Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2](=[C:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[CH:30][CH:29]=1>CS(C)=O.C(N(CC)CC)C.O>[F:1][C:2]([C:3]1[CH:19]=[CH:18][CH:17]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][N:8]=2)[CH:4]=1)=[C:20]1[CH2:25][CH2:24][N:23]([C:35]([NH:34][C:31]2[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[O:36])[CH2:22][CH2:21]1
Reactant: COc1ccc(NC(=O)Oc2ccccc2)cn1
Reactant: FC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(NC(=O)N2CCC(=C(F)c3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1
Reaction time: 12 h
Yield: 44.7 %

Procedure:
To a solution of 2-(3-(fluoro(piperidin-4-ylidene)methyl)phenoxy)-5-(trifluoromethyl)pyridine (110 mg, 0.312 mmol) and phenyl 6-methoxypyridin-3-ylcarbamate (76.2 mg, 0.312 mmol) in DMSO (5 mL) under a N2 atmosphere was added 5 drops of triethyl amine and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water several times to remove the excess DMSO. The title compound was crystallized from hexane and diethyl ether to give the pure title compound (70 mg). 1H NMR (500 MHz, CDCl3): δ 2.5 (brs, 2H), 2.6 (brs, 2H), 3.5 (brs, 2H), 3.6 (brs, 2H), 4.0 (s, 3H), 6.7 (d, 1H, J=9 Hz), 7.0 (d, 1H, J=8.5 Hz), 7.1-7.3 (m, 3H), 7.4 (t, 1H, J=8.5 Hz), 7.9 (m, 1H), 8.1 (s, 1H), 8.4 (s, 1H); 13CNMR (125 MHz, CDCl3): 25.5, 27.7, 29.7, 44.0, 44.3, 53.8, 60.4, 110.3, 111.6, 114.2, 114.3, 121.3, 121.4, 121.7, 122.0, 122.5, 124.7, 125.3, 129.6, 129.9, 133.6, 133.8, 134.1, 136.8, 138.5, 145.3, 145.4, 149.9, 151.8, 153.0, 155.2, 160.3, 165.4; m/z (503.3 M+ H+); HPLC: 97.6%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[C:9]([O:12][CH3:13])([CH3:11])[CH3:10].CC(C)=[O:16].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:13][O:12][C:9]([C@@H:5]1[C:6](=[O:8])[NH:7][C@@H:4]1[CH2:3][C:2]([OH:16])=[O:1])([CH3:11])[CH3:10]
Reactant: CC(C)=O
Reactant: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CC(=O)O
Reaction time: 0.67 h

Procedure:
A solution of (3R, 4R)-4-(2-hydroxyethyl)-3-(1-methoxy-1-methylethyl)azetidin-2-one (250 mg) in acetone (26.7 ml) as added to a solution of 2N Jones reagent (2.67 ml) in acetone (24.03 ml) at ambient temperature over a period of 40 minutes and the mixture was stirred for another 40 minutes. After addition of an excess of isopropyl alcohol to the mixture, the solvent was distilled off. The residue was dissolved in chloroform and washed with a saturated aqueous sodium chloride. The aqueous layer was extracted four times with chloroform. The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The crystalline residue was washed with hexane to give 2-[(2R, 3R)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (211 mg).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:17](Cl)(Cl)Cl.Cl>C(O)C.O>[CH2:3]([C:10]1[CH:11]=[C:12]([CH:17]=[O:1])[C:13]([OH:16])=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: ClC(Cl)Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=Cc1cc(Cc2ccccc2)ccc1O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
157 g of sodium hydroxide (50% in water) was added all at once to a stirred mixture of 100 g of p-benzylphenol in 165 ml of ethanol. The mixture was heated to 75°-80° C., and 161.5 g of chloroform was added drop-by-drop to the stirred mixture over a 5-hour period, at 75°-80° C., then was stirred for 2 hours at 75° C. Then 80.8 g of chloroform was added drop-by-drop, at 75°-80° C., and the mixture was stirred for 1 hour at 75° C. This procedure was repeated. The mixture was concentrated under reduced pressure to give a solid residue. The residue was poured into water, and the stirred mixture was acidified with concentrated hydrochloric acid. The aqueous phase was separated, extracted with ether and the extract was concentrated under reduced pressure to give an oil. The oil was extracted with petroleum ether. The extract was concentrated under reduced pressure. The residue was suspended in 150 ml of a saturated solution of sodium bisulfite and the mixture was stirred for 1 hour at room temperature. The liquid was decanted, and the solid was washed with water, stirred with ethanol and the mixture was filtered. The solid was washed with ether, then suspended in 10% sulfuric acid solution. The resulting mixture was stirred for 11/2 hours, then extracted with ether. The extract was dried (MgSO4) and concentrated under reduced pressure to give 5-benzylsalicylaldehyde (1A).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C@H:16]3[C@H:21]([NH2:22])[CH2:20][CH2:19][CH2:18][O:17]3)[CH2:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:32]([C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([C:35]1[CH:36]=[C:37]([NH:41][C:42]([NH:22][C@@H:21]2[CH2:20][CH2:19][CH2:18][O:17][C@H:16]2[CH2:15][N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:24][CH:23]=3)[CH2:10]2)=[O:43])[CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: N[C@@H]1CCCO[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2CCCO[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 0.01 h
Yield: 64.9 %

