Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].CCN(C(C)C)C(C)C.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21](Cl)=[O:22]>ClCCl.CC#N>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:21](=[O:22])[C:20]1[C:19]([Cl:18])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28]
Reactant: Nc1ccncc1F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccncc1F)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a cooled (0° C.) mixture of 3-fluoropyridin-4-amine (1.0 g, 8.9 mmol) and DIPEA (2.7 mL, 18 mmol) in dichloromethane (20 mL) and MeCN (10 mL) was added a solution of 2,6-dichlorobenzoyl chloride (2.1 g, 9.8 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was partitioned between EtOAc (30 mL) and sat. NaHCO3 (30 mL). The aqueous layer was extracted with EtOAc (2×15 mL) and then the combined organic extracts were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to afford N-(3-fluoropyridin-4-yl)-2,6-dichlorobenzamide (1.2 g, yield: 47%). 1H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 8.59 (d, J=2.8, 1H), 8.41 (d, J=5.4, 1H), 8.21 (dd, J=6.7, 5.4, 1H), 7.77-7.33 (m, 3H). LCMS (ESI) m/z: 285.2 [M+H+]
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][O:16][CH3:17])[CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[C:20]1[N:21]2[N:27]=[C:26]([S:28]([CH3:31])(=O)=O)[CH:25]=[C:22]2[S:23][CH:24]=1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O1CCCC1>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][O:16][CH3:17])[CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[C:20]1[N:21]2[N:27]=[C:26]([S:28][CH3:31])[CH:25]=[C:22]2[S:23][CH:24]=1
Reactant: COCc1cc(OC)c(-c2csc3cc(S(C)(=O)=O)nn23)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COCc1cc(OC)c(-c2csc3cc(SC)nn23)c(OC)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
To tetrahydrofuran (20 mL) was added dropwise titanium tetrachloride (1.10 mL, 10.1 mmol) at −78° C., and the mixture was stirred for 10 minutes. At the same temperature, a tetrahydrofuran (20 mL) solution of lithium aluminum hydride (767 mg, 20.1 mmol) was gradually added dropwise and stirred for 30 minutes. To the mixture was added 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-(methylsulfonyl)pyrazolo[5,1-b][1,3]thiazole (384 mg, 1.01 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was heated at 50° C. for one hour. After the reaction was completed, 5N sodium hydroxide was gradually added dropwise while cooling on ice to stop the reaction. The reaction mixture was filtered with Celite and extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate=1/1) to obtain the title compound (32.8 mg, 0.094 mmol).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[OH:25])[CH2:20][CH2:19]2)=[CH:10][CH:9]=1)=[O:6])C.C(=O)(O)[O-].[Na+].O.C(O)(=O)C>C(O)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([OH:25])[CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]([OH:40])=[O:3])=[CH:9][CH:10]=3)[CH2:19][CH2:20]2)=[CH:34][CH:35]=1
Reactant: CCOC(=O)C(=O)Nc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C(=O)Nc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1

Procedure:
A solution of [[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl]amino]oxoacetic acid ethyl ester in 50 ml of ethanol is treated with 20 ml of a 2N sodium bicarbonate solution and the mixture is heated at reflux overnight. The mixture is cooled and poured into 500 ml of water containing 10 ml of acetic acid. The resulting solution is collected by filtration and dried to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:44]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:45])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:4])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)C1CCCCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (see example 8) as described in general procedure D using cyclohexanecarbonyl chloride. The final product was obtained in 74% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].CC(C)([O-])C.[K+]>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:22][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of diphenylmethyl ester of N-tert-butoxycarbonyl-L-tyrosine (447 mg) prepared in Preparation 7 (1), N-(3-bromopropyl)phthalimide (644 mg) and potassium tert-butoxide (268 mg) in dimethyl sulfoxide (7 ml) was stirred for 6 hours at room temperature. The reaction mixture was diluted with water, and extracted with diethyl ether. The extract was washed with water and brine, dried, and evaporated to dryness to give diphenylmethyl ester of N-tert-butoxycarbonyl-O-(3-phthalimidopropyl)-L-tyrosine quantitatively as oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])/[CH2:9]O)=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:26].O>C(OC)(C)(C)C>[Br:26][CH2:9]/[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: BrP(Br)Br
Reactant: OC/C(=C/c1ccccc1Cl)c1ccc(F)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: Fc1ccc(/C(=C\c2ccccc2Cl)CBr)cc1
Yield: 236 %

