Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:21])[CH2:5][CH2:6][N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]1=[O:20].[CH:22](OCC)=[O:23]>C(COC)OC>[CH:22]([CH:14]([CH2:13][C:10]1[CH:11]=[CH:12][N:7]([CH2:6][CH2:5][N:4]([CH3:3])[CH3:21])[C:8](=[O:20])[CH:9]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:23]
Reactant: CCOC(=O)CCc1ccn(CCN(C)C)c(=O)c1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccn(CCN(C)C)c(=O)c1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a stirred, cooled suspension of 50% sodium hydride in oil (5.73 g) in dimethoxyethane (50 ml) was added dropwise over 50 minutes a mixture of ethyl β-[N-(2-dimethylaminoethyl)- 2-oxo-4-pyridyl]propionate (25.43 g) and ethyl formate (10.60 g). The reaction temperature was maintained below 3° C., and then was allowed to warm to room temperature overnight. The reaction mixture was poured on to ice and the resultant brown solution was extracted with petroleum ether (40°-60°) (80 ml) and diethyl ether (3×60 ml). The combined organic extracts were washed with water (20 ml). The combined aqueous solution and aqueous washings were taken to pH 5 with glacial acetic acid, the solvent volume was halved by evaporation under reduced pressure and taken to pH 8 with sodium bicarbonate solution. The solvents were removed by thorough evaporation under reduced pressure and the residue taken up in hot isopropanol-acetone, filtered over diatomaceous earth and evaporated under reduced pressure to yield an oil which was washed with petroleum ether (40°-60°) to afford as a brown oil, ethyl α-formyl-β-(N-(2-dimethylaminoethyl)-2-oxo-4-pyridyl]propionate (25.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([NH2:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:15]([S:22](Cl)(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:12][S:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])([CH3:11])[C:9]#[N:10])=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(N)(C#N)COc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C#N)(COc1ccc(Cl)cc1)NS(=O)(=O)Cc1ccccc1

Procedure:
suspension of 1-(4-chloro-phenoxy)-propan-2-one (3.7 g, 20 mmol), ammonium chloride (1.6 g, 29.2 mmol) and sodium cyanide (1.15 g, 23.3 mmol) in a solution of aqueous ammonia (100 ml, 28%) is stirred vigorously at room temperature for 20 hours. The aqueous phase is extracted repeatedly with ethyl acetate. The collected organic extracts are dried and the solvent is evaporated under reduced pressure to give the 2-(4-chlorophenoxy-methyl)-2-amino-propionitrile as a solid. c) A solution of 2-(4-chlorophenoxy-methyl)-2-amino-propionitrile (0.5 g, 2.4 mmol) and benzylsulfonyl chloride (0.5 g, 2.6 mmol) in pyridine (5 ml) is heated at +80° C. with stirring in the presence of DMAP (0.02 g) for about 16 hours. The reaction mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate and the product is purified by flash chromatography (eluent: ethyl acetate/hexanes 1:3) to give the 2-(4-chlorophenoxy-methyl)-2-benzylsulfonylamino-propionitrile in form of a colorless solid, m.p. 120-121° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=2[C:4]([O:6][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:5])=[CH:18][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc(F)cc1)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1

Procedure:
To a solution of 2-hydroxy-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 117; 2 g, 9.70 mmol) in acetone (50 ml) was added 1-(bromomethyl)-4-fluorobenzene (4.04 g, 21.35 mmol), potassium carbonate (4.02 g, 29.1 mmol) and the reaction was heated to reflux overnight. The mixture was filtered to remove the solid potassium carbonate. The solid was washed with acetone (50 ml). The organics were combined and evaporated under reduced pressure on a buchi to yield the title compound. The crude yellow oil was used directly without further purification. 4.1 g.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH:5]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[NH:32])=[CH:27][CH:26]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:7]=1[F:23])C.[Na].Cl>C(O)C>[C:37]([O:36][C:34]([NH:33][C:31](=[NH:32])[C:28]1[CH:29]=[CH:30][C:25]([NH:24][CH:5]([C:6]2[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:7]=2[F:23])[C:4]([OH:41])=[O:3])=[CH:26][CH:27]=1)=[O:35])([CH3:39])([CH3:38])[CH3:40]
Reactant: CCOC(=O)C(Nc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)c1cc(OCC)cc(OC2CCN(C)CC2)c1F
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOc1cc(OC2CCN(C)CC2)c(F)c(C(Nc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)C(=O)O)c1
Reaction time: 1 h
Yield: 105.2 %

Procedure:
A solution of 2.3 g (RS)-[4-(tert-butoxycarbonylamino-imino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester in 23 ml ethanol was treated with 6.06 ml 1N sodium hydroxyde solution. After one hour, 2.6 ml 1N hydrochloric acid were added until pH=8. The solvent was evaporated and the residue dried to constant weight. It was dissolved in absolute ethanol, filtered, the solution evaporated in vacuo, the residue dried and triturated in ether to yield 2.3 g of (RS)-[4-(tert-butoxycarbonylamino-imino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-acetic acid.off-white solid. MS: 545 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To an ice-cooled solution of 125 mL of 4-fluoroaniline and 18.4 mL of triethylamine in 300 mL of methylene chloride was added dropwise over 30 min 14.8 mL of trimethylacetyl chloride. After addition was complete, the cooling bath was removed and stirring was continued at ambient temperature for 1 h. The reaction mixture was brought to pH 3 with 6N HCl and was partitioned between methylene chloride and water. Evaporation of the organiclayer afforded a solid which was collected and washed with hexane to afford 21.35 g (83%) of the title compound as a crystalline solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[C:22]([BH3-])#N.[Na+].C=O.CC(O)=O.C([O-])(O)=O.[Na+]>CO>[CH3:22][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: c1ccc(-c2[nH]c3ccccc3c2C2CCNCC2)cc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Reaction time: 2 h
Yield: 24.1 %

