Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19](O)[C:20]([OH:22])=O)=[CH:17][CH:16]=1)([OH:12])=[O:11].[CH2:26](O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]2[O:9][C:20](=[O:22])[CH:19]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:10]([O:12][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26])=[O:11])=[CH:25][CH:24]=3)[C:4]=2[CH:5]=1
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(O)c(C)c1
Reactant: O=C(O)COc1ccc(C(O)C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)COc1ccc(C2C(=O)Oc3c(C)cc(C)cc32)cc1
Temperature: 185 °C
Reaction time: 3.5 h
Yield: 38.1 %

Procedure:
A mixture of 18.3 g (0.15 mol) of 2,4-dimethylphenol and 11.3 g (0.05 mol) of 4-carboxymethoxymandelic acid is stirred at about 185° C. for 3.5 hours. Excess 2,4-dimethylphenol is then distilled off in a high vacuum. 12.5 g (0.046 mol) of 1-octadecanol and 0.3 g (1.58 mmol) of p-toluenesulfonic acid are added to the residue, and the mixture is maintained at about 185° C. under a slight vacuum (50 mbar) for 1.5 hours. The reaction mixture is diluted with 50 ml of toluene and washed with water. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from acetonitrile gives 9.9 g (38%) of 5,7-dimethyl-3-(4-n-octadecyloxycarbonylmethoxyphenyl)benzofuran-2-one, melting point 57°-59° C. (Compound (109), Table 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH3:11])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:19]1[CH2:22][CH2:21][CH2:20]1>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH3:11])=[C:6]([O:8][CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH:7]=1
Reactant: BrC1CCC1
Reactant: CCOc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)cc1OC1CCC1
Temperature: 65 °C
Yield: 97.3 %

Procedure:
The intermediate 5-bromo-2-ethoxy-phenol (15 g, 73.9 mmol) was dissolved in DMF (100 mL) then treated with anhydrous K2CO3 (20.4 g, 148 mmol) followed by the addition of bromocyclobutane (19.1 g, 128 mmol). The reaction was heated at 65° C. for 12 h, then cooled to room temperature, diluted with diethyl ether, and the solution washed with a 1 N aqeuous NaOH solution followed by water. The organic layer was then dried over MgSO4, filtered, and concentrated to afford titled compound as an oil (19.5 g, 90%). 1H NMR (CDCl3) 6.98 (dd, J=8.4, 2.1, 1H), 6.83 (d, J=2.4, 1H), 6.73 (d, J=8.7, 1H), 4.65-4.57 (m, 1H), 4.05 (q, J=7.1, 2H), 2.50-2.42 (m, 2H), 2.30-2.18 (m, 2H), 1.90-1.81 (m, 1H), 1.73-1.63 (m, 1H), 1.44 (t, J=7.1, 3H). 13C NMR 148.2, 147.8, 123.4 (CH), 117.0 (CH), 114.7 (CH), 112.7, 72.5 (CH), 64.8 (CH2), 30.6 (CH2), 14.7 (CH3), 13.1 (CH2). LC/MS (Method B) 4.18 min, [M+1]+ 271/273.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].N12CCCN=C1CCCCC2.[CH:43]([CH:45]=[CH2:46])=[O:44]>O1CCCC1.O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:46][CH2:45][CH:43]=[O:44])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: C=CC=O
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C[C@@H]2CN(CCC=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: -30 °C
Reaction time: 6 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (500 mg) and 1,8-diazabicyclo [5.4.0]undec-7-ene (1.5 μl) in tetrahydrofuran (2.5 ml) was cooled to −30° C. with stirring under nitrogen atmosphere. Acrolein (90%, 0.225 ml) was added to the mixture while maintaining the temperature at −20˜−40° C. for a period of 10 minutes and then the resulting mixture was stirred at 0° C. After 6 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was chromatographed on a silica gel using a mixture of hexane and ethyl acetate as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-formylethyl)piperazine (332 mg) as an oil.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19])(=O)OCC)C.C1OCCOCCOCCOCCOC1.[H-].[Na+].[O:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>C1COCC1.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[C:41]2[CH2:42][CH2:43][O:38][CH2:39][CH2:40]2)=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=1
Reactant: CCOP(=O)(Cc1ccc(OC)cc1[N+](=O)[O-])OCC
Reactant: O=C1CCOCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C=C2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of diethyl-(4-methoxy-2-nitrobenzyl)phosphonate (3 g; 9.89 mmol; 1 eq) and 15-crown-5 (196.31 μL; 0.99 mmol; 0.1 eq) in THF (30 mL) at 0° C. is added portionwise sodium hydride (431.65 mg; 9.89 mmol; 1 eq). After 15 min, a solution of tetrahydro-2H-pyran-4-one (990.43 mg; 9.89 mmol; 1 eq) in THF (30 mL) is added dropwise at 0° C. After stirring at room temperature for 3 h, the reaction is complete. The mixture is diluted with water at 0° C. and the product is extracted with EtOAc. The organic layer is washed with saturated aqueous NaHCO3 and brine then dried over MgSO4. The solvent is removed under reduced pressure and the yellow residue is washed with pentane (to remove the oil from NaH) to afford 1.8 g (73%) of the title compound as an orange powder. 1H NMR (DMSO-d6) δ 7.53 (d, J=2.3 Hz, 1H), 7.32-7.24 (m, 2H), 6.39 (s, 1H), 3.84 (s, 3H), 3.67-3.63 (m, 2H), 3.55-3.51 (m, 2H), 2.34-2.31 (m, 2H), 2.19-2.16 (m, 2H). HPLC (max plot) 87%; Rt 3.96 min.
Reaction SMILES: COC([N:5]1[C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[C@@H:9]([NH:18][C:19]2[N:20]=[N:21][N:22]([CH3:24])[N:23]=2)[CH2:8][CH2:7][CH2:6]1)=O.[OH-].[Na+]>C(O)C>[CH3:16][C:14]1[CH:13]=[C:12]([CH3:17])[C:11]2[NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([NH:18][C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)[C:10]=2[CH:15]=1
Reactant: COC(=O)N1CCC[C@H](Nc2nnn(C)n2)c2cc(C)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)c2c(c1)[C@@H](Nc1nnn(C)n1)CCCN2
Temperature: 85 °C
Yield: 84.4 %

