Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.[Mg].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>C1COCC1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:10]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)([C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[OH:12])=[CH:22][CH:21]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COC(=O)c1ccccc1Cc1ccccc1
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc(OC)cc2)c2ccccc2Cc2ccccc2)cc1
Reaction time: 16 h

Procedure:
Methyl 2-benzylbenzoate (10.0 g) was added dropwise to a stirred solution of 4-methoxyphenyl magnesium bromide, which was prepared in situ from magnesium (3.2 g) and 4-bromoanisole (24.9 g), in THF at room temperature. After 16 hours, the mixture was quenched with ammonium chloride solution and the solvent evaporated in vacuoo The residue was extracted with ethyl acetate, dried (MgSO4), filtered, and evaporated in vacuo to give di-(4-methoxyphenyl)-(2-benzylphenyl)carbinol as an oil. This oil was dissolved in acetic acid (50 mL) and concentrated H2SO4 (2.0 mL) was added the resulting mixture was heated to 100° C. for one hour and then neutralized with NaOH solution. The mixture was extracted with ether and the organic extracts were combined, dried (MgSO4), filtered, evaporated in vacuo and chromatographed on silica gel eluting with hexane/ethyl acetate (10/1) to give 9,9-bis(4-methoxyphenyl)-(9H, 10H)-dihydroanthracene (7.1 g) as a solid. M.P. 138°-140° C. Demethylation was performed using the sodium ethanethiolate/DMF procedure described in Example 3 to give the title product in 77% yield as a solid. M.P. 230°-232° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C:13]2[CH:14]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:16]=[C:17]([O:19][CH2:37][C:34]3[CH:35]=[CH:36][C:31]([Br:30])=[CH:32][CH:33]=3)[CH:18]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: BrCc1ccc(Br)cc1
Product: CCOC(=O)N1CCN(C(=O)c2cc(OCc3ccc(Br)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 79.7 %

Procedure:
Using 0.75 g (1.89 mmol) of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]-piperazine-1-carboxylic acid ethyl ester and 1-bromo-4-bromomethyl-benzene (0.472 g, 1.89 mmol) and following the procedure of Example 42(b) afforded 0.85 g of the required product. Percentage purity (LCMS): 75.2%, (M+1)=563.1+1.
Reaction SMILES: C[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H].[CH3:15]O>>[CH3:15][CH:5]([CH2:4][C:3]1[CH:2]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CO
Reactant: Cc1ccccc1C=CC(=O)O
Product: CC(Cc1ccccc1)C(=O)O
Reaction time: 19 h

Procedure:
0.41 g (2.53 mmol) of 2-methylcinnamic acid and 5 ml of degassed methanol are introduced in succession into a Schlenk vessel filled with argon. A catalyst solution consisting of 4.73 mg (0.01265 mmol) of [Rh(norbornadiene)2]BF4, 8.77 mg (0.0133 mmol) of ligand A and 5 ml of degassed methanol is prepared in a second Schlenk vessel filled with argon. This solution and the catalyst solution are then transferred in succession by means of a steel capillary into a 50 ml autoclave filled with argon. The ratio of substrate/catalyst is 200. The autoclave is closed and a pressure of 5 bar is set by means of 4 flushing cycles (pressurization to 10 bar of hydrogen). The autoclave is thermostated at 25° C. and the reaction is started by switching on the stirrer. The reactor is stirred for 19 hours. After opening the autoclave, a reddish reaction solution is isolated. The conversion is quantitative (determined by means of GC and 1H-NMR). Removal of the solvent on a rotary evaporator gives a quantitative yield of 2-methyl-3-phenylpropionic acid having an enantiomeric purity of 29% ee (determined by means of HPLC after conversion into the methyl ester; column: Chiracel OB.).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl>[Si:22]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O

