Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH:2]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2.N1CCCC1>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: COc1ccc(C=O)cc1-c1cccnc1
Solvent: C1CCNC1
Solvent: CCO
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1-c1cccnc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A mixture of 3-(3-pyridyl)-4-methoxybenzaldehyde (0.25 g), 5-chloro-2-oxindole (0.2 g) and pyrrolidine (0.5 ml) in ethanol (2 ml) was placed in a sealed tube and heated to 100° C. A precipitate formed within 10 minutes so the reaction was diluted with another 10 ml of ethanol and heating resumed. After 4 hours, the reaction was cooled and the solid was removed by filtration and washed with ethanol and then hexanes to afford 0.27 g (61%) of 5-chloro-3-(3-(3-pyridyl)-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[ClH:39].O>[Cl-].[NH+]1C=CC=CC=1>[ClH:39].[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
cis-7-Methoxy-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (4 g) was dissolved in melted pyridinium chloride, prepared from a mixture of pyridine (20 ml) and conc. hydrochloric acid (21 ml) where the water was removed by distillation at 140° C. The mixture was heated at 140° C. for 3 hours and then at 150° C. for 6 hours. The mixture was cooled down to 100° C. Water was added (30 ml) and the mixture was cooled down to 30° C. Toluene (30 ml) and sodium hydroxide (32,5%) to pH 12 was added. The mixture emulsified and was again made pH 3 with conc. hydrochloric acid. The hydrochloride of cis-7-hydroxy-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane precipitated as a sticky product. It was dissolved in ethanol (200 ml) and water (10 ml), treated with active carbon, filtered and evaporated. Redissolved in ethanol (50 ml) and water until dissolved at 79° C. The product crystallised when the solution was cooled down to room temperature.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH:17]([CH3:19])[CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:20]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=3)[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)Cc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
120 mg (95%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-isobutyl-1H-pyrazol-5-yl)propanal (80 mg, 0.312 mmol), 1-phenylpiperazine (0.047 mL, 0.312 mmol), DIPEA (0.081 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]1[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=2)[C:4](=[O:3])[CH2:5][CH2:6][CH2:7]1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (4-(trifluoromethoxy)phenyl)methanamine and commercially available 2-methoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions H): tR=1.37 min.; [M+H]+: 379.75 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: Cc1cc(C(=O)N[C@@H](C)c2nc3cc([N+](=O)[O-])ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(N)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 83 %

Procedure:
40 mg of 3-methyl-N-[(1S)-1-(5-nitro-1H-benzimidazol-2-yl)ethyl]-4-(pyrrolidin-1-ylcarbonyl)benzamide if dissolved in 40 mL of methanol, combined with 10 mg of palladium on activated charcoal (10%), and hydrogenated for 3 hours with hydrogen (3 bar). Then the catalyst is filtered off and the solvent is distilled off. Yield: 83%; Rf value: 0.50 (silica gel; dichloromethane/ethanol=4:1); C22H25N5O2 (391.47); mass spectrum: (M+H)+=392 and (M−H)−=390
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:47])[C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[O:39][Si](C(C)(C)C)(C)C)[CH:23]=1>C1COCC1>[CH3:19][O:20][C:21](=[O:47])[C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[OH:39])[CH:23]=1
Reactant: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O)c1
Reaction time: 0.5 h

Procedure:
The solution of tetrabutyl ammonium fluoride (42.8 g, 0.13 mol) in THF (350 mL) was added dropwise to a solution of compound of Example 1g (35 g, 0.068 mol) in THF (150 mL) under nitrogen at 5° C. and stirred for 30 min. Solvent was removed from the reaction mixture and ice water (200 mL) was added. The solid separated was filtered, and washed with water (3×100 ml). The crude obtained was purified by column chromatography (silica gel, ethyl acetate/pet. ether) to obtain the title compound. Yield: 24 g, (88%); 1H NMR (CDCl3, 300 MHz): δ 2.44 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 4.26 (s, 2H, CH2), 6.81 (t, 1H, Ar), 7.20-7.26 (m, 2H, Ar), 6.81 (t, 1H, Ar), 7.70 (s, 1H, Ar); MS: m/e (El) 401 (M+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]#[CH:3].[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15]Br>>[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15][O:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:1][C:2]#[CH:3])=[CH:11][CH:10]=1
Reactant: C#CCOc1ccc(O)cc1
Reactant: CC(C)=CCBr
Product: C#CCOc1ccc(OCC=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 1, by reacting hydroquinone monopropargyl ether with 3-methyl-2-butenyl bromide, there is obtained 1-[(3-methyl-2-butenyl)oxy]-4-propargyloxy-benzene; B.P. 145°-148° C/1 mmHg.
Reaction SMILES: [CH3:1][OH:2].[NH2:3][C:4]1[C:11]([F:12])=[CH:10][C:7]([C:8]#[N:9])=[C:6](F)[CH:5]=1>O1CCCC1>[NH2:3][C:4]1[C:11]([F:12])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:2][CH3:1])[CH:5]=1
Reactant: CO
Reactant: N#Cc1cc(F)c(N)cc1F
Solvent: C1CCOC1
Product: COc1cc(N)c(F)cc1C#N
Temperature: 25 °C
Yield: 97 %