Procedure:
Combine methyl-(5S)-7,9-dimethyl-5-[(2-methyl-2H-tetrazol-5-yl)amino]-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carboxylate (20.1 g), NaOH (12.10 g), and ethanol (80 mL) in a 250 mL teflon flask with overhead stirring. Sparge with nitrogen for 10 minutes, heat to reflux (85° C.) for ˜5.5 hours. Cool to room temperature with a cool water bath. Add acetic acid/water (17.5 mL/53 mL) slowly at room temperature and transfer to 500 mL flask about half way through addition (−30 min total time for addition). Seed with ˜5 mg of (5S)-7,9-dimethyl-N-(2-methyltetrazol-5-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine Heat to 50° C. (up to temperature in about 15 minutes). Add 54 mL of water over about 30 minutes. The next day, cool in ice bath, filter and rinse with methanol:water (1:1; 2×30 mL). Dry wet cake in vacuo at 60° C. to yield 13.99 g of (5S)-7,9-dimethyl-N-(2-methyltetrazol-5-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine HPLC analysis: 99.4%, ret time is 4.84 min. Chiral HPLC: 98.5% chiral purity.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[C:15]([C:16](=[O:22])[C:17]2[S:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:7]2[CH2:8][CH:9]([C:11](Cl)=[O:12])[O:10][C:6]=2[C:5]=1[Cl:23].CO.[Cl-].[NH4+]>>[C:11]([CH:9]1[CH2:8][C:7]2[CH:14]=[C:15]([C:16](=[O:22])[C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)[C:4]([Cl:3])=[C:5]([Cl:23])[C:6]=2[O:10]1)(=[O:12])[CH3:1]
Reactant: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)Cl)C2
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)C1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Cuprous iodide (5.7 g., 0.03 mole) is placed in a 250 ml. three-necked round-bottom flask equipped with a magnetic stirring bar, septum stopper, nitrogen inlet and CaSO4 drying tube. The flask is flame dried while purging it with nitrogen. Diethyl ether (80 ml.) is added and the flask is cooled to 0° C. Methyl lithium (42.8 ml. of 1.4 M solution, 0.06 mole) is added to the stirred mixture. After ten minutes at 0° C. the temperature is lowered to -78° C. A cooled etheral solution (25 ml.) of 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carbonyl chloride (3.6 g., 0.01 mole) is added. After stirring 15 minutes at -b 78° C., the reaction is quenched by adding methanol (3.52 g., 0.011 mole). The reaction mixture is allowed to warm up to 25° C. and then is poured into 150 ml. of saturated aqueous ammonium chloride. The mixture is extracted with ether (3×50 ml.). The ether extracts are combined, dried over MgSO4 and evaporated in vacuo to give 2-acetyl-6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran.
Reaction SMILES: O=O.Cl[C:4](Cl)([O:6][C:7](=[O:13])[O:8][C:9](Cl)(Cl)Cl)Cl.CN(C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.[C:25]1(C)C=CC=CC=1>>[CH3:25][C:4]1[O:6][C:7](=[O:13])[O:8][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1
Reactant: CN(C)c1ccccc1
Agent: O=O
Solvent: O
Product: Cc1oc(=O)oc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound of Reference Example 2 (8.5 g) in toluene (75 ml) was added triphosgene (6.4 g), and thereto was added dropwise dimethylaniline (15 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Then, the mixture was further stirred for 4 hours under reflux. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with 1N aqueous hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=4:1) to give the desired product as white crystal (6.16 g).
Reaction SMILES: [C:1]1([S:7][C:8](=[CH2:11])[CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[C:1]1([S:7]([C:8](=[CH2:11])[CH2:9][OH:10])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(CO)Sc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=C(CO)S(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a stirred solution of 0.91 g (5.5 mmol) of 2-(phenylthio)-2-propenyl alcohol in 60 mL of CH2Cl2 at -78° C. was added 1.11 g (5.5 mmol) of 85% m-chloroperbenzoic acid. The reaction mixture was stirred for 1 hour at -78° C. The cooling bath was removed and the mixture allowed to warm to room temperature. The mixture was filtered, and then extracted with three 50-mL portions of saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. The residue was flash chromatographed on silica gel (230-400 mesh, 4×12-cm packed column) with 80% EtOAc/Skelly B as eluant, to give 0.57 g (57%) of the sulfoxide as a colorless oil; IR (neat) cm1 3360, 1440, 1030, 990, 930, 750, 690; 1H NMR (CDCl3) δ4.00 (s, 1H, allylic), 4.15 (s, 1H, allylic), 4.40 (bs, 1H, OH), 5.90 (t, J=1 Hz, 1H, vinyl), 6.05 (s, 1H, vinyl), 7.35-7.80 (m, 5H, phenyl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][CH2:19][C:20]([O:22]CC4C=CC=CC=4)=[O:21])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:30]([CH3:32])[CH3:31])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[NH3:9].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:30]([CH3:32])[CH3:31])=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCC(=O)OCc1ccccc1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCC(=O)O)CCC2
Product: N
Temperature: 25 °C

