Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[CH3:46][O:47][C:48]([C:50]1[N:51]=[C:52]([NH2:55])[S:53][CH:54]=1)=[O:49]>C(Cl)Cl>[CH3:46][O:47][C:48]([C:50]1[N:51]=[C:52]([NH:55][C:35](=[O:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[S:53][CH:54]=1)=[O:49]
Reactant: COC(=O)c1csc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution triphenylphosphine (164 mg, 0.63 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (112 mg, 0.63 mmol) in small portions. The resulting orange reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in a Example 54A, 150 mg, 0.52 mmol). The reaction mixture was stirred at 0° C. for an additional 15 min and then allowed to warm to 25° C. The reaction mixture was then treated with 2-aminothiazole-4-carboxylic acid methyl ester (181 mg, 1.15 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) to afford impure (2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester. The impure product was diluted with ethyl acetate and then washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide pure (2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (92 mg, 41%) as a white solid: mp 143-144° C.; [α]23589=−10.2° (c=0.98, chloroform); EI-HRMS m/e calcd for C19H20Cl2N2O3S (M+) 426.0572, found 426.0562.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)=O>[CH:6]([C:5]1[CH:4]=[C:3]([CH3:11])[C:2]([O:1][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:10])[CH:8]=1)=[O:7]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(C)cc(C=O)cc1C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (500 mg, 3.33 mmol) in acetone (20 mL) was added cesium carbonate (1.41 g, 4.33 mmol), followed by ethyl bromoacetate (0.555 mL, 5 mmol). The mixture was refluxed in acetone under stirring for 1 hour. After evaporation of acetone under reduced pressure, 100 mL of water were added and the mixture was extracted with dichloromethane (200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 580 mg of an oil (74% yield). 1H NMR (250 MHz, CDCl3): δ 1.25 (t, J=6.9 Hz, 3H), 4.27 (s, 6H), 4.21 (q, J=6.9 Hz, 2H), 4.38 (s, 2H), 7.44 (s, 2H), 9.77 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 15.2, 17.4, 62.2, 70.1, 131.6, 132.8, 133.8, 161.7, 169.5, 192.1.
Reaction SMILES: O.NN.[CH2:4]([N:11]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1C(=O)C2=CC=CC=C2C1=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C(O)C.CCOCC>[CH2:4]([N:11]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccccc1OCCN(CCCCN1C(=O)c2ccccc2C1=O)Cc1ccccc1
Agent: Cl
Agent: NN
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: COc1ccccc1OCCN(CCCCN)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of hydrazine hydrate solution (0.83 ml, 0.017 mole) in ethanol (20 ml) is added to a solution of N-[4-{benzyl[2-(2-methoxyphenoxy)ethyl]amino}butyl]phthalimide (7.2 g, 0.016 mole) in ethanol (70 ml), the solution is stirred and heated to reflux for 3 hours. After cooling to ambient temperature, the solvent is evaporated at reduced pressure and the residual oil is treated with 1 N hydrochloric acid (40 ml). The precipitate formed is removed by filtration, washed in water, and the filtrate and the washing liquids are made basic with potassium carbonate (16 g). The separated oil is extracted with dichloromethane (3×80 ml) and the extracts dried over magnesium sulfate. Filtration and evaporation of the solvent at reduced pressure yields 4.4 g (86%) of the theoretical yield in the form of an oil. The treatment of an etherized solution of the free base with a saturated solution of hydrogen chloride gas in ether makes it possible to obtain N-benzyl-N-[2-(2-methoxyphenoxy)ethyl]-1,4-butanediamine as a dihydrochlorated salt; mp 200-202 degrees C. after recrystallization from ethanol.
Reaction SMILES: ClCC([C:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:38][C:39]([N:10]4[C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=5[CH2:13][CH2:14][C:15]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=5)=[O:40])[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: O=C(CCl)c1cccc2c1CCc1ccccc1N2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC#N
Solvent: CCO
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1c2ccccc2CCc2ccccc21