Procedure:
To a mixture of methanol (10.48 mL, 0.25 mol) and anh. tetrahydrofuran (60 mL) was added dropwise a solution of potassium tert-butilate (6.76 g, 0.05 mol) in anh. tetrahydrofuran (52 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred for minutes at room temperature and then 4-amino-2,5-difluorobenzonitrile (4 g, 0.02 mol) was added. The reaction mixture was stirred at 70° C. for 3 hours. The solvent was partially removed and ether was added into the mixture. The organic layer was washed with bicarbonate and brine, dried and filtered. The organic solvent was removed under reduced pressure to give the title compound as a yellow solid (97%), which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][N:13]=1)[C:9]#[N:10].C([O-])(O)=O.[Na+]>C(O)C>[N:5]1[CH:2]=[CH:3][N:13]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=12
Reactant: O=CCCl
Reactant: N#Cc1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccn2ccnc2c1
Temperature: 80 °C

Procedure:
Chloroacetaldehyde (˜50% in H2O, 3.24 ml, 26 mmol) was added to a stirred mixture of 2-amino-isonicotinonitrile (1.6 g, 3.4 mmol) and NaHCO3 (2.23 g, 26.5 mmol) in ethanol (20 ml) at RT under N2. The reaction was stirred and heated at 80° C. for 18 hours. After cooling to RT the volatiles were removed in vacuo and the residue was partitioned between EtOAc/H2O. This mixture was filtered to remove some dark insoluble residue. The solid was washed with MeOH. The aqueous layer was extracted with EtOAc (×2). The combined EtOAc extracts were dried (Na2SO4) and filtered. The MeOH washings were added and the volatiles were removed in vacuo. The residue was purified by chromatography on silica: 100% DCM→1% 2M NH3-MeOH/DCM to give the title product. 1H NMR (400 MHz, DMSO-d6): 8.74 (1H, dd), 8.35 (1H, s), 8.19 (1H, s), 7.86 (1H, s), 7.21 (1H, dd).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.N1C=CN=C1.[Cl-].[C:17]([SiH:21]([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.CCOCC>[Si:21]([O:8][CH2:7][C:3]1[CH:2]=[C:1]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: OCc1cccc(CO)c1
Reactant: C[SiH](C)C(C)(C)C
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Reaction time: 12 h

Procedure:
A solution of 1,3-benzenedimethanol (2 g; 14.47 mmol) in 50 ml of dimethylformamide is stirred at ambient temperature. Imidazole (1.97 g; 28.94 mmol) and tert-butyl(dimethyl)silane chloride (2.18 g; 14.47 mmol) are added in succession. After stirring for 12 hours, the reaction mixture is diluted with ether and washed with a saturated aqueous sodium chloride solution. After extraction, the ethereal phase is dried over magnesium sulphate and concentrated to yield the expected compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[C:6]2[CH:7]=[CH:8][C:9]3[O:14][CH2:13][CH2:12][O:11][C:10]=3[C:5]=2[C:4](=[O:15])[N:3]1[CH2:16][CH2:17][CH2:18][CH2:19]O.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[O:1]=[S:2]1(=[O:21])[C:6]2[CH:7]=[CH:8][C:9]3[O:14][CH2:13][CH2:12][O:11][C:10]=3[C:5]=2[C:4](=[O:15])[N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][Br:23]
Reactant: O=C1c2c(ccc3c2OCCO3)S(=O)(=O)N1CCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1c2c(ccc3c2OCCO3)S(=O)(=O)N1CCCCBr

