixture was added 0.5 mL of 1 M hydrochloric acid, followed by concentration under reduced pressure. The obtained residue was purified by separation using preparative high performance liquid chromatography (column: registered trademark SunFire, Waters, particle diameter of 5 μm, inner diameter of 19 mm, and length of 100 mm), flow rate: 25 ml/min., column temperature: 20° C., methanol—a 0.1% aqueous formic acid solution) to obtain 8.4 mg of 4-{[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}benzoic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(-c2cccc(F)c2)ccc(F)c1CNc1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2C)c1F
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a solution of 2,4-difluoro-3-[[6-fluoro-3-(3-fluorophenyl)-2-methyl-phenyl]methylamino]phenol (230 mg, 0.63 mmol, 1.0 eq) in DMF (4 mL) was added Cs2CO3 (420 mg, 1.2 mmol, 2 eq). The reaction was stirred for 10 min, then ethyl bromoacetate (130 mg, 0.76 mmol, 1.2 eq) was added. The reaction mixture was stirred for a further 30 min, then water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 25:1) to give title compound as a colourless oil (240 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[C@H:9]2C(OC)=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.ClC1C=CC([C@@H]2CNC(=O)[C@H]2C(O)=O)=CC=1>C1(C)C(C)=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C(=O)NC[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(O)[C@@H]1C(=O)NC[C@H]1c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: O=C1C[C@H](c2ccc(Cl)cc2)CN1
Temperature: 135 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Under a nitrogen atmosphere, to methanol (220 ml) was added methyl (3S,4R)-4-(4-chlorophenyl)-2-oxopyrrolidine-3-carboxylate (28.0 g, 110 mmol), and 2 mol/L sodium hydroxide aqueous solution (66 ml) was dropped over a period of 1 hour. After completion of dropping, the mixture was further stirred for 1 hour, and neutralized with 2 mol/L hydrochloric acid (71 ml), and methanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate (150 ml×2), to obtain an ethyl acetate solution containing (3S,4R)-4-(4-chlorophenyl)-2-oxopyrrolidine-3-carboxylic acid. This solution was dropped over a period of 4 hours into xylene (150 ml) heated at 130 to 140° C. while distilling off ethyl acetate. After completion of the reaction, xylene (100 ml) was added, and the mixture was filtrated and concentrated under reduced pressure. Crystallization from xylene/heptanes was performed to obtain 19.3 g (98.6 mmol) of a title compound. Yield: 90%. The spectrum data corresponded to the value in non-patent document 1. The optical purity of the resultant title compound was measured by HPLC to find a value of 99% ee.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.O.NN.[OH-].[K+]>COCCOCCOC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(CCC(F)(F)F)c1cccc(Br)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: FC(F)(F)CCCc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of 1-(3-bromo-phenyl)-4,4,4-trifluoro-butan-1-one (3.1 g, 11 mmol) and diglyme was treated with hydrazine mono hydrate (5.5 g, 110.3 mmol), and stirred at 100° C. for 2 hours then treated with powder KOH (3.1 g, 55.1 mmol). The stirring continued at 150° C. for 6 hours. The mixture was cooled to room temperature, poured into a mixture of ice/water and extracted with ethyl ether. The extracts were combined, dried over MgSO4 and concentrated in vacuo. The crude product was purified on silica gel (ISCO) using hexanes as the eluting solvent to give 1-Bromo-3-(4,4,4-trifluoro-butyl)-benzene as a colorless oil (2.4 g, 88% yield). m/e (M)+ 266; 1H NMR (400 MHz, DMSO-d6) δ ppm, 1.7-1.8 (m, 2H), 2.1-2.2 (m, 2H), 2.6 (t, J=7.6 Hz, 2H), 7.2-7.25 (m, 2H), 7.3-7.35 (m, 1H), 7.4 (s, 1H)
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[O:11]C(C(C)C)=[N:9][C@H:8]2[CH2:15][CH2:16][CH3:17])=[O:6])[CH2:3][CH2:2]1.[ClH:18]>CC(C)=O>[ClH:18].[CH:1]1([NH:4][C:5](=[O:6])[C@@H:7]([OH:11])[C@@H:8]([NH2:9])[CH2:15][CH2:16][CH3:17])[CH2:3][CH2:2]1
Reactant: CCC[C@@H]1N=C(C(C)C)O[C@@H]1C(=O)NC1CC1
Agent: Cl
Solvent: CC(C)=O
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Temperature: 50 °C
Reaction time: 39 h
Yield: 70.2 %

Procedure:
(4S,5S)—N-Cyclopropyl-2-isopropyl-4-propyl-4,5-dihydro-1,3-oxazole-5-carboxamide (3.11 g, 8.7 mmol), acetone (15 ml) and concentrated hydrochloric acid (1.39 g, 1.5 equivalents) were mixed, and the mixture was stirred at 50° C. for 39 hours. The solvent was evaporated away under reduced pressure. Isopropanol (10 ml) was added, and the mixture was concentrated. The same operation was repeated again. Methanol (2.7 ml) was added to the obtained solid, and the mixture was stirred at 60° C. for 1 hour. Ethyl acetate (20 ml) was gradually added thereto dropwise. After the addition, the mixture was gradually cooled to 5° C. The precipitated crystal was collected by filtration, and dried under reduced pressure to obtain the title compound as a white crystal (1.36 g, yield: 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@@H:8]3[O:17][C@@H:7]3[C:6]=2[CH:18]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][C:28]2[N:29]=[N:30][N:31]([CH3:33])[N:32]=2)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH3:16])([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C@H:8]([OH:17])[C@@H:7]([N:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH2:27][C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)[C:6]=2[CH:18]=1
Reactant: Cn1nnc(CNc2ccc(F)cc2)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc(Br)cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc(Br)cc2[C@H](N(Cc2nnn(C)n2)c2ccc(F)cc2)[C@H]1O
Yield: 47.9 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2S,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (209 mg, 0.66 mmol) and N-(4-fluorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (138 mg, 0.66 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=6:1), to give desired compound (165 mg, yield: 51%).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([OH:11])[CH:5]=1.[CH:13]1([CH:19]=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C>CO>[CH:13]1([C:19]2[O:11][C:6]3[CH:5]=[C:4]([C:3]([OH:2])=[O:12])[CH:9]=[CH:8][C:7]=3[N:10]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=CC1CCCCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CO
Product: O=C(O)c1ccc2nc(C3CCCCC3)oc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-amino-3-hydroxy-benzoic acid methyl ester (5 g, 29.91 mmol) in CH3OH (150 mL) was added cyclohexanecarbaldehyde (3.6 mL, 29.91 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed by evaporation and CH3CN (150 mL) was added to the residue. Lead (IV) acetate (13.26 g, 29.91 mmol) was added as one portion under N2 and the resulting mixture was refluxed for 10 min. After cooling, the resulting solid was filtered and washed with CH3CN. To the filtrate was then added 3N NaOH (40 mL). The resulting mixture was stirred at 50° C. for 18 h. The solvent was removed by evaporation and the resulting residue was purified by flash chromatography on silica gel to yield 2-cyclohexyl-benzooxazole-6-carboxylic acid. MS m/z (M+H+) 246.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:20].CCOCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][Br:20])=[CH:4][CH:3]=1
Reactant: OCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(C(CCBr)c2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
50.1 g (0.202 mol) of 3,3-bis(4-fluorophenyl)propanol were dissolved in 150 ml of toluene, and a solution of 21.8 g (0.081 mol) of PBr3 in 50 ml of toluene was added dropwise. The mixture was stirred at room temperature for 30 minutes and at 60° C. for 90 minutes and, for hydrolysis, was poured onto 400 ml of ice, 200 ml of ether were added, the organic phase was separated off, washed with NaHCO3 solution and NaCl solution, dried and concentrated and the residue was distilled in vacuo for purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][C:13]([NH2:15])=O)[N:11]=2)=[CH:3][CH:2]=1.[Cl-]>N1C=CC=CC=1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][C:13]#[N:15])[N:11]=2)=[CH:5][CH:6]=1
Reactant: NC(=O)Cc1csc(-c2ccncc2)n1
Agent: [Cl-]
Solvent: c1ccncc1
Product: N#CCc1csc(-c2ccncc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 2-[2-(4-pyridyl)thiazol-4-yl]acetamide (2.19 g., 0.01 mole) in pyridine (30 ml.) is added gradually p-toluenesulfuryl chloride (1.91 g., 0.01 mole). After stirring for one hour the mixture is poured into excess ice-water to give the title compound.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]3([CH2:42][OH:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[NH:13]2)=[O:11])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]2([CH2:42][OH:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)[NH:13]1)=[O:11]