Procedure:
Phenylmethyl 3-[1-[(4-chlorophenyl)methyl]-2-(1-methylethyl)-4,5,6,7-tetrahydro-1H-benzimidazol-7-yl]propanoate (second isomer from chiral HPLC, 18 mg) was dissolved in Methanol (1.5 mL). 3.3 M aqueous sodium hydroxide solution (0.5 mL) was added and the reaction mixture was left to stir at RT. After stirring for 18 h, LCMS of the reaction mixture demonstrated full consumption of the starting material and the formation of the desired acid product. The reaction mixture was concentrated in vacuo and taken up in acetonitrile/water. The resulting solution was acidified to pH 5-6 and loaded onto a 20 g SCX column. The column was washed with two column volumes of acetonitrile/water and then eluted with 10% ammonia in ethanol. The basic washings were concentrated in vacuo to afford the desired product as the ammonium salt (10.1 mg). LC/MS MH+ 361/363, Rt 1.87 mins (5 min system, TFA modifier).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[CH:13]=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22](Cl)(=[O:26])[C:23](Cl)=[O:24].C1C[O:31][CH2:30]C1.C[O-].[Na+].CO>CCOCC>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:22](=[O:26])[C:23]([O:31][CH3:30])=[O:24])=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2ccn(CCO[Si](C)(C)C(C)(C)C)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c2cc(OC)ccc12
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 1-[2-(tert-butyldimethylsilyloxy)ethyl]-6-methoxy-1H-indole (14.6 g, 46.5 mmol) in Et2O (300 mL) was cooled to 4° C. (ice bath) and 2.0 M solution of oxalyl chloride in THF (25.6 mL, 51.2 mmol) was added dropwise. The ice bath was removed and the reaction was allowed to warm to room temperature (1.5 h). The reaction was then cooled to −78° C. and a solution of 25% (w/w) NaOMe in MeOH (23.2 mL, 107.0 mmol) was introduced over 5 min. The reaction was allowed to warm to room temperature. The reaction was quenched with H2O (300 mL) and poured into EtOAc (300 mL). The water layer was separated and extracted with EtOAc (2×200 mL). The combined organic solution was washed with saturated aqueous NH4Cl (300 mL) and brine (400 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 50% hexanes/EtOAc) gave the title compound (16.2 g, 89%) as a yellow solid. 1H NMR (300 MHz, CDCl3) 8.44 (m, 2H), 7.12 (d, J=7.2 Hz, 1H), 6.98 (s, 1H), 4.38 (m, 2H), 4.10–4.00 (m, 5H), 3.96 (s, 3H), 0.94 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:29]([O-])=O)=[C:13]([CH:28]=1)[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:21])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1.[H][H]>[Pd].CO>[NH2:29][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:28][C:13]=1[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[CH3:21])=[O:19]
Reactant: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N)C1CCCCC1

