Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:22])[CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.Cl[CH2:31][C:32]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[O:34][N:33]=1>C(O)(C)(C)C>[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:22])[CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:31][C:32]4[CH:36]=[C:35]([C:37]5[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:41][CH:42]=5)[O:34][N:33]=4)[CH2:20][CH2:21]3)=[CH:8][C:6]=2[N:7]=1
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Cc1nc2cc(OCC(O)CN3CCN(Cc4cc(-c5ccc(C(F)(F)F)cc5)on4)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol hydrochloride (50 mg) in t-butanol at room temperature was added triethylamine (60 μl), and the mixture was stirred at room temperature for 5 minutes. To this mixture was added 3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]isoxazole (26 mg), and the mixture was stirred at 100° C. overnight. The solvent was removed under reduced pressure, and the residue was dissolved in 1 ml of methanol, and purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to afford 1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)piperazinyl]propan-2-ol, a compound of Formula I.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:5]2[CH2:4]1)[CH3:2].Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CO.C(OCC)C.C(OCC)(=O)C.O>[Br:20][C:18]1[CH:19]=[C:14]([NH:12][C:10]2[CH:11]=[C:5]3[CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7][N:6]3[N:9]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: CCN1CCn2nc(N)cc2C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 27.5 %

Procedure:
A sealed tube was equipped with a magnetic stirrer and charged with 285b (1.1 g, 6.4 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one 5 (1.7 g, 6.4 mmol) and cesium carbonate (4.6 g, 14 mmol) in 1,4-dioxane (64 mL). After bubbling nitrogen through the solution for 30 min, Xantphos (440 mg, 0.8 mmol) and tris(dibenzylideneacetone) dipalladium(0) (400 mg, 0.5 mmol) were added, and the reaction mixture was heated to 100° C. for 16 h. After this time, water (50 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. The resulting residue was purified by column chromatography eluting with a gradient of methylene chloride-60:35:5 methylene chloride:diethyl ether:methanol to afford a 28% yield (620 mg) of 285c.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH2:22]([N:24]([CH2:33][CH3:34])[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:33]([N:24]([CH2:22][CH3:23])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:19][CH2:20][CH3:21])=[CH:27][CH:26]=1)[CH3:34]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: CCN(CC)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)Cc1ccc(N(CC)CC)cc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 34 %

Procedure:
0.473 g (1.65 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 9.5 ml of ethanol, and 583 mg (3.29 mmol, 2.0 equivalents) of 4-diethylaminobenzaldehyde were charged in a 50 ml recovery flask under a nitrogen stream. The mixture was then cooled to 0° C. After the addition of 0.837 g (3.95 mmol, 2.4 equivalents) of sodium triacetoxyborohydride, the mixture was stirred at room temperature for 17 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 50 ml of a saturated sodium bicarbonate aqueous solution, and was extracted twice with 50 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH, chloroform:n-hexane=1:1), thereby obtaining 0.252 g of 4-{[(4-diethylaminobenzyl)-(4-dipropylaminobutyl)amino]methyl}benzonitrile (16) as a light yellow oily substance (yield: 34.1%). [HPLC: 98.7% (HPLC measurement conditions B)]
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([CH:14]=[N:15][N:16]=[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[NH:19][C:18]2=[O:27])[NH:10][C:9]=1[CH3:28])=[O:7].CO.[Li+].[OH-].Cl>O>[F:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:27])[C:17]2=[N:16][N:15]=[CH:14][C:11]1[NH:10][C:9]([CH3:28])=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:29])=[O:2])=[O:7])[C:12]=1[CH3:13]
Reactant: COC(=O)CNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.2 %

Procedure:
2-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-acetic acid methyl ester (399 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (128 mg, 33% yield) as a red solid. LC-MS (m/z) 386 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].[C:6]([O-:9])(=[O:8])[CH3:7].[Na+].O=O.C(=O)C.S([O-])([O-])=O.[Na+].[Na+]>O.O.O.[Ru](Cl)(Cl)Cl.C(O)(=O)C.C(OCC)(=O)C>[C:6]([O:9][CH:4]1[NH:1][C:2](=[O:5])[CH2:3]1)(=[O:8])[CH3:7]
Reactant: O=C1CCN1
Reactant: CC(=O)[O-]
Agent: Cl[Ru](Cl)Cl
Agent: CC=O
Agent: O=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC1CC(=O)N1
Temperature: 40 °C
Reaction time: 3 h
Yield: 352 %