Procedure:
103.1 g of E-2-(4-fluorophenyl)-3-(2-chlorophenyl)-prop-2-enol are dissolved in 700 ml of methyl tert-butyl ether, and 2 ml of pyridine are added. The reaction solution is stirred under a nitrogen atmosphere at 0° C., while 27.2 g of phosphorus tribromide are added in the course of 90 minutes. After the end of the addition, the mixture is refluxed for two hours and then poured onto 500 ml of water and extracted several times with methyl tert-butyl ether. The organic phase is washed with sodium bicarbonate solution and water and dried over sodium sulfate, and the solvent is evaporated down under reduced pressure. 77.2 g (61%) of E-1-bromo-2-(4-fluorophenyl)-3-(2-chlorophenyl)-prop-2-ene of melting point 68° C. are obtained from ethanol.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH2:1]=[C:2]1[CH2:3][CH2:4][C:5]([CH2:8][OH:9])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:6][CH2:7]1
Reactant: C=C1CCC(C(=O)OCC)(c2cccc(Oc3ccccc3)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C1CCC(CO)(c2cccc(Oc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of ethyl 4-methylene-1-(3-phenoxyphenyl)cyclohexanecarboxylate (96 mg, 0.285 mmol) in THF (5 mL) at 0° C. was added lithium aluminum hydride (0.314 mL of a 1.0 M in Et2O; 0.314 mmol). The solution was warmed to rt and stirred for 1 h. The reaction was then quenched at 0° C. by adding EtOAc followed by a saturated aq sodium sulfate. The mixture was diluted with EtOAc and filtered through a pad of CELITE®. The filtrate was dried (Na2SO4) and concentrated in vacuo to afford the title compound (84 mg, 100% yield) as a colorless oil. LCMS, [M+Na]+=317.1. 1H NMR (500 MHz, CDCl3) δ 7.38-7.32 (m, 3H), 7.20-7.16 (m, 1H), 7.15-7.09 (m, 2H), 7.04-7.00 (m, 2H), 6.88 (ddd, J=8.1, 2.3, 0.8 Hz, 1H), 4.63 (s, 2H), 3.53 (s, 2H), 2.28-2.19 (m, 4H), 2.16-2.07 (m, 2H), 1.72-1.64 (m, 2H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.[CH3:14][N:15]([CH3:26])[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1>>[CH3:26][N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22]2[NH:2][C:4]3[C:13]([C:21]=2[CH2:20]1)=[C:8]1[C:9]([CH3:12])=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3
Reactant: Cc1csc2ccc(NN)cc12
Reactant: CN(C)CCCN1CCC(=O)CC1
Agent: Cl
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(CCCN(C)C)CC4

Procedure:
The compound is formed analogously to that described in Example 5, from 5-hydrazino-3-methylbenzothiophene hydrochloride and 8.5 ml of 1-(3-dimethylaminopropyl)-4-piperidone. Melting point: 184° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[CH:18]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:23]([S:20]([CH:18]=[CH:19][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17])(=[O:22])=[O:21])[CH3:24]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: C=CS(=O)(=O)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 65.3 %

