Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][CH:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].C1(OC)C=CC=CC=1>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[N:1]1([C:10]2[N:18]=[C:17]([N:19]3[CH2:20][CH2:21][CH:22]([NH2:25])[CH2:23][CH2:24]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)CC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
100 mg of product obtained in Example 22 are mixed with 3 ml of methylene chloride and 1.5 ml of trifluoroacetic acid containing 10% of anisole. The mixture is stirred at ambient temperature for 5 hours. It is concentrated to dryness and co-evaporation with toluene and then with methylene chloride is carried out. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. 128 mg of expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[S:19](Cl)(=[O:21])=[O:20])[CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:19]([C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:9]=[CH:10][CH:11]=[CH:12]2)(=[O:20])=[O:21]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccc3cccnc23)c1Br
Yield: 62 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-8-quinolinesulfonamide was prepared, in the same manner as described in Example 96, from 5-amino-4-bromo-3-methylisoxazole and 8-quinolinesulfonyl chloride in 62% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 169°-171° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:14])[CH:12]=[CH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:14])[CH2:12][CH2:13][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Oc1ccccc1I
Reactant: C=CC(O)c1ccc(OC)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CCc2ccccc2O)cc1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
To a solution of 1-(3,4-dimethoxy-phenyl)-prop-2-en-1-ol (236 mg, 1.22 mmol) in THF (2 mL) was added under a nitrogen atmosphere 2-iodophenol (267 mg, 1.22 mmol), cesium carbonate (158 mg, 0.47 mmol) and palladium(II) acetate (8 mg, 0.04 mmol). The reaction mixture was stirred for 4 h at 80° C. After cooling to ambient temperature it was diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=90:10 to 60:40) afforded the title compound (155 mg, 45%) as a colourless oil. MS m/e: 285.0 [M−H]
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@@H:11]([C:12](OC)=[O:13])[C@H:10]([C:16](OC)=[O:17])[CH2:9][CH2:8][O:7][C:6]=2[CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@@H:11]([CH2:12][OH:13])[C@H:10]([CH2:16][OH:17])[CH2:9][CH2:8][O:7][C:6]=2[CH:20]=1
Reactant: COC(=O)[C@@H]1c2ccc(F)cc2OCC[C@H]1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H]1CCOc2cc(F)ccc2[C@H]1CO
Temperature: 25 °C

Procedure:
A solution of the product from Example 107D (695 mg, 2.46 mmol) in 10 mL of tetrahydrofuran was chilled to −70° C. under nitrogen and treated dropwise with lithium aluminum hydride (5.0 mL of a 1.0 M solution in tetrahydrofuran). After the addition was completed the reaction was allowed to warm to room temperature over 3 hours and then quenched with 5 mL of ethyl acetate followed by 15 mL of 2 N aqueous hydrochloric acid solution. The layers were separated and the aqueous portion was extracted with 4×10 mL of ethyl acetate and the combined organic extracts were dried over sodium sulfate. The organic solution was concentrated and the residue was purified via flash chromatography on a silica gel column (100%) ethyl acetate to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.71 (dd, J=12.89, 2.03 Hz, 1H) 2.01-2.15 (m, 2H) 2.86 (td, J=7.71, 3.90 Hz, 1H) 3.16-3.29 (m, 2H) 3.52 (ddd J=10.51, 7.12, 5.43 Hz, 1H) 3.66-3.78 (m, 2H) 4.12 (dt, J=12.12, 4.11 Hz, 1H) 4.48 (t, J=5.09 Hz, 1H) 4.59 (t, J=5.43 Hz, 1H) 6.71 (dd, J=10.17, 2.71 Hz, 1H) 6.81 (td, J=8.31, 2.71 Hz, 1H) 7.12 (dd, J=8.48, 6.78 Hz, 1H); MS (DCI+) m/z 226.1 [M+NH4]+.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[S:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][C:35](O)=O)=[CH:33][C:28]=2[CH:27]=[CH:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1.CO.C(OCC)(=O)C.C(Cl)Cl>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:35][CH2:34][C:32]2[CH:31]=[CH:30][C:29]3[S:25][CH:26]=[CH:27][C:28]=3[CH:33]=2)[CH2:4][CH2:3]1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: O=C(O)Cc1ccc2sccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OC1(c2cccc(C(F)(F)F)c2)CCN(CCc2ccc3sccc3c2)CC1
Temperature: 0 °C
Yield: 37 %