Procedure:
In a Schlenk's tube were charged 710 mg (10 mmole) of azetidin-2-one, 205 mg (2.5 mmole) of anhydrous sodium acetate, and 130 mg (0.5 mmole, 5 mole%) of ruthenium chloride trihydrate. After thoroughly displacing the atmosphere with oxygen, a balloon filled with oxygen was fitted to the reactor. To the mixture were added 100 ml of ethyl acetate and 5 ml of acetic acid, followed by heating at 40° C. for 30 minutes with stirring. To the reaction mixture was added 1.1 ml (20 mmole) of acetaldehyde all at once while stirring at 40° C., and the reaction was continued for an additional 3 hours. The reaction mixture was poured into 400 ml of a 10% sodium sulfite aqueous solution and extracted twice with 500 ml portions of ethyl acetate. The extract was washed with 200 ml of a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using a 3:1 (by volume) mixed solvent of n-hexane and ethyl acetate to obtain 1.14 g (8.8 mmole, percent yield: 88%) of 4-acetoxyazetidin-2-one as an oily substance.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[C:2]=[O:3].[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1>C(Cl)Cl>[C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][NH:1][C:2]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[N:15]2)=[O:3])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C=NCCCCc1ccccc1
Reactant: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Product: O=C(NCCCCc1ccccc1)n1nnc2ccccc21
Temperature: 22.5 °C
Reaction time: 8 h

Procedure:
(4-Isocyanatobutyl)benzene (463 mg, 2.64 mmol) was added dropwise to a stirred solution of 1H-benzo[d][1,2,3]triazole (300 mg, 2.52 mmol) in DCM (18 ml) at 0-5° C. The clear reaction mixture was allowed to stir at 20-25° C. overnight. The solvent was removed in vacuum to give a clear oil. The oil solidified on standing into a colourless solid. The product was recrystallised from 2-propanol, the solid was collected, dried in vacuum at 45° C. Yield 477 mg (64%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[C:10](F)[N:9]=1>C(OC)(C)(C)C>[NH2:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[C:10]([O:6][CH2:3][C:4]#[CH:5])[N:9]=1
Reactant: C#CCO
Reactant: Nc1nc(F)c(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: C#CCOc1nc(N)c(Cl)cc1C(F)(F)F

Procedure:
3.9 g (0.153 mol) of sodium hydride were introduced, under nitrogen, into 250 ml of methyl tert-butyl ether, with stirring, and 20 ml of propargyl alcohol were then added dropwise with stirring at 25°-30° C. over 20 minutes. After the mixture had been stirred for 30 minutes at 25° C., 32.9 g (0.153 mol) of 2-amino-3-chloro-6-fluoro-5-trifluoromethylpyridine in 100 ml of methyl tert-butyl ether were added in the course of 10 minutes and the mixture was stirred for 14 hours at 25° C. The reaction mixture was extracted with water, dried and concentrated, giving 37.8 g (99% of theory) of the title compound as a colorless oil of ηD24 =1.5217 (Table I, No. 1.035).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:19][SH:20].O>CN(C)C=O>[F:11][C:6]1[C:3]2[CH:4]=[C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])[S:20][C:2]=2[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(F)cc(F)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
To a suspension of 2,4,6-trifluorobenzaldehyde (5.00 g, 31.2 mmol) and potassium carbonate (5.61 g, 40.6 mmol) in N,N-dimethylformamide (63 mL) was added ethyl thioglycolate (3.40 g, 28.3 mmol) at 0° C. The mixture was stirred at room temperature overnight, and then heated to stir at 60° C. for 6 hours. The mixture was cooled to room temperature, and then to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→93:7) to give ethyl 4,6-difluoro-1-benzothiophene-2-carboxylate (1.95 g, 29%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10]C)=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:38]=[CH:37][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:39][CH3:40])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:33]1[CH:34]=[CH:35][CH:36]=[C:32]1[C:28]1[O:29][C:30]([CH3:31])=[C:26]([CH2:25][O:24][C:23]2[CH:37]=[CH:38][C:20]([CH2:19][O:1][C:2]3[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][N:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:3]=3)=[CH:21][C:22]=2[O:39][CH3:40])[N:27]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (406 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. A mixture of the obtained colorless crystals, 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and methanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetic acid (748 mg, yield 88%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 179–180° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][CH:8]=1)(=O)=O.[N:23]1[CH:28]=[CH:27][C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:25][CH:24]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C(C)=CC=CC=1>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][CH:8]=[C:7]([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Oc1ccc(Br)c(Cc2ccccc2)n1)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Brc1ccc(-c2ccncc2)nc1Cc1ccccc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A mixture of 298 mg of 2-benzyl-3-bromo-6-pyridyl trifluoromethanesulfonate, 277 mg of (4-pyridyl)tributyltin, 87 mg of tetrakis(triphenylphosphine)palladium(0), 209 mg of tetrabutylammonium chloride and 5.0 ml of xylene was heated under stirring in an oil bath kept at 140° C. for one hour in a nitrogen atmosphere. After cooling as it was, the solvent was removed, and the residue was subjected to NH-silica gel column chromatography and eluted with hexane/ethyl acetate (5:1) and then with hexane/ethyl acetate (3:1), to give 196 mg of the target compound.
Reaction SMILES: Cl.C([N:5]1[C@H:10]([CH3:11])[CH2:9][N:8]([C@H:12]([C:20]2[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=2)[C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[C@@H:7]([CH3:33])[CH2:6]1)C=C.O>[Pd].CO>[CH3:33][C@H:7]1[CH2:6][NH:5][C@H:10]([CH3:11])[CH2:9][N:8]1[C@H:12]([C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=1)[C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CC)CC)c2)C[C@H]1C
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)c1cccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)c1
Yield: 74.7 %