Procedure:
A solution of thymidine dT (2.85 g, 11.76 mmol), imidiazole (2.44 g, 35.80 mmol) and TBSCl (1.77 g, 11.76 mmol) in anhydrous CH2Cl2 (20 mL) was stirred at room temperature overnight under a N2 atmosphere. The reaction mixture was then concentrated in vacuo to a viscous oil, followed by the addition of ethyl ether (60 mL) and water (60 mL). The organic layer was separated and washed twice with water (20 mL each), and the combined aqueous layer was extracted with ethyl ether (20 mL). The combined organic layer was dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to give 5′-O-tert-butyldimethylsilyl-thymidine dT.01 (3.44 g, 82%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)[CH:8]=2)=[C:4]([F:30])[CH:3]=1.FC1C=C(N[C:55](=[O:67])[CH2:56][C:57]([NH:59][C:60]2[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=2)=[O:58])C=CC=1OC1C=CN=C(NCCN2CCOCC2)C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.COC1C=CC(CNC2N=C(OC3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)C=CN=2)=CC=1>CN(C=O)C>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:55](=[O:67])[CH2:56][C:57]([NH:59][C:60]4[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=4)=[O:58])=[CH:3][C:4]=3[F:30])[CH:8]=2)=[CH:19][CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1)Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)n2)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Yield: 87.5 %

Procedure:
The title compound was prepared from a mixture 6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy)phenyl)pyrimidin-4-amine (45 mg, 0.11 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 24 mg, 0.12 mmol), TBTU (48 mg, 0.15 mmol), DIPEA (0.26 mL, 0.15 mmol), and DMF (1 mL) using a similar procedure described for the preparation of Compound C of Example 1. The crude product was triturated with isopropyl ether to give the title compound (56 mg, 88%) as a pink solid. 1H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.27 (s, 1H), 9.45 (s, 1H), 8.25 (s, 1H), 7.77 (dd, 1H, J=12.7, 2.0 Hz), 7.65-7.62 (m, 2H), 7.46 (d, 4H, J=7.3 Hz), 7.40 (dd, 2H, J=7.6, 7.3 Hz), 7.37-7.29 (m, 3H), 7.17 (dd, 2H, J=9.0, 8.3 Hz), 7.00 (d, 2H, J=9.0 Hz) 6.09 (s, 1H), 5.09 (s, 2H) 3.49 (s, 2H); MS (ESI+) m/z 582.3 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=2[O:24][CH3:25])=[CH:5]1)(=[O:3])[CH3:2].[CH:26]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:32](=[O:33])[CH2:31][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:10][CH:11]=2)[C:6]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=2[O:24][CH3:25])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: O=C(O)CC1CCCC1
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc(N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc(NC(=O)CC3CCCC3)cc12
Yield: 13.4 %

Procedure:
A solution of 4-(1-acetyl-5-aminoindol-3-ylmethyl)-3-methoxybenzoic acid (Z) (0.31 g.), cyclopentylacetic acid (0.117 g.), 4-(dimethylamino)pyridine (0.233 g.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.35 g.) in dichloromethane (20 ml.), under a nitrogen atmosphere, was stirred at ambient temperature for two hours. The mixture was acidified with hydrochloric acid (1N, 30 ml.), extracted with ethyl acetate (3×50 ml.), and the combined extracts dried (MgSO4) and evaporated. The residual oil was purified by flash chromatography on silica gel (100 ml.), eluting with 50:45:5 v/v/v hexane:dichloromethane:ethyl acetate, to give a product which was recrystallized from a mixture of tetrahydrofuran and ether, and then from a mixture of ethanol and water, to give the title compound (0.055 g., 14%), as a white solid, m.p. .245°-247° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)[NH:11][CH:12]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:19][C:20]1[CH:25]=[C:24]([N:15]2[CH2:16][CH2:17][O:18][CH:13]([C:10]3[NH:11][CH:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:9]=3)[CH2:14]2)[N:23]=[C:22]([NH2:27])[N:21]=1
Reactant: Clc1ccccc1-c1c[nH]c(C2CNCCO2)n1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccccc4Cl)c[nH]3)C2)n1
Yield: 30.7 %