Procedure:
A mixture of 1.47 g (0.006 mol) of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 30 ml of methylene chloride, 2.25 ml (0.0162 mol) of triethylamine, 1.15 g (0.006 mol) of benzothiophene-5-acetic acid (prepared according to the method described in J. Med. Chem. 1997, 40(7):1049-72) and 2.7 g (0.006 mol) of BOP is stirred at ambient temperature for 3 hours. Ethyl acetate is added to the mixture and the mixture is washed with 1N hydrochloric acid and then with water, with a solution of NaHCO3 and again with water. The organic phase is dried over sodium sulfate and filtered and the solvent is evaporated off. The crude product thus obtained, dissolved in 20 ml of anhydrous tetrahydrofuran (THF), is refluxed for 5 hours and 1.1 ml of a solution of BH3Me2S and 15 ml of anhydrous THF are added thereto. The mixture is cooled to 0° C. and 20 ml of methanol are added thereto dropwise. The mixture is refluxed for 30 minutes, the methanol is evaporated off and the residue is taken up in a 1/1 NH4OH/ethyl acetate mixture. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off. The reaction crude is purified by chromatography on a silica gel column, eluting with ethyl acetate. 0.9 g of the title product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([F:27])[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20]CC)=[O:19])[CH:8]=1)=[O:5].[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:26]=[C:25]([F:27])[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a suspension of ethyl 5-(2-chloro-4-fluoro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Example 117A, 15.0 g, 32.3 mmol) in IMS (150 mL), was added 2M aqueous sodium hydroxide solution (83 mL) and the reaction stirred at room temperature for 3 hours. Aqueous hydrochloric acid solution (90 mL, 2 M) was then added. The resulting solid was collected by filtration, washed with water (10 mL) and dried under vacuum to give the title compound (12.7 g, 90%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[CH:13][N:12]3[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)=O.C(N(CC)CC)C.[C:33]1([C:39]2[NH:43][N:42]=[C:41]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[N:40]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl>[C:20]1([C:19]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]#[N:18])[C:11]3=[N:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([CH2:1][N:47]3[CH2:46][CH2:45][CH:44]([C:41]4[NH:40][C:39]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[N:43][N:42]=4)[CH2:49][CH2:48]3)=[CH:8][CH:7]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)cc1
Reactant: N#Cc1cccn2c(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: N#Cc1cccn2c(-c3ccccc3)c(-c3ccc(CN4CCC(c5nnc(-c6ccccc6)[nH]5)CC4)cc3)nc12
Reaction time: 0.08 h