Procedure:
To a solution of 1,1-dioxido-2-(4-hydroxybutyl)-4,5-ethylenedioxy-1,2-benzisothiazol-3(2H)-one (313 mg, 1 mmol) and carbon tetrabromide (432 mg, 1.3 mmol) in methylene chloride (2 mL) cooled in an ice bath under a nitrogen atomosphere was added dropwise a solution of triphenylphosphine (341 mg, 1.3 mmol) in methylene chloride (3.5 mL). The reaction was allowed to stir with gradual warming to room temp. over a four hour period and then the solvent was evaporated and the residue chromatographed on a column of silica gel by elution with chloroform to give crystalline 1,1-dioxido-2-(4-bromobutyl)-4,5-ethylenedioxy-1,2-benzisothiazol-3(2H)-one from diethyl ether/hexane, melting point 135-136° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH2:17])[C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>O.CCOCC>[NH:17]([C:24]([CH3:25])=[O:26])[C@H:5]([C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])[CH2:4][CH:2]([CH3:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Reaction time: 1 h
Yield: 74 %

Procedure:
Leu-Leu (1.0 g, 3.8 mmol) and potassium carbonate (7.0 g, 5 mmol) are dissolved in 100 ml of water. The solution is cooled with ice and 5.0 ml acetic anhydride in 50 ml of ether is added dropwise under vigorous stirring. Stirring is continued for one hour, then the ice-bath is removed and the stirring continued for further 2 hours. The water phase is separated, acidified with hydrochloric acid. The precipitate is stirred for one hour, filtered, washed with water and dried yielding 0.8 gram (74%) of Ac-Leu-Leu.
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:21])C(=O)C1>CN(C=O)C>[C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:12])([F:13])[F:11])[C:6]=1[Cl:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)c1cc(C(F)(F)F)n[nH]1
Solvent: CN(C)C=O
Product: CC(C)(C)c1[nH]nc(C(F)(F)F)c1Cl

Procedure:
Following protocol L, 5-tert-butyl-3-trifluoromethyl-1H-pyrazole was treated with NCS in DMF to yield title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]2[CH:12]=[N:13][C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=[CH:9][C:10]=23)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cccc2c(-c3ccc(F)cc3)ncn12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2c(-c3ccc(F)cc3)ncn12
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(4-fluorophenyl)-imidazo[1,5-a]pyridine-5-carboxylic acid ethyl ester (2.0 g, 7.0 mmol) in MeOH (233 mL) is added a solution of 85% KOH (4.6 g, 69 mmol) in H2O (35 mL) and the mixture is warmed at reflux. After 15 minutes, the reaction mixture is evaporated, diluted with water, and washed with EtOAc (2×200 mL). The aqueous layer is acidified with 1 N aqueous HCl (pH 5-6) to afford a precipitate. The solid is collected by filtration and triturated with 10% MeOH—CH2Cl2 to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:18])=[C:13]([F:30])[CH:12]=1>>[F:30][C:13]1[C:12]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:11][CH:16]=[CH:15][C:14]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:18]
Reactant: OB(O)c1cccnc1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1cccc(-c2ccncc2)c1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure FF starting from 3-pyridine boronic acid and (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone. MS (ES+) 354.2
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH2:24]([N:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([CH3:34])=[N:27]1)[CH3:25]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:31]([C:29]3[C:28]([CH3:34])=[N:27][N:26]([CH2:24][CH3:25])[CH:30]=3)=[O:32])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: CCn1cc(C(=O)O)c(C)n1
Product: CCn1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c(C)n1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.73 min; [M+H]+=469.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:37])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:40]1[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=1>>[C:1]([O:5][C:6](=[O:38])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:37])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:29]=3)[CH:19]=[C:20]([O:22][C:40]3[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Reactant: N#Cc1ccc(F)cc1
Product: CCOC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 91.5 %

Procedure:
Using 0.56 g (1.06 mmol) of (4-{3-[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester and 4-fluoro-benzonitrile (0.32 g, 2.65 mmol) and following the procedure of Example 42(b) afforded 0.61 g of the required product. Percentage purity (LCMS): 45.2%, (M+1)=628.3+1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl>[F:13][C:11]1[CH:10]=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([CH:12]=1)[O:6][CH:1]1[CH2:5][CH:4]2[CH:3]([O:22]2)[CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1OC1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1CC2OC2C1
Temperature: 25 °C