Procedure:
A mixture of (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide monohydrochloride (8.22 g, 17.1 mmol. Example 1) and 5.45 g (2.5 mmol) of 5% palladium on charcoal in 160 ml of methanol:water/3:1 was heated at reflux for 20 hours. The reaction mixture was filtered through Celite under nitrogen and the filtrate was evaporated. The residue was diluted with water and the pH was adjusted to 8 with aqueous 1M sodium hydroxide. The mixture was extracted with ethyl acetate, dried over sodium sulfate, and evaporated to give 5.05 g (75%) of (+)-3-((αR)-α-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide as a light yellow solid. NMR (DMSO-d6, 200 MHz): δ1.1 (m, 12H); 2.0 (m, 1H); 2.6-2.9 (m, 3H); 3.0-3.5 (m, 7H); 5.25 (s, 1H); 6.7 (m, 3H); 7.2 (m, 3H); 7.4 (m, 2H); 9.5 (s, 1H). [α]D20 =+11.9° (abs ethanol, c=2.3). Titration of 0.20 g of product with ethanolic hydrogen chloride in ethanol solution to pH 3.5 and precipitation from dichloromethane with diethyl ether gave 0.103 g (47% recovery) of the monohydrochloride salt as an off-white solid. Calc. for C24H33N3O2HCl 0.75 H2O: C, 64.70; H, 8.03; N, 9.43; Cl, 7.96. Found: C, 64.97; H, 7.97; N, 9.38; Cl, 8.04. Mass spectrum (CI--CH4) m/e 396 (M+1, 38%); 282 (39%); 115 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[CH:14][N:15]([CH3:18])[N:16]=2)[CH:12]=[CH:11][CH:10]=1.[Br:19]Br>C(O)(=O)C>[Br:19][C:14]1[N:15]([CH3:18])[N:16]=[C:17]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: BrBr
Reactant: Cn1cc2cccc(-c3ccc(Cl)cc3Cl)c2n1
Solvent: CC(=O)O
Product: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1Br

Procedure:
To a solution of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole (0.659 g, 2.38 mmol) in 2 mL of acetic acid was added bromine (0.122 mL, 2.38 mmol) dropwise. The yellow-orange solution was stirred for 15 m, in which time an orange solid precipitated. The mixture was concentrated to a yellow solid, which was partitioned between 20 mL of a 10% aqueous NaOH solution and 20 mL of diethyl ether. The organic layer was washed with 20 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to a yellow-stained white solid. Column chromatography (0→10% EtOAc/hexanes) afforded 3-bromo-7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole as a white solid (24: Ar=2,4-dichlorophenyl; 0.525 g; 62%; m.p. 137-139).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:8][N:7]1[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=[C:3]1[CH2:2][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[N:7]([CH3:8])[C:6]3[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=3[N:4]=2)[CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: COc1cc2c(nc(CCl)n2C)c(OC)c1OC
Product: COc1cc2c(nc(CN3CCN(Cc4nc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
2-Chloromethyl-1-methyl-4,5,6-trimethoxybenzimidazole (75 mg) and piperazine (10 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@:5]1([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C:16]([O:18][CH3:19])=[O:17])[CH:2]=[CH2:3].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH2:1]([C@H:4]1[CH2:8][NH:7][CH2:6][C@@:5]1([NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])[C:16]([O:18][CH3:19])=[O:17])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@@]1(NC(=O)C(F)(F)F)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@H]1CNC[C@@]1(NC(=O)C(F)(F)F)C(=O)OC
Reaction time: 2 h