Procedure:
A solution of 2-[4-(2-chlorophenyl)-1H-imidazol-2-yl]morpholine (250 mg, 0.833 mmol), 4,6-dichloro-2-pyrimidinamine (137 mg, 0.833 mmol) and Hunig's base (0.36 mL, 2.08 mmol) in ethanol (80 mL) was heated at 85° C. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography using 50% EtOAc in petroleum ether to afford the title compound (100 mg) as a white solid. LC-MS (ES) m/z=391, 393 [M+H]+.
Reaction SMILES: CC([N:5]([C:9]1SC=[C:12]([CH2:14]Br)[N:13]=1)C(=O)[O-])(C)C.[H-].[Na+].Br.Br[CH2:20][C:21]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=1.Br[CH2:29][C:30]1C(O)=CC=C[N:31]=1.CN(C=[O:41])C>>[OH:27][C:26]1[C:21]([CH2:20][N:31]2[CH:30]=[CH:29][C:9]([NH:13][C:12](=[O:41])[CH3:14])=[N:5]2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)N(C(=O)[O-])c1nc(CBr)cs1
Reactant: Oc1cccnc1CBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: CC(=O)Nc1ccn(Cc2ncccc2O)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 13 %

Procedure:
Intermediate 1 (200 mg, 1.598 mmol) was dissolved in 2 mL of anhydrous DMF at 0° C. Sodium hydride (ALDRICH, 48.5 mg, 1.920 mmol) was added and mixture of reaction was stirred at 0° C. for 20 minutes. 2-(Bromomethyl)-3-pyridinol hydrobromide (ALFAAESAR, 301 mg, 1.598 mmol) was dissolved in 2 mL of DMF (anh) at 0° C. Sodium hydride (ALDRICH, 48.5 mg, 1.920 mmol) was added and this solution was stirred at 0° C. for 20 minutes. Solution of 2-(bromomethyl)-3-pyridinol was added dropwise to reaction mixture. Reaction was stirred at 80° C. for 24 h. Solvent was evaporated to dryness. Residue was partitioned between EtOAc and NH4Cl. Organic layer was dried over MgSO4 (anh), filtered and concentrated to dryness. Residue was purified using silica chromatography column using a linear gradient of DCM/MeOH as eluents to give the title compound (48.5 mg, 0.207 mmol, 13% yield). 1H NMR (300 MHz, CDCl3) δ ppm: 9.70 (br s, 1H), 8.04 (m, 1H), 7.46 (d, 1H), 7.33 (m, 1H), 7.24 (m, 1H), 6.53 (d, 1H), 5.42 (s, 2H), 2.27 (s, 3H). [ES+MS] m/z 233 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:36][CH:35]2[O:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]3[O:60][CH2:59][CH2:58][N:57]([CH2:61][CH2:62][CH2:63][O:64][CH3:65])[C:56]=3[CH:66]=2)=[CH:30][CH:29]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:36][CH:35]2[O:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]3[O:60][CH2:59][CH2:58][N:57]([CH2:61][CH2:62][CH2:63][O:64][CH3:65])[C:56]=3[CH:66]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN)cc3)cc21
Reactant: O=C(O)Cc1ccccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNC(=O)Cc4ccccc4F)cc3)cc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.135 g of 2-fluorophenyl acetic acid is dissolved in 5 ml of dichloromethane. 0.127 g of carbonyldiimidazole is added and the reaction solution is stirred at 20° C. over 1 hour. A solution of 0.472 g of benzyl 4-[4-(2-aminoethoxy]phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 184) in 4 ml of dichloromethane is added dropwise and the solution is subsequently stirred at 20° C. over 1 hour. The reaction solution is diluted with 10 ml of dichloromethane and subsequently washed with 10 ml each of 1M NaOH and water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a light yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (4:1 EtOAc-heptane); Rt=5.14.
Reaction SMILES: [Mg].[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4].[C:18](=[S:20])=[S:19].Cl>C1COCC1>[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C:18]([SH:20])=[S:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4]
Reactant: CCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reactant: S=C=S
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(C(=S)S)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution obtained by suspending 2.25 g (93 mmol) of magnesium in 50 mL of THF, a solution of 20.0 g (71 mmol) of 4-(trans-4-propylcyclohexyl)phenyl bromide in 100 mL of THF was added dropwise with stirring at the room temperature for 45 minutes and stirred with reflux for 30 minutes, to prepare a Grignard reagent. To the solution, 16.3 g (214 mmol) of carbon disulfide was added dropwise for 15 minutes at the room temperature and stirred for one night. To the reaction solution, 60 mL of 3M hydrochloric acid was added to stop the reaction, extracted with ether, and dried with anhydrous magnesium sulfate. After filtering off magnesium sulfate, the filtrate was concentrated under reduced pressure, to obtain 3.5 g (yield 17.7%) of 4-(trans-4-propylcyclohexy)phenyl dithiocarboxylic acid.
Reaction SMILES: Cl[CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[S:17])=[CH:14][CH:13]=1)#[N:11]>CO>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]2[S:17][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([CH3:9])[N:18]=2)=[CH:19][CH:20]=1)#[N:11]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: N#Cc1ccc(C(N)=S)cc1
Solvent: CO
Product: COC(=O)c1sc(-c2ccc(C#N)cc2)nc1C
Temperature: 0 °C
Yield: 55.7 %