Procedure:
To a solution of 0.250 g (0.838 mM) of 2-(4-formylphenyl)-3-phenylimidazo[1,2-a]pyridine-8-carbonitrile in 6 mL of THF is added triethylamine (2 eq). The reaction mixture is stirred for 5 minutes. To this solution is added 4-(5-phenyl-1H-1,2,4-triazol-3-yl)piperidine (Intermediate M) (1.5 eq) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH(OAc)3 (6 eq) over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained is taken up in chloroform and washed with water, dried and concentrated. The crude is purified on a flash column chromatography to obtain the desired compound.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.ClCCl>CN(C=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:4]2[CH:3]=[C:2]([Br:1])[N:6]=[CH:5]2)=[CH:16][CH:17]=1
Reactant: Brc1cnc[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2cnc(Br)c2)cc1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To a suspension of 5-bromo-1H-imidazole (10 g, 68.5 mmol) and K2CO3 (37.8 g, 274 mmol) in DMF (100 mL) was added 1-(chloromethyl)-4-methoxybenzene (11.8 g, 75.4 mmol) dropwise at room temperature. The resulting mixture was stirred for 16 hours, and then dichloromethane (DCM) was added. The mixture was successively washed with water and brine, dried and concentrated to give a residue that was purified by column chromatography to afford 12.3 g of the desired compound as a solid. LC-MS: m/z 267 (M+H+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14](O)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].OS([O-])(=O)=O.[K+].O>CCOCC>[C:1]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The Weinreb amide of BocLeucine was dissolved in dry Et2O and added by cannula to an Et2O suspension of an equimolar amount of LiAlH4 at 0° C. After stirring for one hour, the reaction flask was removed from 0° C. and allowed to warm to room temperature. After a reaction time of 80 minutes, an aqueous solution of KHSO4, (2 equiv. of KHSO4, 5 ml H2O/mmnol of Weinreb amide) was added slowly while stirring. The aqueous phase was extracted with Et2O and the confined Et2O phases were washed with 3N HCl, saturated NaHCO3, and saturated NaCl. After drying (MgSO4,) and rotary evaporation, the oil was found to contain one compound by thin layer chromatography.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[C:13]1([S:19]([N:22]2[C:30]3[C:25](=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CI.[Cl-].[NH4+]>O1CCCC1>[C:13]1([S:19]([N:22]2[C:30]3[C:25](=[C:26]([C:31]([F:33])([F:34])[F:32])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]2[CH3:1])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(C(F)(F)F)cccc21
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc2c(C(F)(F)F)cccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 ml of n-butyllithium (1.6M in hexane) are added dropwise to a solution of 0.7 ml of diisopropylamine in 10 ml of tetrahydrofuran under argon at −30° C. The solution is stirred for 30 min at ambient temperature, and cooled to −60° C. and a solution of 1.07 g of 1-benzenesulfonyl-4-trifluoromethyl-1H-indole in 10 ml of tetrahydrofuran is added dropwise. The reaction medium is brought back up to ambient temperature and then taken back to −60° C. in order to add, dropwise, 0.31 ml of methyl iodide. After addition, the mixture is allowed to come back up to 0° C. with stirring for 10 minutes, and then to 10° C. for 10 min, before adding a further 0.3 ml of methyl iodide. After returning to ambient temperature, the reaction mixture is stirred for 1 h 30 and then poured into a 10% ammonium chloride solution and extracted with ethyl acetate. The organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2, then 95/5: v/v), so as to give 476 mg of 1-benzenesulfonyl-2-methyl-4-trifluoromethyl-1H-indole, in the form of an oil, which is used in the next step.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10]S(C1C=CC(C)=CC=1)(=O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([NH:8][CH2:9][CH2:10][S:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: SCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)CCNC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSCc1ccccc1
Reaction time: 18 h

Procedure:
N-Boc-2-Tosyl-ethylamine (100 mg, 0.32 mmol) was added to a mixture of benzylmercaptan (45 mL, 0.38 mmol) and Cs2CO3 (68 mg, 0.21 mmol) in 1.6 mL of dry DMF. The reaction was stirred for 18 hours after which time the reaction mixture was poured onto water. The aqueous layer was extracted three times with AcOEt. The combined organic layers were washed with water, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated. The residue was purified using SiO2 with AcOEt/Petroleum ether 5:95 to 15:75. A yellow oil was obtained (72 mg, 83%). NMR 1H (ppm, CDCl3): 7.31-7.25 (m, 5H), 4.79 (br. s., 1H), 3.70 (s, 2H), 3.25 (m, 2H), 2.55-2.53 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].Cl.[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26]Cl)[CH3:23]>>[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:23]
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Li+]
Product: CCN(CC)CCn1c(=Nc2ccccc2)sc2ncccc2c1=O
Yield: 47.8 %

Procedure:
The reaction procedure of Example 11 was followed except that 383 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 259 mg of 2-diethylaminoethylchloride hydrochloride were used. As a result, 254 mg of 3-(2-diethylaminoethyl)-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])[CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: Fc1ccccc1CCl
Product: COc1ccc(O)c(Cc2ccccc2F)c1

Procedure:
Alkylation of 4-methoxyphenol with 2-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(2′-fluorobenzyl)phenol. This material was converted to compound 73 and compound 74 by the procedure similar to that in Example 18 method B.
Reaction SMILES: Cl.[CH3:2][NH:3]C.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].[CH2:14]([CH:21]([NH:31][C:32]([C:34]1[NH:35][C:36]2[C:41]([CH:42]=1)=[CH:40][C:39]([Cl:43])=[CH:38][CH:37]=2)=[O:33])[C:22](=[O:30])[N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH2:14]([CH:21]([NH:31][C:32]([C:34]1[NH:35][C:36]2[C:41]([CH:42]=1)=[CH:40][C:39]([Cl:43])=[CH:38][CH:37]=2)=[O:33])[C:22]([N:23]1[CH2:28][CH2:27][CH:26]([NH:3][CH3:2])[CH2:25][CH2:24]1)=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNC
Reactant: O=C1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CNC1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reaction time: 18 h
Yield: 82 %