Procedure:
A mixture of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (0.25 g), ethyl vinyl sulphone (0.14 g), tri-o-tolylphosphine (0,075 g), palladium (II) acetate (0.013 g), triethylamine (0.25 mL) and acetonitrile (3 mL) was heated under reflux for 17 hours in an atmosphere of nitrogen. The mixture was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:8:1) gave the title compound as a foam (0.185 g): TLC (dichloromethane/-ethanol/concentrated aqueous ammonia, 90:10:1): Rf =0.5. Anal. Calcd for C18H24N2O2S. 0.2 CH2Cl2 : C,62.55; H,7.04; N,8.02. Found: C,62.65; H,6.94; N,7.92.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([O:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])(=[O:5])=[O:4].N1C=CN=C1.[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31].[Cl-].[NH4+]>CN(C=O)C>[F:24][C:2]([F:23])([F:1])[S:3]([O:6][C:7]1[CH:12]=[C:11]([O:13][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])(=[O:5])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(F)c(-c2ccc(O)cc2OS(=O)(=O)C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl trifluoromethanesulfonate (2.85 g) and imidazole (800 mg) in DMF (50 mL) was added tert-butyldimethylchlorosilane (1.42 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.99 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[CH3:12][N:13](C(=O)C(F)(F)F)[CH2:14][CH2:15][CH:16](OC(=O)C(F)(F)F)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:14][NH:13][CH3:12])=[CH:8][C:7]=2[CH:11]=1
Reactant: CN(CCC(OC(=O)C(F)(F)F)c1ccccc1)C(=O)C(F)(F)F
Reactant: COc1ccc2occc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNCCC(c1ccccc1)c1cc2cc(OC)ccc2o1
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
5-methoxybenzofuran (0.48 g) and trifluoro-acetic acid 3-[methyl-(2,2,2-trifluoro-acetyl)-amino]-1-phenyl-propyl ester (0.48 g) were mixed and heated in a sealed tube at 110° C. for 90 minutes. Upon cooling, the reaction mixture was taken up in methanol and treated with excess 1N sodium hydroxide solution, sufficient to form a strongly basic solution. After stirring for 20 minutes, the reaction mixture was concentrated at reduced pressure to remove the bulk of the methanol. The resulting mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was evaporated to dryness. Purification by column chromatography (silica gel, dichloromethane (130):methanol (10):ammonium hydroxide (1)) followed by preparative tlc afforded [3-(5-Methoxy-benzofuran-2-yl)-3-phenyl-propyl]-methyl-amine (M+H=296) as the major component.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:26])([CH3:25])[O:16][C:15]3=[O:27])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[C@@H:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17]([CH3:25])([CH3:26])[O:16][C:15]3=[O:27])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[Br:35]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(=O)N(c2ccc(-c3ccc(N)nc3)cc2)[C@H]1c1ccccc1
Solvent: ClCCl
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)c(Br)c3)cc2)[C@H]1c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (S)-3-(4-(6-aminopyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (1 g, 2.78 mmol) in DCM (13.91 mL) at 0° C., was added NBS (0.545 g, 3.06 mmol). The reaction mixture was then stirred for 1 hour at the same temperature. LC-MS indicated clean and complete conversion to desired product. The solution was concentrated and water was added. The solid was filtered and washed with water three times. The solid was then air-dried affording (S)-3-(4-(6-amino-5-bromopyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (1.26 g, 2.87 mmol, 103% yield) as a tan solid. The material was used without further purification. m/z (ESI) 439.8 (M+2)+.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[C:9]([C:17]1[CH:43]=[CH:42][C:20]([O:21][CH2:22][CH:23]([OH:41])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:28]([OH:40])[CH:27]=2)=[CH:19][C:18]=1[OH:44])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:45]([CH2:47][C:48](O)=[O:49])#[N:46]>ClCCCl>[C:45]([CH2:47][C:48]([O:41][CH:23]([CH2:22][O:21][C:20]1[CH:42]=[CH:43][C:17]([C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:18]([OH:44])[CH:19]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:28]([OH:40])[CH:27]=1)=[O:49])#[N:46]
Reactant: O=C(c1ccccc1)c1ccc(OCC(O)COc2ccc(C(=O)c3ccccc3)c(O)c2)cc1O
Reactant: N#CCC(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Product: N#CCC(=O)OC(COc1ccc(C(=O)c2ccccc2)c(O)c1)COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C
Yield: 87 %

Procedure:
3 g of trifluoromethanesulfonic acid were added to a solution of 48.5 g (0.1 mole) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-2-propanol and 51 g (0.6 mole) of cyanoacetic acid in 750 ml of 1,2-dichloroethane, and the solution was heated for 9 hours at a temperature of 80° to 85° C. After cooling to room temperature, the reaction mixture was washed with three times 400 ml of water. The 1,2-dichloroethane was distilled off from the reaction mixture under a pressure of 50 mbar and a temperature of 35° to 45° C. The residue remaining was recrystallized from acetonitrile. After drying, 48 g (87 percent of theory) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-prop-2-yl cyanoacetate were obtained in the form of slightly yellow, fine crystals having a melting point of 167° to 168° C. and a purity of 99 percent (HPLC).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:8]=[CH:7]2)(=[O:3])[CH3:2].[CH2:19](OCC)C>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15]([O:17][CH3:19])=[O:16])[CH:8]=[CH:7]2)(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(=O)c1ccc2cc(C(C)C(=O)O)ccc2c1
Product: COC(=O)C(C)c1ccc2cc(C(C)=O)ccc2c1