Reactant: CC1(C)OC[C@H](CCNC(=O)C2NC(CC3(CO)CCCCC3)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)O1
Agent: Cl
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2(CO)CCCCC2)NC(C(=O)NCC[C@H](O)CO)C1c1cccc(Cl)c1F
Yield: 94.2 %

Procedure:
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 118a (0.27 g, 0.4 mmol) was reacted with aqueous HCl solution (1 N, 1 mL, 1 mol) in tetrahydrofuran (9 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.23 g, 91%).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B.[OH-:29].[Na+].OO>O1CCCC1.O>[CH2:1]([O:17][CH2:18][CH:19]([O:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCCCCC(COCCCCCCCCCCCCCCCC)OC
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(CCCCCCO)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8-(hexadecyloxy)-7-methoxy-1-octene in 100 ml of tetrahydrofuran was added a solution of 112.3 ml of 1.0M borane in tetrahydrofuran at 0° C. over a 1 hour period. The mixture was stirred on addition 3 hours at 25° C. The solution was recooled to 0° C. and a solution of 187.3 ml of 3M sodium hydroxide was slowly added followed by 216 ml of 30% hydrogen peroxide. After 30 minutes, the mixture was poured into water and extracted with ether. The ether solution was dried and evaporated. The residue was purified by chromatography giving 20 g of the title compound as a solid.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][CH:17]([F:20])[CH2:18]O.C(N(CC)CC)C>ClCCl>[F:16][CH:17]([F:20])[CH2:18][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:11])=[O:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCC(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 74.6 %

Procedure:
In a flask under argon was placed triflic anhydride (10.22 mL, 61 mmol) and dichloromethane (10 mL) and it was cooled to −70° C. To this cooled mixture was added slowly a solution of 2,2-difluoroethanol (5.00 g, 61 mmol) and triethylamine (8.5 mL, 61 mmol) in dichloromethane (10 mL). After the addition was complete, the mixture was warmed to 25° C. and then concentrated in vacuo. This material was distilled at 60° C. and 50 mm Hg which afforded trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (9.74 g, 75%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[CH3:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1.C(OC(=O)C)C>[CH3:32][C:4]1[CH:5]=[C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(C)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a stirred solution of 2-(4-(aminomethyl)-3-methylphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (83 mg, 0.19 mmol) in pyridine was added methanesulfonyl chloride (0.02 mL, 0.24 mmol) The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with ethylacetate and washed with 1N HCl and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-Methyl-4-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 97) (60 mg) was obtained as 61% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2].[I-:24].[Na+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:24])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc2cnccc2c1Nc1ccc(Br)cc1F
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc2cnccc2c1Nc1ccc(I)cc1F
Temperature: 105 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
A mixture of 3-(4-bromo-2-fluoro-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester (288 mg, 0.73 mmol), copper (1) iodide (7 mg, 0.036 mmol), sodium iodide (219 mg, 1.46 mmol) and trans-N,N′-dimethyl-1,2-cyclohexane diamine (10.4 mg, 0.073 mmol) in 1,4-dioxane (1.0 ml) was heated at 105° C. for 24 hours under an argon atmosphere. Copper (I) iodide (7 mg, 0.036 mmol) and trans-N,N′-dimethyl-1,2-cyclohexane diamine (10.4 mg, 0.073 mmol) were added and heating continued for a further 24 hours. The reaction was cooled to room temperature and the mixture was partitioned between DCM (30 ml), concentrated aqueous ammonia (2 ml) and water (13 ml). The organic layer was isolated, dried over sodium sulphate, filtered and evaporated then the residue was purified by flash chromatography (Si-SPE, DCM) to afford the title compound as a yellow solid (275 mg, 85%). LCMS (method B): RT=4.23 min, M+H+=443.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].Br[CH2:22][CH2:23][OH:24].O>CN(C)C=O.C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:22][CH2:23][OH:24])=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: OCCBr