Procedure:
Dimethylamine hydrochloride (1.1 mmol), sodium acetate (2.1 mmol), activated 3Å molecular seives, and sodium cyanoborohydride (0.25 mmol) were added in this order to 5-chloro-1H-indole-2-carboxylic acid [1-benzyl-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-amide (0.21 mmol) in methanol (2 mL) at 0° C. After 18 hours, the mixture was concentrated, the residue taken up in ethyl acetate, the resulting solution washed with 2N NaOH and brine, dried with Na2SO4 and concentrated. The product was purified by chromatography on silica gel eluted with 1-8% ethanol in dichloromethane containing 0.5% NH4OH followed by trituration with ether: Yield 82%; HPLC (60/40) 2.79 minutes (98%); PBMS 439/441 (MH+,100%);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I.Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([I:15])=[N:6][CH:7]=1
Reactant: II
Reactant: Oc1cncc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cc(Br)cnc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 5-bromopyridin-3-ol (2.75 g, 15.8 mmol) and sodium carbonate (3.35 g, 31.6 mmol) in water (45 mL) was added iodine (4.01 g, 15.8 mmol), and the mixture was stirred at room temperature for 1 hr. 6N Hydrochloric acid (7 mL) was added thereto, and the mixture was weakly acidified with 1N hydrochloric acid (about 5 mL) (pH 4). The resulting solid was collected, washed with water and dissolved in ethyl acetate. The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained solid was washed with a small amount of acetonitrile to give the title compound (3.57 g, yield 75%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:15]([O:19][C:20]([NH:22][C:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:15]([O:19][C:20]([NH:22][C:23]1([C:28]([NH:8][C:7]2[CH:6]=[CH:5][C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])=[CH:3][CH:2]=2)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Reactant: COC(=O)/C=C/c1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCCC2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl (2E)-3-(3,4-diaminophenyl)acrylate (from Step 3.1 eq), 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (1 eq) in DMF (0.02 M), HATU (1 eq) and DIPEA (3 eq) were added. The reaction mixture was left at RT with stirring overnight. The resulting mixture was partitioned between EtOAc and HCl (1 N). The combined EtOAc layers were washed with brine, and the organic phase was dried over Na2SO4, separated, and evaporated in vacuo to afford methyl (2E)-3-{4-[({1-[(tert-butoxycarbonyl)amino]cyclopentyl}carbonyl)amino]phenyl}acrylate, which was used without further purification. MS (ES+) m/z 404 (M+H)+. The foregoing product was dehydrated by heating it at 65° C. in presence of acetic acid. (0.16 M); the reaction residue was purified by RP-HPLC (Conditions Symmetry (Waters) C18 Column, 7 micron, 19×300 mm; flow: 20 mL/min; Gradient: A H2O+0.1% TFA; B: MeCN+0.1% TFA; 70% A isocratic for 2 min., linear to 20% A in 16 min isocratic for 0.5 min. and linear to 10% A for 2 min). Fractions containing pure product were pooled and lyophilized to give methyl (2E)-3-(2-{1-[(tert-butoxycarbonyl)amino]-cyclopentyl}-1H-benzimidazol-5-yl)acrylate. MS (ES−) m/z 384 (M−H)−.
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)/[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:32][NH:33][C:34]([NH2:36])=[O:35].N1C=CC=CC=1.Cl>FC1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[CH:1]1(/[CH:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:13]=2)/[C:9]([NH:36][C:34]([NH:33][CH3:32])=[O:35])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNC(N)=O
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Fc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)NC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
A solution of (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (282 mg, 0.75 mmol) in fluorobenzene (1 mL) and N,N-dimethylformamide (3 μL) at 25° C. was treated dropwise with oxalyl chloride (81 μL, 0.9 mmol) over 2-3 min. The clear solution was stirred at 25° C. for 1 h and then treated with methyl urea (167 mg, 2.25 mmol). The resulting suspension was heated at 70° C. (bath temperature) for 10 min and then treated with pyridine (121 μL, 1.5 mmol). The reaction mixture was then stirred at 70° C. for 20 h. The reaction mixture was then cooled to 25° C. and diluted with ethyl acetate (50 mL) and a 3N aqueous hydrochloric acid solution (40 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded the (E)-1-[3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acryloyl]-3-methyl-urea (104 mg, 32%) as a white solid: mp 199-202° C. EI-HRMS m/e calcd for C19H23F3N2O4S (M+) 432.1331, found 432.1332.