Procedure:
A suspension of methyl 2-chloroacetoacetate (30 g, 0.19 mol) and 4-cyanothiobenzamide (21.5 g, 0.13 mol) in MeOH (250 mL) was refluxed for 15 h. The reaction mixture was then cooled to 0° C., filtered after 20 h and washed with cooled (-20° C.) MeOH and with ether. The resulting off-white solid was dried to give methyl 2-(4-cyanophenyl)-4-methylthiazole-5-carboxylate (18.7 g, 55%). If desired, additional product may be recovered by flash chromatography of the washings: mp 186°-187° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.07 (dt, Jt =1.6, Jd =8.3, 2H, arom), 7.74 (dt, Jt =1.6, Jd =8.3, 2H, arom), 3.91 (s, 3H, OMe), 2.79 (s, 3H, Me-thiazole). Analysis calculated for C13H10N2O2S: C 60.45; H 3.90; N 10.85; S 12.41. Found: C 60.31; H 3.80; N 10.53; S 11.79.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([Cl:21])[CH:14]=1.O>C(O)(C)(C)C>[Cl:21][C:15]1[CH:14]=[C:13]([O:4][C@@H:2]2[CH2:9][CH2:8][CH2:7][C@@H:11]2[OH:10])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: N#Cc1ccc(O[C@@H]2CCC[C@@H]2O)cc1Cl
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A 1.0 M solution of potassium t-butoxide in t-butanol (3.2 mL) was added to a 16 mL vial fitted with a septa cap containing 3 mL of dry THF and 300 mg (3 mmoles) of cis-1,2-dihydroxy cylcopentanol at 5° C. The mixture was stirred for 0.5 h at 5° C., after which time 3 mL of a 1.0 M THF solution of 4-fluoro-2-chloro-benzonitrile was added. The reaction was stirred at 5° C. for 3 h and then allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was cooled to 0° C., poured into a seperatory funnel containing 15 mL of water, and extracted with 20 mL of methyl tert-butyl ether. The organic phase was washed with water, brine, dried (MgSO4), concentrated in vacuo, and the residue purified by reverse phase HPLC (Shimadzu) to give 185 mg 2-Chloro-4-(cis-2-hydroxy-cyclopentyloxy)-benzonitrile. GC/MS: 237 (M/Z for C13H14ClNO).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.Cl.[O:49]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[N:51]=[C:50]1[CH2:58][NH2:59]>>[O:49]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[N:51]=[C:50]1[CH2:58][NH:59][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:42]
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1nc2ccccc2o1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cl
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1nc2ccccc2o1
Yield: 85 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with benzo[d]oxazol-2-ylmethanamine hydrochloride, the title compound was obtained as an off-white solid in 85% yield: 1H NMR (300 MHz, CDCl3) δ 7.74-7.68 (m, 1H), 7.56-7.49 (m, 1H), 7.40-7.24 (m, 4H), 7.09-6.99 (m, 2H), 6.50 (t, J=4.6 Hz, 1H), 6.14 (s, 1H), 4.88 (d, J=4.6 Hz, 2H), 4.44 (s, 2H), 3.85-3.76 (m, 2H), 3.49-3.39 (m, 2H), 2.53 (s, 3H); MS (ES+) m/z 465.2 (M+1), 487.2 (M+23).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]([C:29](=[O:41])[NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=2)([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:39]([C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][NH:30][C:29]([C:18]2([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[O:41])=[CH:34][CH:35]=1)[CH3:40]
Reactant: CCc1ccc(CCNC(=O)C2(Cc3ccccc3F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(CCNC(=O)C2(Cc3ccccc3F)CCNCC2)cc1
Yield: 79.7 %