Procedure:
To a solution of (2S,3R)-2-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine dihydrochloride (16 mg, 0.043 mmol—prepared according to Part I) and excess triethylamine (100 μL, 0.719 mmol) in methylene chloride (1 mL) was added 3-acetylphenyl isocyanate (6.9 mg, 0.043) dissolved in methylene chloride (1 mL). The resulting yellow solution was shaken vigorously for 20 sec, and allowed to stand at 23° C. for 10 min. The solution was then concentrated in vacuo, and the resulting residue was purified by flash chromatography (5% methanol in methylene chloride) to yield the desired urea (13 mg, 65%) as a pale yellow oil. MS (ESI), m+/z: (M+H)+=468.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccccc5Cl)n4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2ccccc2Cl)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(6-(2-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.010 g, 0.0177 mmol) in 3:1 THF/ethanol (1 ml) was added 1M sodium hydroxide (0.0373 ml, 0.0373 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated and diluted with water. The reaction was acidified with 1M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel preparative thin-layer chromatography eluting with 95:5:1 DCM/MeOH/glacial acetic acid to yield the desired compound (0.007 g, 0.0124 mmol, 70.0% yield). MS (apci) m/z=535.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].I[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[CH:31][CH:30]=1>>[C:40]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:39]=[CH:38][C:37]([CH2:36][CH2:35][C:32]2[CH:33]=[CH:34][C:29]([CH2:28][CH2:27][CH2:26][O:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[C:12]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]3)=[O:13])=[CH:30][CH:31]=2)=[CH:42][CH:41]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Reactant: ICCCc1ccc(CCc2ccc(-c3ccccc3)cc2)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(CCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 4-{2-[4-(3-iodopropyl)phenyl]ethyl}biphenyl.
Reaction SMILES: [SH2:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1>CO>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[S:1])[NH2:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccncc1
Reactant: S
Solvent: CO
Product: NC(=S)Cc1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
Hydrogen sulfide was passed through a solution of 2-(pyridin-4-yl)acetonitrile (2.5 g) in 30% strength ammoniacal methanol (12 ml) at 0° C. for 30 minutes. The resulting reaction mixture was stirred at 25° C. for 16 hours. The solid which had precipitated was filtered out, washed with ether and dried. The desired product was obtained in a yield of 76%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>C(#N)C.CN(C=O)C>[F:29][C:11]1[N:12]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[S:9][C:10]=1[N:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(-c2cncc(F)c2)s1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1sc(-c2cncc(F)c2)nc1F
Temperature: 25 °C
Reaction time: 168 h
Yield: 82.2 %