Procedure:
To a mixture of 24 g. of 6-acetyl-2-naphthyl-α-methylacetic acid and 200 ml. of diethyl ether are added 4.2 g. of diaxomethane in 100 ml. of diethyl ether. The resulting mixture is evaporated to give methyl 6-acetyl-2-naphthyl-α-methylacetate. The product is added to 200 ml. of aqueous 20% sodium hypochlorite. The resulting mixture is allowed to stand for four hours at room temperature. The mixture is acidified by the addition of aqueous 1N hydrochloric acid and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-carboxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][S:8][CH:9]([CH2:21][CH2:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1C=CC=CC=1>[Cl:3][CH2:6][CH2:7][S:8][CH:9]([CH2:21][CH2:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCO)OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCCl)OC(C)=O

Procedure:
Thionyl chloride (13.1 g., 0.11 mole) is added dropwise with stirring to a solution of ethyl 8-(2-hydroxyethylthio)-12-acetoxyheptadecanoate (43.2 g., 0.10 mole) in benzene (150 ml.). The solution is heated at reflux for 2 hours. Then, the solvent and excess thionyl chloride are removed by evaporation in vacuo to leave the title compound as an orange yellow residual oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCc1ccc(-c2ccc(C=CC(=O)OC)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(CCC(=O)OC)cc2)cc1
Yield: 95.9 %

Procedure:
A mixture of Methyl 3-[4-(4-pentylphenyl)phenyl]acrylate (2.0 g) and 10% palladium on carbon (50% wet, 0.2 g) in tetrahydrofuran (20 ml) was stirred for 8 hours under atmospheric pressure of hydrogen at ambient temparature. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give Methyl 3-[4-(4-pentylphenyl)phenyl]propionate (1.93 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([OH:14])[N:11]([CH3:15])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:27])([F:26])[CH2:24]O.CC1C=CC(S([O-])(=O)=O)=CC=1.[I-].[Na+]>CN1CCCC1=O>[F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH2:24][C:23]([F:27])([F:26])[F:22])[N:11]([CH3:15])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1O
Reactant: OCC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN1CCCC1=O
Product: Cn1nc(-c2ncc(Cl)cc2F)cc1OCC(F)(F)F
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
3.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-hydroxy-1-methyl-[1H]-pyrazole (Example H14) are initially introduced into 30 ml of N-methylpyrrolidone (NMP) together with 3.64 g of potassium carbonate, and 3.49 g of 2,2,2-trifluoro-ethanol 4-methylbenzenesulfonate are added. 0.3 g of sodium iodide is then added and the mixture is stirred overnight at 80° C. It is then cooled to 22° C. and partitioned between dilute hydrochloric acid and diethyl ether. After extraction by shaking and separation of the phases, the ether phase is washed with brine, filtered and concentrated in vacuo together with twice the amount of silica gel. After application of the silica gel to a flash column, the column is eluted with n-hexane/ethyl acetate 2/1. 2.68 g of the desired title compound are obtained as a yellow solid of melting point 72-73° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=3[N:11]=[C:10]2[CH:20]([F:22])[F:21])[N:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=3[N:11]=[C:10]2[CH:20]([F:22])[F:21])[N:5]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(Cl)n1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(N2CCOCC2)n1
Yield: 89 %

Procedure:
Reaction of 1-(4,6-dichloro-2-pyrimidinyl)-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (International Publ. No. WO 2005/095389, the disclosure of which is incorporated herein by reference in its entirety) (50 mg, 0.145 mmol) with a ten-fold of excess morpholine in THF at room temperature gave 51 mg (89% yield) of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole: mp (CH2Cl2/MeOH) 261-263° C.; 1H NMR (CDCl3) δ 7.90 (dd, J=8.4, 0.7 Hz, 1H), 7.47 (t, JHF=53.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 6.47 (s, 1H), 4.07 (s, 3H), 3.84 (m, 4H), 3.73 (m, 4H); Anal. Calcd. for C17H16ClF2N5O2: C, 51.6; H, 4.1; N, 17.7. Found: C, 51.7; H, 4.1; N, 17.9%.