Procedure:
A mixture of 3-(5-benzoyl-2-nitro-benzylamino)-N-cyclohexyl-N-methyl-propionamide (9 g, 0.02 mol), 10% palladium on carbon (2 g), and thiophene solution (2 mL) in MeOH (250 mL) was hydrogenated until 3 equivalents of hydrogen were consumed. The reaction mixture was filtered through Dicalite, and the filtrate was concentrated to yield a residue.
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC([O:22]C)=CC=3)C=CN=2)C=C(F)C=1.FC(F)(F)[C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[NH:48][CH:47]=[C:46]2[CH2:52][C:53]([OH:55])=O.[Cl:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[C:66]([C@H:70]([NH2:80])[CH2:71][C:72]3[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=3)=[N:67][O:68][CH:69]=2)=[CH:61][CH:60]=1.FC1C=C(C[C@@H](C2N(C3C=CC(OC)=CC=3)C=CN=2)N)C=C(F)C=1>>[Cl:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[C:66]([C@H:70]([NH:80][C:53](=[O:55])[CH2:52][C:46]3[C:45]4[C:49](=[CH:50][CH:51]=[C:43]([OH:22])[CH:44]=4)[NH:48][CH:47]=3)[CH2:71][C:72]3[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=3)=[N:67][O:68][CH:69]=2)=[CH:61][CH:60]=1
Reactant: N[C@H](Cc1cc(F)cc(F)c1)c1nocc1-c1ccc(Cl)cc1
Reactant: O=C(O)Cc1c[nH]c2ccc(C(F)(F)F)cc12
Reactant: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: COc1ccc(-n2ccnc2[C@@H](N)Cc2cc(F)cc(F)c2)cc1
Product: O=C(Cc1c[nH]c2ccc(O)cc12)N[C@H](Cc1cc(F)cc(F)c1)c1nocc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented in the synthesis of 5F substituting 2-(5-hydroxy-1H-indol-3-yl)acetic acid for 2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid and 28A for 5E to provide the desired compound (28B): 1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 9.04 (s, 1H), 8.65 (d, 1H), 7.32-7.20 (m, 3H), 7.06 (d, 1H), 6.95-6.83 (m, 2H), 6.74 (dd, 3H), 6.54 (dd, 1H), 5.25 (q, 1H), 3.41-3.25 (m, 2H), 3.08 (d, 2H); MS (m/z) 509.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([F:10])=[CH:5][N:4]=1.[CH3:11][NH2:12].C(Cl)Cl.CO.N>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:12][CH3:11])[C:6]([F:10])=[CH:5][N:4]=1
Reactant: CSc1ncc(F)c(Cl)n1
Reactant: CN
Agent: N
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CNc1nc(SC)ncc1F

Procedure:
Prepared from 2-methylsulphenyl-4-chloro-5-fluoro-pyrimidine by reacting with methylamine in ethanol at 100° C., Rf value: 0.53 (silica gel; methylene chloride/methanol/conc. aqueous ammonia=20:1:0.1)
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H][H]>O.C(O)C.[Pd]>[OH:10][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=Cc1ccc(C=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(CO)cc1
Yield: 99.3 %