Procedure:
To 2-(cyclopent-3-enyloxy)-4-fluoro-1-nitrobenzene (2.05 g) in methylene chloride (45.0 ml) at 0° C. was added 3-chloroperoxybenzoic acid (2.95 g) and the mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with 10% aq. K2CO3. The organic layer was passed through a hydrophobic frit and solvent evaporated to give the desired product.
Reaction SMILES: P(=O)([O-])O[C:3](CC)(CC)[C:4]#[N:5].[H-].[Na+].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1>C1COCC1>[CH3:22][O:21][C:17]1[CH:16]=[C:15](/[CH:14]=[CH:3]/[C:4]#[N:5])[CH:20]=[CH:19][CH:18]=1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: COc1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(/C=C/C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.8 %

Procedure:
Diethylcyanomethyl phosphonate (28.6 mL, 176 mmol) was added to a suspension of NaH (7.0 g, 176 mmol, washed with hexanes to remove oil) in 450 mL of THF at RT and the resulting mixture was stirred at RT for 30 min. A solution of m-anisaldehyde (20.0 g, 140 mmol) in 50 mL of THF was added and the resulting mixture was stirred at RT overnight, resulting in the formation of a thick brown oil at the bottom of the mixture. The crude reaction mixture was concentrated in vacuo and the residue was partitioned between saturated aqueous NaHCO3 solution and methylene chloride. The organic phase was separated and the aqueous phase was extracted with methylene chloride. The combined organic phases were then dried over MgSO4, filtered, and concentrated in vacuo to provide 27.6 g of a brown oil (99% crude yield) which was carried on without further purification. 1H NMR (CDCl3) δ 7.30-7.40 (m, 2H), 6.92-7.05 (m, 3H), 5.86 (d, J=24 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[C:2]1([O:1][C:8]2[CH:13]=[CH:12][C:11]([Br:15])=[C:10]([CH3:14])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Oc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1cc(Oc2ccccc2)ccc1Br
Yield: 97.8 %

Procedure:
A mixture of 3-phenoxytoluene (2.5 g, 0.0136 mol) and N-bromosuccinimide (2.54 g, 0.0142 mol) was stirred in acetonitrile (20 mL) for 2.5 hours under an atmosphere of nitrogen. The solvent was removed under reduced pressure. Carbon tetrachloride was added to the residue and the resulting solid was removed by filtration. The filtrate was concentrated to yield 4-bromo-3-methylphenyl phenyl ether as yellow oil (3.5 g, 0.0133 mol):
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42](O)=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[C:18]([O:20][CH3:21])=[O:19])=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)c(C(=O)OC)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 115 %

Procedure:
To a stirred solution of dimethyl (S)-4-(2-pyrrolidinylmethoxy)isophthalate (616 mg, 2.10 mmol) in DMF (13 mL) was added pentafluoro ester of 3-methoxy4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.00 g, 2.08 mmol) and Et3 N (425 μl, 3.12 mmol), and the resulting mixture was stirred for 3.5 hr at room temp. The resulting mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over Na2SO4. After removal of the solvent, the residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 1.41 g(q.y.) dimethyl (S)-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalate as a yellow oil. 1H-NMR (CDCl3) δ 1.86–2.29 (m, 4 H), 2.30 (s, 3 H), 3.47–3.57 (m, 2 H), 3.58 (s, 3 H), 3.59 (s, 2 H), 3.83 (s, 3 H), 3.91 (s, 3 H), 4.22–4.37 (m, 2 H), 4.42–4.47 (m, 1 H), 6.44–8.46 (series of m, 12 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:11][N:12]([CH3:14])[CH3:13])[S:9][CH:10]=1.[NH2:15][C:16]1[C:19](=[O:20])[C:18](=[O:21])[C:17]=1OC>>[NH2:15][C:16]1[C:19](=[O:20])[C:18](=[O:21])[C:17]=1[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:11][N:12]([CH3:13])[CH3:14])[S:9][CH:10]=1
Reactant: COc1c(N)c(=O)c1=O
Reactant: CN(C)Cc1cc(OCCCN)cs1
Product: CN(C)Cc1cc(OCCCNc2c(N)c(=O)c2=O)cs1

Procedure:
An equimolar mixture of 4-[3-(amino)propoxy]-N,N-dimethyl-2-thiophenemethanamine [prepared according to the procedure described in published European Patent Application 27,744] and 1-amino-2-methoxycyclobutene-3,4-dione is reacted according to the general procedure of Example 19 to yield the title compound.