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution 4-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-4-(2-fluoro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester (0.300 g, 0.64 mmol) in dichloromethane (50 mL). After 1 h the reaction mixture was concentrated under reduced pressure, the crude product taken up in 1M sodium hydroxide (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.188 g (80 %) of 4-(2-fluoro-benzyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide LRMS m/z 369.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)=O.CCCCCCCCCCCC[N+](CC([O-])=O)(C)C.[Na+].[Cl-:33].O.Cl>C1(C)C=CC=CC=1>[Cl:33][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: [Cl-]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCCCCCCCCCCC[N+](C)(C)CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(CCl)o1
Reaction time: 3 h

Procedure:
To a three-necked flask equipped with a condenser and a stirrer were added 5 g (0.028 mole) of a commercially available D-(-)-fructose and a surface active agent, 82.3 mg (0.00028 mole) of lauryldimethylbetaine. Then, 5 ml of water and 30 ml of toluene were added thereto and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride was passed through the mixture at room temperature for about 30 minutes with thorough stirring. After the reaction was continued at room temperature for a further 3 hours, the upper toluene layer was separated from the lower aqueous layer. Thirty milli-liters of toluene and the above surface active agent in the same amount as above were then freshly added to the aqueous layer. After the reaction was carried out at room temperature for 3 hours, the upper toluene layer was again separated. This toluene extraction operation was repeated three times in total. All the toluene layers were combined and filtered through Celite. The filtrate was neutralized with an aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated. Thus, about 2.9 g of 5-chloromethylfurfural was obtained as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].ClC1C=C(F)C(N2C(Cl)=CC(C(F)(F)C(F)(F)F)=NC2=O)=CC=1[C:33](OC(C)C)=[O:34].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])[N:17]=[C:16]2[O:34][CH3:33])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)cc(C(F)(F)C(F)(F)F)nc2=O)c(F)cc1Cl
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F
Temperature: 25 °C

Procedure:
The residue, a mixture of isopropyl 2-chloro-5-[2-chloro-6-oxo-4-pentafluoroethyl -1(6H)-pyrimidinyl]-4-fluorobenzoate and isopropyl 2-chloro-5-[6-chloro-2-oxo-4-pentafluoroethyl -1(2H)-pyrimidinyl]-4-fluorobenzoate, is dissolved in 20 ml of methanol and 3.8 ml of a 2N sodium methylate solution are added to the solution while stirring at 25° C. The temperature of the reaction mixture rises to 30° C. The mixture is subsequently stirred for 30 minutes and evaporated to dryness under reduced pressure. The residue is separated by chromatography on a silica gel column using n-hexane/diethyl ether (3:1). The first fraction, which still contains some diethylaniline, is dissolved in diethyl ether and the solution is extracted with 2N hydrochloric acid, washed to neutrality with water and dried over anhydrous sodium sulphate. The organic phase is evaporated to dryness under reduced pressure and the residue is recrystallized from n-hexane. There is obtained isopropyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-benzoate, m.p. 82°-84° C. By further elution of the column with n-hexane/diethyl ether (1:2) there is obtained a second fraction which is recrystallized from diethyl ether/n-hexane. In this manner there is also obtained isopropyl 2-chloro-4-fluoro-5-[6-methoxy-2-oxo-4-pentafluoroethyl -1(2H)-pyrimidinyl]-benzoate, m.p. 127°-129° C.