Procedure:
A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 24.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K2O3 (3.5 g, 40 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO2 ; eluted with dichloromethane (DCM) and 1-2% CH3OH in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample (1.5 g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 890 mg of white crystals, m.p. 182°-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH3:28])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of trans-methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-methylbenzoate (3 g, 6.81 mmol) in acetonitrile (40 mL), cesium carbonate (4.4 g, 13.62 mmol) and methyl iodide (4.83 g, 34.05 mmol) were added; the resulting reaction mixture was heated at 80° C. for 7 h. Upon completion, the reaction mixture was cooled to room temperature and filtered, the residue was washed with ethyl acetate and filtrate was concentrated to afford desired crude compound which then purified by column chromatography giving the desired compound (1.3 g, 43%).
Reaction SMILES: C([Mg]Br)#C.CON(C)[C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=O.[Cl-].[NH4+].[O:23]1CC[CH2:25][CH2:24]1>>[CH2:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]([C:8]#[C:25][CH:24]=[O:23])[CH2:19]1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)N1CCc2ccccc2C1
Agent: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: O=CC#CN1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
9.08 ml of a 0.5 molar solution of ethynylmagnesium bromide in tetrahydrofuran were added dropwise within 20 min. to a solution of 1 g of 3,4-dihydro-1H-isoquinoline-2-carboxylic acid methoxy-methyl-amide in 5 ml of tetrahydrofuran under argon at 0° C. The reaction mixture was stirred at 0° C. for 1 h. and at room temperature for 1 h. The orange solution was poured into 50 ml of a saturated ammonium chloride solution and extracted twice with 50 ml of ethyl acetate each time. The combined organic phases were washed twice with 50 ml of water each time, once with 50 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 0.48 g (57%) of 1-(3,4-dihydro-1H-isoquinolin-2-yl)-propynone was obtained as a yellowish oil. MS (EI): 185M30 .
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[C:7]1([CH:13]2[CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][N:21]3[C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH:1]1([C:4]([N:18]2[CH2:19][CH2:20][C:15]3([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]4[CH:13]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:14]3)[CH2:16][CH2:17]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc(C2OC3(CCNCC3)N3CCCCC23)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC2(CC1)OC(c1ccccc1)C1CCCCN12
Reaction time: 8 h

Procedure:
The hexahydro-1'-(cyclopropylcarbonyl)-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-pipridine] used as the starting material in the above procedure can be prepared by the following procedure. Cyclopropanecarboxylic acid chloride, 2 g, is added dropwise to a stirred solution of 4 g of hexahydro-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine] and 2.8 ml of triethylamine in 100 ml of methylene dichloride at 50° C. the reaction mixture is allowed to stand at room temperature overnight and then stirred with 75 ml of water. The organic layer is separated, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness. The residual oil is crystallized from 30 ml of cyclohexane to obtain 4.2 g of hexahydro-1'-(cyclopropylcarbonyl)-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 110°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=Cc1ccncc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccncc1)c1ccc(F)cc1
Temperature: 150 °C

Procedure:
A mixture of 4-fluorophenylacetic acid (9 g, 58.4 mmol), 4-pyridinecarboxaldehyde (5.6 ml, 58.6 mmol), pyridine (6 ml) and acetic anhydride (6 ml) was heated at 150° C. for 1 h followed by evaporation and co-distillation with water. The resulting material crystallized on addition of ethanol. The solids were filtered and washed with ethanol and ethyl acetate to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCO
Reactant: COc1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCOc1cccs1
Temperature: 25 °C

Procedure:
A mixture of 2-methoxythiophene (5.13 g, 44.93 mmol), n-C11H23OH (15.5 g, 89.87 mmol), toluene (50 mL), and p-toluenesulfonic acid monohydrate (0.85 g, 4.47 mmol) was heated to reflux under nitrogen for 19 hours. After cooling to room temperature, the reaction mixture was poured into water (150 mL), and the mixture was extracted with dichloromethane (DCM, 250 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to flash column on silica gel with hexane as eluent (slowly up to a hexane:DCM (8:2, v/v) mixture), leading to a colorless oil as the product (7.76 g, 67.9%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16].C(Cl)Cl.[C:22]([C@@H:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)#[N:23]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11]([Cl:13])([Cl:14])[Cl:12])=[O:8])[C@H:3]1[C:15]([O:17][C@H:24]([C:22]#[N:23])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:26]=1)=[O:16]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Yield: 76.3 %