Reactant: CN(C)c1ccc(C(=O)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C(=O)c2ccc(OCCO)cc2)cc1
Temperature: 105 °C

Procedure:
A solution of 12.0 g of 1-[4-(dimethylamino)phenyl]-1-[4-hydroxyphenyl)-methanone and 2.2 g sodium hydroxide in 120 ml dimethylformamide was heated at 90° C. until all the sodium hydroxide had dissolved. 6.9 g 2-bromoethanol was added and the reaction heated at about 105° C. for 24 hours. The reaction mixture was poured into water and the product isolated by extraction with methylene chloride to yield 7.7 g, m.p. 142°-143° C., λmax (chloroform) 348 nm (ε=26,400), 271 nm (ε=12,500), 255 nm (ε=11,900 nm).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.N1C=CC=CC=1.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18].O>C(#N)C>[C:15]([N:2]1[C:3](=[O:8])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)Cl
Reactant: O=C1NC2C=CC1C2
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCC(=O)N1C(=O)C2C=CC1C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
100.3 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in acetonitrile (720 ml) and pyridine (142 ml) under nitrogen. At 12° C., 141.8 g of butyryl chloride were added dropwise over the course of 1 hour. The reaction was then stirred at room temperature for 3 hours. 720 ml of water were added to the mixture. The acetonitrile was evaporated off in vacuo, and the aqueous phase was extracted 3 times with ethyl acetate (300 ml). The combined org. phases were washed with 1N HCl (350 ml), saturated NaCl (400 ml) and water (500 ml), dried with magnesium sulphate and completely evaporated. The product was purified by distillation. 107.76 g of product were obtained as a clear liquid. The yield was 85%.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[OH:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1>>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[O:15][CH:16]1[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19]1
Reactant: Clc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(Oc2cnccn2)C1

Procedure:
Compound P22 was prepared according to the general procedure described for the synthesis of P21 in Preparation 21, using 2-chloropyrazine in place of 2-bromopyridine, to afford P22. LCMS (ESI) m/z 252.4 (M÷1). 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 3.97 (m, 2H), 4.32 (m, 2H), 5.30 (m, 1H), 8.03 (dd, J=2.5, 1.2 Hz, 1H), 8.16 (d, J=2.5 Hz, 1H), 8.26 (d, Hz, 1H). Compound P22 was deprotected with trifluoroacetic acid as described for tert-butyl 3-hydroxyazetidine-1-carboxylate in the preparation of C19 in Example 3, before being used in the coupling step.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:37]>CC(=O)CC.C(O)C.C(OCC)(=O)C.O>[ClH:37].[OH:13][C:7]1([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)[CH2:8][CH2:9][N:10]([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=2)[CH2:11][CH2:12]1
Reactant: CS(=O)(=O)Nc1ccc(OCCBr)cc1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(CC2(O)CCN(CCOc3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Yield: 41 %

Procedure:
A mixture of 4-(4-methyl-benzyl)-piperidin-4-ol (0.35 g, 1.7 mmol), N-[4-(2-bromethoxy)-phenyl]-methansulfonamide (0.5 g, 1.7 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in 2-butanone (20 ml) was refluxed overnight. It was cooled to room temperature, 30 ml of H2O were added and the organic phase was separated. The water phase was extracted two times with ethyl acetate. The organic phases were then pooled, dried with Na2SO4 and the solvent evaporated. The residue was chromatographed over silica gel (CH2Cl2 --MeOH, 95:5) to give a yellowish foam which was dissolved in ethanol (5 ml) and ethyl acetate (10 ml). 1.1 Equivalent of ethanolic HCl were added to give N-(4-{2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethoxy}-phenyl)-methanesulfonamide hydrochloride (0.32 g, 41%) as colorless solid, m.p. >75°-78° C. dec. and MS: m/e=419.5 (M+H+).