Procedure:
To a degassed solution of di(tert-butyl) 2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-ylimidodicarbonate (1.0 g, 2.53 mmol) in anhydrous acetonitrile (20 mL) and DMF (10 mL) was added F-TEDA (SELECTFLUOR™) (1.8 g, 5.06 mmol). The reaction mixture was stirred at ambient temperature for 7 days. Water was added to the reaction mixture and the target extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, was filtered and was concentrated. The crude mixture was purified via silica gel chromatography (0-100% ethyl acetate/hexanes) to afford a beige solid (860 mg, 82%): mp 143-143° C.; 1H NMR (300 MHz, CDCl3) δ 8.87 (t, J=1.4 Hz, 1H), 8.54 (d, J=2.7 Hz, 1H), 7.91 (ddd, J=8.9, 2.7, 1.8 Hz, 1H), 1.48 (s, 18H); ESIMS m/z 414 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7]([O:11][C:12]([O:14]N=C(C1C=CC=CC=1)C#N)=O)([CH3:10])([CH3:9])[CH3:8].C[O-].[Na+]>CCOCC>[C:7]([O:11][C:12]([N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH3:6])=[O:14])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CNCCNC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CNCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
8.8 g of N,N'-dimethylethylenediamine were dissolved in 50 ml of ether and the solution was cooled to 0° C. 18.5 g of BOC-ON [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile] were slowly added dropwise and the mixture was stirred at RT for 16 hours. 6 g of sodium methylate were added and stirring was continued at RT for 18 hours. The substance which had precipitated out was filtered off with suction and washed with ether. The combined ether solution was concentrated in vacuo and the residue was distilled (boiling point 58°-60° C./0.5 mbar). 11.3 g were obtained as a colorless oil. MS(Cl): 189 (M+H)⊕, 133
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[CH:7][C:2]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 6.78 ml, 54.9 mmol), tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 10 g, 49.9 mmol) and DIPEA (26.2 ml, 150 mmol) in DMSO (160 ml) was heated at 140° C. for 18 hours. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organics were washed with brine (3×100 ml), filtered through a hydrophobic frit, further dried over magnesium sulphate and then concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-40% ethyl acetate/petrol). Impure fractions were further purified by column chromatography (silica, 10-40% ethyl acetate/petrol) and combined to afford the title compound.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].[CH3:18][C:19](=O)[CH2:20][CH2:21][C:22](=O)[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:23][C:22]1[N:2]([S:1]([C:5]2[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:3])=[O:4])[C:19]([CH3:18])=[CH:20][CH:21]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-sulfamoyl-5-(trifluoromethyl)benzoic acid (200 mg) and 2,5-hexanedione (0.26 ml) in toluene (1 ml) was added p-toluenesulfonic acid monohydrate (28 mg), and the mixture was stirred under reflux with Dean-Stark Trap for 24 hours. Then 2,5-hexanedione (0.26 ml) and p-toluenesulfonic acid monohydrate (30 mg) was added to the mixture, and the mixture was stirred under the same condition for 24 hours. The mixture was evaporated and purified with column chromatography (silica gel, 50 ml, methanol:dichloromethane (5:95–20:80)) to give 3-[(2,5-dimethylpyrrol-1-yl)-sulfonyl]-5-(trifluoromethyl)benzoic acid (280 mg) as a crude solid. The solid was dissolved in a mixture of 1N sodium hydroxide aqueous solution (10 ml) and water (20 ml), and then adjusted to pH 1–2 with 1N hydrochloric acid (20 ml). The resulting powder was collected by filtration and dried under reduced pressure to give pure product (191.1 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:7]=1)=[O:5].CC(C)=O.[N:24]([O-:26])=[O:25].[Na+].CCCCCC>O>[N+:24]([CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:7]=1)=[O:5])([O-:26])=[O:25]
Reactant: CCCCCCCCc1ccc(C(=O)CCCl)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCCCCCCCc1ccc(C(=O)CC[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
3-Chloro-1-(4-octylphenyl)propan-1-one (110 g) and acetone (1 L) are charged into a round bottom flask equipped with a condenser and guard tube and stirred. Sodium nitrite (271 g) is added and the mixture is slowly heated to 80° C. and maintained at that temperature for about 21 hours. The mass is cooled to 58° C., sodium nitrite (10 g) is added, and the mass is maintained at 78° C. for about 6 hours. The solvent is evaporated under reduced pressure. The compound obtained is diluted with water (250 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layer is dried over anhydrous sodium sulphate (50 g) and concentrated under reduced pressure to give solid. Hexane (500 mL) is added and the mixture is cooled to −10° C. and stirred for 20 minutes. The formed solid is separated by filtration and washed with cold hexane (2×100 mL) to obtain the title compound as an off-white solid. Yield: 75 g.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[F:37][C:38]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41].C(N(CC)CC)C>CN(C)C=O>[F:37][C:38]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:39]=1[C:40]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)=[O:41]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccc(F)cc4F)cc3)cc21
Yield: 55.9 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), 2,4-difluorobenzoylchloride (141 mg), triethylamine (232 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (251 mg).
Reaction SMILES: C(C1C=CC=CC=1N[C@@H](CC1C=CC(C2C=CC=C(NC)C=2)=CC=1)C(OCC)=O)(=O)C1C=CC=CC=1.[NH2:37][C@@H:38]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][NH:58][CH2:59][C:60](=[O:67])[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:52]=2)=[CH:47][CH:46]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40].O=[C:69]1[CH2:74][CH2:73][CH2:72][CH2:71][CH:70]1[C:75]([O:77][CH2:78][CH3:79])=[O:76]>>[C:60]([CH2:59][NH:58][CH2:57][C:53]1[CH:52]=[C:51]([C:48]2[CH:47]=[CH:46][C:45]([CH2:44][C@H:38]([NH:37][C:71]3[CH:72]=[CH:73][CH:74]=[CH:69][C:70]=3[C:75]([O:77][CH2:78][CH3:79])=[O:76])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:50][CH:49]=2)[CH:56]=[CH:55][CH:54]=1)(=[O:67])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1
Agent: CCOC(=O)[C@H](Cc1ccc(-c2cccc(NC)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Product: CCOC(=O)c1ccccc1N[C@@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)C(=O)OCC
Yield: 9.9 %