Procedure:
6.2 g of dicyclohexycarbodiimide were added to a solution of 9.5 g of the product of Step C, 30 ml of methylene chloride and 3 ml of pyridine and the reaction mixture was stirred for half an hour. 6.8 g of (S)α-cyano-3-phenoxy-benzyl alcohol were added thereto and the mixture was stirred for an hour and half and filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral, dried, and evaporated to dryness. The 15.3 g of oil residue were chromatographed over silica gel and eluted with a 97-3 mixture of benzene-ethyl acetate to obtain 12 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonylethynyl)-cyclopropane-carboxylate melting at 101° C.
Reaction SMILES: [CH2:1]([N:3]([CH:10]=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]=[CH:10][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCN(C=O)c1ccccc1
Reactant: Nc1ccccn1
Product: CCN(C=Nc1ccccn1)c1ccccc1

Procedure:
Prepared following the procedure of Example 1 from N-ethylformanilide and 2-aminopyridine. Vacuum distillation of the crude product gave pure 4 as a pale yellow oil: bp 164° C. @ 0.5 mm Hg. 1H-NMR (CDCl3) 8.83 (S, 1H), 8.30 (m,1H), 7.5-6.9 (m, 8H), 4.09 (q, 2H, J=7 Hz) 1.26 (t, 3H, J=7 Hz); IR(neat) 2990, 1620, 1570, 1500, 1460, 1440, 1390, 1230, 1130; MS (m/e) 225 (M+), 78 (base).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=1.Br[C:26]#[C:27][CH3:28]>CN(C)P(=O)(N(C)C)N(C)C>[Cl:3][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:9](=[O:11])[N:10]([CH2:28][C:27]#[CH:26])[C:6]=2[CH:5]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Reactant: CC#CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C#CCn1c(=O)n(C2CCN(C(=O)OCC)CC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.9 parts of sodium hydride dispersion 75% in 100 parts of hexamethylphosphoric triamide are added portionwise 16.2 parts of ethyl 4-(5-chloro-2-oxo-1-benzimidazolinyl)-1-piperidinecarboxylate (exothermic reaction: temperature rises to 40° C). After stirring for one hour at room temperature, there are added dropwise 8.9 parts of 3-bromo-2-propyne (exothermic reaction: temperature rises to about 40° C). Upon completion, stirring is continued overnight at 60° C. The reaction mixture is cooled, poured onto ice-water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane. The solid product is filtered off and dried, yielding ethyl 4-[5-chloro-1,3-dihydro-2-oxo-3-(2-propynyl)-2H-benzimidazol-1-yl]-1-piperidine-carboxylate; mp. 126.1° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[F:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[O:4][C@@H:5]2[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Brc1ccccc1O[C@@H]1CCCNC1
Product: Nc1ncc(-c2ccc(-c3ccccc3O[C@@H]3CCCNC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (R)-3-(2-bromophenoxy)piperidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48-8.45 (m, 2H), 7.60-7.48 (m, 2H), 7.46-7.34 (m, 3H), 7.23 (d, J=8.0, 1H), 7.13-7.06 (m, 1H), 6.87 (s, 2H), 4.68-4.56 (m, 1H), 3.35-3.30 (m, 1H), 3.11-2.99 (m, 2H), 2.98-2.89 (m, 1H), 2.03-1.93 (m, 1H), 1.88-1.77 (m, 1H), 1.72-1.58 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([S:12][CH3:13])[C:3]=1[CH:14]([F:16])[F:15].[OH-].[Li+].O>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:12][CH3:13])[C:3]=1[CH:14]([F:16])[F:15]
Reactant: COC(=O)c1ccc(Cl)c(C(F)F)c1SC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1c(C(=O)O)ccc(Cl)c1C(F)F
Yield: 93 %