Procedure:
While under nitrogen, a solution of racemic 1-tert-butyl 3-methyl (3R,4S)-4-allyl-3-[(trifluoroacetyl)amino]pyrrolidine-1,3-dicarboxylate (Step 3, 0.207 g, 0.544 mmol) in methylene chloride (11 mL) was treated with trifluoroacetic acid (838 uL, 10.9 mmol). After stirring for 2 h, the mixture was concentrated and dried under high vacuum overnight to give methyl (3R,4S)-4-allyl-3-[(trifluoroacetyl)amino]pyrrolidine-3-carboxylate trifluoroacetate as a faint yellow foam that was used without further purification. A stirred solution of this intermediate in dry methylene chloride (11 mL) under nitrogen was treated with Et3N (0.341 mL, 2.45 mmol) followed by 4-fluorobenzoyl chloride (0.0979 mL, 0.816 mmol). After stirring at room temperature for 1.5 h, the solution was diluted with methylene chloride (15 mL), washed successively with water (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated aqueous sodium chloride (5 mL). The resulting organic phase was dried over Na2SO4 and concentrated, and purification by radial chromatography (2000 micron silica gel rotor, 40-75% ethyl acetate in hexanes) to give methyl (3R,4S)-4-allyl-1-(4-fluorobenzoyl)-3-[(trifluoroacetyl)amino]-pyrrolidine-3-carboxylate (racemic) (220 mg, 100%) as a faint yellow film. Rf=0.33 (50% Ethyl acetate in hexanes). For intermediate pyrrolidine trifluoroacetate, LC-MS ESI+ MS found for C11H15F3N2O3 m/z 281.1 (M+H). For amide product, LC-MS ESI− MS found for C18H18F4N2O4 m/z 401.1 (M−H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[N+](C1C=CC([O:18][C:19](=O)[N:20]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH:28]([CH3:30])[CH3:29])[N:22]=2)=CC=1)([O-])=O>C(Cl)Cl>[F:37][C:34]1[CH:33]=[CH:32][C:31]([N:20]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH:28]([CH3:30])[CH3:29])[N:22]=2)[C:19]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[O:18])=[CH:36][CH:35]=1
Reactant: NCc1ccncc1
Reactant: CC(C)Nc1nccc(N(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(F)cc2)n1
Solvent: ClCCl
Product: CC(C)Nc1nccc(N(C(=O)NCc2ccncc2)c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Aminomethyl)pyridine (100 μL, 0.974 mmol) is added dropwise to a solution of (4-fluorophenyl)-(2-isopropylamino-pyrimidin-4-yl)-carbamic acid 4-nitro-phenyl ester, 5, (334 mg, 0.812 mmol) in methylene chloride (8 mL) at room temperature. The orange solution is stirred at ambient temperature overnight. The reaction mixture is diluted with methylene chloride (50 mL) and washed with a 0.5 N aqueous solution of sodium hydroxide (2×50 mL) and water (50 mL), dried over sodium sulfate, filtered and concentrated to a yellow oil which is purified over silica (20% Et2O/CH2Cl2 to 100% EtOAc) to afford the desired product as a white solid: 1H NMR (300 MHz, CDCl3) δ 10.76 (br s, 1H), 8.61 (d, J=6.0 Hz, 2H), 7.93 (d, J=5.7 Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.29-7.16 (m, 4H), 5.43 (d, J=5.9 Hz, 1H), 5.02 (br s, 1H), 4.60 (d, J=5.5 Hz, 2H), 4.15 (br s, 1H), 1.15 (d, J=6.4 Hz, 6H); MS (ESI) m/z 381 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH:9]1[CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:37]([CH3:36])(=[O:39])=[O:38])[CH:9]1[CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1CCNC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution containing 112 (1.68 g, 4.60 mmol) and DIPEA (0.71 g, 5.53 mmol) in DCM (20 mL) was cooled to 0° C. MsCl (0.52 g, 4.60 mmol) was added. After 1 h, the reaction mixture was diluted with EtOAc and washed successively with dilute aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 to 1:3 hexanes/EtOAc) to afford 2.6 g (quant.) of 113.