Procedure:
In a manner similar to the preparation of the ethyl (S)-2-(2-benzoylphenylamino)-3-(3′-methylaminobiphenyl-4-yl)propionate (Example 1g), using 6.7 g (16.1 mmol) of ethyl (S)-2-amino-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}propionate (Example 28f) and 3 ml (19.3 mmol) of ethyl 2-oxocyclohexanecarboxylate, 0.90 g of ethyl (S)-2-(2-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-1-ethoxycarbonylethylamino)-benzoate is isolated with a 10% yield.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[I:10][CH3:11]>>[I-:1].[OH:8][C:7]1[C:11]([I:10])=[N+:3]([CH3:2])[C:4]([CH3:9])=[CH:5][CH:6]=1
Reactant: CI
Reactant: Cc1ccc(O)c(I)n1
Product: Cc1ccc(O)c(I)[n+]1C
Product: [I-]

Procedure:
2-Iodo-3-hydroxy-6-methylpyridine (835 mg) and iodomethane (3 mL) were added in glass sealed cube, and the reaction mixture was reacted at 130° C. for 4 h and at 180° C. for 1 h. The reaction mixture was completely evaporated to give 3-hydroxy-2-iodo-1,6-dimethylpyridinium iodide (2-014-02) (1.42 g).
Reaction SMILES: O.[OH-].[Na+].[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[CH:10]=[C:9]2[C@H:25]1[CH2:27][C@H:26]1[CH2:28][N:29]([CH3:31])[CH3:30])#[N:5]>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C@H:25]1[CH2:27][C@H:26]1[CH2:28][N:29]([CH3:31])[CH3:30])#[N:5]
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3CN(C)C)c3cc(C#N)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)C[C@@H]1C[C@@H]1c1c[nH]c2ccc(C#N)cc12
Temperature: 70 °C
Yield: 75 %

Procedure:
Water (4 ml) and an aqueous solution of sodium hydroxide (2 ml, 10 N) were sequentially added to a flask charged with a solution of crude cis-2-[5-cyano-1-(p-toluenesulfonyl)indol-3-yl]-1-(N,N-dimethylaminomethyl)cyclo-propane dissolved in anhydrous ethanol (15 ml). The resulting mixture was heated at 70° C. for 1 h. The solvent was evaporated and the residue was taken up in brine (10 ml). The aqueous layer was extracted with 10% methanol/ethyl acetate (3×5 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography and eluted using a step gradient of a solvent mixture [chloroform/(2 M ammonia/methanol), 90/10, 80/20]. The cis-2-[5-cyanoindol-3-yl]-1-(N,N-dimethylaminomethyl)cyclopropane was obtained as a white solid (63 mg, 75% yield over 3 steps): 1H NMR (400 MHz, CDCl3): δ8.47 (1H, br s), 8.07 (1H, s), 7.41 (2H, apparent q, J=8.0 Hz), 7.03 (1H, s), 2.37 (1H, dd, J=12.6, 4.7 Hz), 2.18 (6H, s), 1.97 (1H, m), 1.69 (1H, dd, J=12.6, 8.6 Hz), 1.34 (1H, m), 1.22 (1H, m), 0.71 (1H, q, J=5.0 Hz); MS m/e 240 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1)=O.[CH:10]1([CH2:13][NH2:14])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][N:14]=[CH:1][C:3]2[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=2)[CH2:12][CH2:11]1
Reactant: Cc1cc(C=O)ccn1
Reactant: NCC1CC1
Product: Cc1cc(C=NCC2CC2)ccn1

Procedure:
Reaction of 4-formyl-2-methylpyridine [prepared in Example 33(a)] and cyclopropylmethyl amine by the procedure of example 1(c) affords the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][CH:17]=[CH:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][CH2:20]1.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:26](=[O:32])[O:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:23][CH2:24]2)[C:3]2[S:18][CH:17]=[CH:16][C:4]=2[N:5]=1
Reactant: CC(C)COC(=O)NC1CCNCC1
Reactant: COc1ccccc1-c1nc(Cl)c2sccc2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1nc(N2CCC(NC(=O)OCC(C)C)CC2)c2sccc2n1
Yield: 54.6 %

Procedure:
A solution of 4-chloro-2-(2-methoxyphenyl)thieno[3,2-d]pyrimidine (0.15 g, 0.54 mmol), isobutyl piperidin-4-ylcarbamate (0.11 g, 0.54 mmol), and Et3N (0.15 mL, 1.1 mmol) in DMF (1.8 mL) was heated in a microwave oven at 180° C. for 5 min. The reaction was cooled and diluted with CH2Cl2. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum to give isobutyl 1-(2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (0.13 g, 55% yield). LC/MS: m/z 441.5 (M+H)+ at 2.55 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).