Procedure:
Methyl 4-chloro-3-difluoromethyl-2-methylsulphenylbenzoate (9.1 g) and lithium hydroxide (2.2 g) were dissolved in methanol and water and the mixture stirred overnight at room temperature. The mixture was then evaporated and the residue dissolved in water and washed with ethyl acetate. The aqueous layer was acidified to pH 1 with 2M HCl and extracted with ethyl acetate. The organic extract was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 4-chloro-3-difluoromethyl-2-methylsulphenylbenzoic acid (8.02 g) as a beige solid NMR (CDCl3) 2.5(s,3H), 7.5(d,1H), 7.65(t,1H), 7.8(d,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6].C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6]
Reactant: Cc1ccc(CO)cc1Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of 3-chloro-4-methylbenzyl alcohol (2.00 g) and triethylamine (8.9 ml) in a dimethyl sulfoxide (10 ml) was added sulfur trioxide-pyridine complex (4.47 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice water, and extracted with ether. The organic layer was washed with 1N hydrochloric acid, saturated brine and a saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate, and concentrated to dryness under reduced pressure to give the objective compound (1.40 g) as a pale-yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.C1(P(C2CCCCC2)C2(C)CC=CC=C2C2C=CC=CC=2)CCCCC1.O1CCCC1.Cl.C(=O)([O-])O.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:10][CH:11]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: OC1CCNCC1
Agent: [Pd]
Agent: CC1(P(C2CCCCC2)C2CCCCC2)CC=CC=C1c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 4-hydroxypiperidine (100 mg; 0.99 mmol), 4-bromo benzotrifluoride (0.167 mL, 1.19 mmol), tris(dibenzylideneacetone)dipalladium (37 mg; 0.04 mmol) and 2-(dicyclohexylphosphino)-2-methylbiphenyl (29 mg; 0.08 mmol) is thoroughly flushed with argon and tetrahydrofuran is added (1 mL). A molar solution of bis-(trimethylsilyl)-lithium amide in tetrahydrofuran (1.9 mL, 1.90 mmol) is added and the reaction mixture is heated at 65° C. After 17 hours reaction time, aq. 1M hydrochloric acid (7.5 mL) is added and the mixture is stirred for 15 minutes before neutralization by addition of aq. sat. sodium hydrogencarbonate. The mixture is extracted with ethyl acetate (2×10 mL). The combined organic layers are dried over sodium sulfate, filtered and evaporated under reduced pressure to yield crude 1-(4-trifluoromethyl-phenyl)-piperidin-4-ol.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)#[N:9].[CH3:19][C:20]1[C:21](=[O:49])[N:22]([C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[C:39]([C:45]([F:48])([F:47])[F:46])[CH:38]=2)[C:23](=[O:36])[C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O1CCCC1.C(OCC)(=O)C>[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]3[C:23](=[O:36])[N:22]([C:37]4[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[C:39]([C:45]([F:46])([F:47])[F:48])[CH:38]=4)[C:21](=[O:49])[C:20]=3[CH3:19])[CH2:31][CH2:32]2)=[O:15])=[CH:12][CH:11]=1)#[N:9]
Reactant: CC1=C(CCCCCN2CCNCC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(CCCCCN2CCN(C(=O)c3ccc(C#N)cc3)CC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.2 ml of a solution of triethylamine in tetrahydrofuran (1.5 mol/l) and 7 mg of 4-cyanobenzoyl chloride in 0.4 ml of tetrahydrofuran were added to a solution of 9 mg of 4-[2,5-dihydro-3-methyl-2,5-dioxo-4-[5-(piperazin-1-yl)-pentyl]-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile in 0.4 ml of tetrahydrofuran, and the mixture was stirred for 8 hours at room temperature. For working-up, the reaction mixture was diluted with ethyl acetate and washed with semi-saturated sodium bicarbonate solution. After the organic phase was concentrated by evaporation, it was chromatographed with methanol/dichloromethane on silica gel, and 7 mg of the title compound was thus obtained as a yellowish oil.