Procedure:
Terephthalaldehyde (25.0 g) was suspended in water (20 ml) and ethanol (80 ml). Pd/C (220 mg) was added to the suspension and then hydrogen gas (4.3 l ) was introduced. The catalyst was removed by filtration and the filtrate was concentrated to give p-hydroxymethylbenzaldehyde (25.2 g). The product was dissolved in toluene (100 ml) and 48% HBr (50 ml) and the solution was refluxed for 2 hours. The reaction mixture was poured into iced water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline and dried, and then the solvent was removed by evaporation under reduced pressure. The residue was recrystallized from n-hexane to give colorless needles (37.5 g, yield: 82%). mp 97.5°-98.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:13])=O>>[ClH:13].[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:13])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cncc(Br)c1
Product: Cl
Product: O=C(Cl)c1cncc(Br)c1
Reaction time: 4 h

Procedure:
2.00 g (9.90 mmol) 5-bromonicotinic acid were mixed with 20 mL thionyl chloride and boiled for 4 h. The mixture was evaporated to dryness i. vac. and coevaporated twice with toluene. The residue was reacted further as the crude product.
Reaction SMILES: [F:1][C@H:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1.FC(C1C=CC=CC=1F)CO[C@H]1CC[C@H](N)CC1.CS[C:39]1[N:44]=[C:43]([OH:45])[N:42]=[C:41]2[NH:46][N:47]=[CH:48][C:40]=12>CC(O)C.O>[F:1][C@H:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:39]2[N:44]=[C:43]([OH:45])[N:42]=[C:41]3[NH:46][N:47]=[CH:48][C:40]=23)[CH2:7][CH2:6]1
Reactant: N[C@H]1CC[C@H](OC[C@H](F)c2ccccc2F)CC1
Reactant: CSc1nc(O)nc2[nH]ncc12
Agent: N[C@H]1CC[C@H](OCC(F)c2ccccc2F)CC1
Solvent: O
Solvent: CC(C)O
Product: Oc1nc(N[C@H]2CC[C@H](OC[C@H](F)c3ccccc3F)CC2)c2cn[nH]c2n1

Procedure:
From trans-4-[(2R)-2-fluoro-2-(2-fluorophenyl)ethoxy]cyclohexanamine, the resolved product of Example 11, Step 8, and 4-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-6-ol [R. K. Robins, J. Am. Chem. Soc. 79, (1957), 6407-15] in refluxing 2-propanol/water for several days: MS (m+1)=390.4; 1H NMR (400 MHz, CDCl3-CD3OD) 8.2 (s, 1H), 8.0 (s, 1H), 7.5 (m, 1H), 7.4 (dd, 1H), 7.2 (t, 1H), 7.1 (t, 1H), 5.85 (dd, JHF=47 Hz, 1H), 4.2 (m, 1H), 3.75 (m, 2H), 3.4 (m, 1H), 2.7 (m, 1H), 2.1 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+]>CO>[CH2:1]([N:8]1[C:25](=[O:26])[CH:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:20](=[O:21])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NC(=O)N(Cc2ccccc2)C(=O)C1Cc1ccccc1

Procedure:
To a suspension of 22.53 g (150 mmol) of benzylurea and 37.5 g (150 mmol) of diethyl benzylmalonate in 77 ml of methanol, 36.6 ml (150 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 48.35 g (quant., white crystal) of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([OH:27])=O)([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.F[P-](F)(F)(F)(F)F.CN(C)C=[N+](C)C.C(N(CC)CC)C.[NH2:49][NH2:50]>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([NH:49][NH2:50])=[O:27])([CH2:19][CH2:18]1)[CH2:21][CH2:22]2
Reactant: NN
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(=O)O)(CC1)CC2
Agent: CN(C)C=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(=O)NN)(CC1)CC2

Procedure:
A portion of solid (4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]octane-1-carboxylic acid 1-D (2.0 g, 5.27 mmol) was dissolved in anhydrous DMF (30 ml) and treated with N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (2.09 g, 7.91 mmol), triethyl amine (2.3 mL, 16.50 mmol), and hydrazine (0.50 mL, 15.93 mmol) at room temperature and a nitrogen atmosphere overnight. The solvent was removed in vacuo, and the residue was redissolved in methylene chloride (700 ml) and washed with saturated aqueous sodium bicarbonate, water, and brine. The product was dried over MgSO4 and the solvent removed to afford 13-A as a white powder. MS (ESI+)=394.13 (M+1).