Procedure:
3-(Piperidin-4-yl)-2-phenyl-1H-indole (200 mg, 0.7 mmol), sodium cyanoborohydride (51 mg, 0.8 mmol), formaldehyde (60 μl, 40% in H2O, 0.8 mmol) and AcOH (97 μl, 1.7 mmol) were stirred in MeOH (5 ml) at 0° C. for 1 h, then room temperature for 2 h. The solution was poured into saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried, and evaporated in vacuo to give white crystals (49 mg, 23%), mp 245-246° C. (from EtOH); δH (360 MHz, d6-DMSO) 1.88 (2H, d, J 13, NCH2CHAHB), 2.60-2.80 (2H, m, NCH2CHAHB), 2.76 (3H, s, CH3), 3.00-3.20 (3H, m, CH2CH and NCHAHB), 3.44 (2H, d, J 12, NCHAHB), 6.99 (1H, t, J 7, indole-H), 7.09 (1H, t, J 7, indole-H), 7.20-7.50 (6H, m, ArH), 7.98 (1H, d, J 7, ArH), 11.20 (1H, br s, indole NH); m/z (ES+) 291 (M++H).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1.[CH3:17][NH2:18]>O>[CH3:17][NH:18][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1
Reactant: CN
Reactant: O=c1[nH]c2c(cc1Cl)-c1ccccc1CO2
Solvent: O
Product: CNc1cc2c([nH]c1=O)OCc1ccccc1-2

Procedure:
Add 23.1 gm of 2-chloro-4,6-dihydro-3H[2]benzopyrano[3,4-b]pyridin-3-one to 100 ml of 40% aqueous methylamine and 250 ml of water. Heat the system in a steel bomb at 140° C. for 5 days. Stop the reaction and isolate the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]2[C:11]([CH3:17])=[C:12]([C:14]([NH2:16])=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+].Br[CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[CH2:29]([O:28][C:26]([C:25]1[N:16]=[C:14]([C:12]2[O:13][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:10]=3[C:11]=2[CH3:17])[O:15][CH:24]=1)=[O:27])[CH3:30]
Reactant: C=CCOc1cccc2oc(C(N)=O)c(C)c12
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: C=CCOc1cccc2oc(-c3nc(C(=O)OCC)co3)c(C)c12

Procedure:
4-Allyloxy-3-methyl-benzofuran-2-carboxylic acid amide (3370 mg) in tetrahydrofuran (60 ml) was treated with sodium bicarbonate (5.58 g) and ethyl bromopyruvate (2.20 ml) followed by trifluoroacetic anhydride (5.63 ml) to give 2-(4-allyloxy-3-methyl-benzofuran-2-yl)-oxazole-4-carboxylic acid ethyl ester as a white solid [2443 mg, EI-MS: m/z 327 (M+)] as mentioned in Example 77.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH2:6][CH3:7])=[O:15]
Reactant: CCCC(C)CO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: CCCC(C)COC(=O)CCC(=O)CN
Reaction time: 3.5 h

Procedure:
From 2-methyl-1-pentanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 3.5 h. The yield was 1.43 g (95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH2:18]([NH:22][C:23]([CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:30]1[CH2:29][CH2:28][N:27]([CH:25]([C:23]([NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:24])[CH3:26])[CH2:32][CH2:31]1)=[O:9]
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: CC(C)CNC(=O)C(C)N1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NCC(C)C)CC2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
14.40 g of 3,4,5-trimethoxycinnamoyl chloride is added to a solution of 9.20 g of 1-[1-(isobutylaminocarbonyl)ethyl]piperazine and 5.70 g of triethylamine in 200 ml of chloroform, and the resulting solution is kept standing at room temperature for 1 hour.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:18][C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH:17]=1)[C:13]#[N:14].N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:24][C:23]1[N:22]([CH3:25])[N:21]=[C:20]([CH3:26])[C:19]=1[O:18][C:16]1[CH:15]=[C:12]([CH:11]=[C:10]([Cl:9])[CH:17]=1)[C:13]#[N:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C)c(C)c1Oc1cc(Cl)cc(C#N)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nn(C)c(CBr)c1Oc1cc(Cl)cc(C#N)c1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
N-Bromosuccinimide (340 mg, 1.90 mmol) was added to a stirred solution of the pyrazole of Example 112 (500 mg, 1.90 mmol) in carbon tetrachloride (10 ml) and azobisisobutyronitrile (20 mg) at room temperature under nitrogen. The reaction was heated under reflux for 1 hour, cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (80:20, by volume) to provide the title compound (340 mg) as a white solid, m.p. 76–78° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=2)=[N:7][CH:8]=1.[I-].C([Si](C)(C)[O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32](N2C=C[N+](C)=C2)=[O:33])[CH2:28][CH2:27]1)(C)(C)C.C(N(CC)CC)C>C(#N)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:32]([N:29]3[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]3)=[O:33])=[N:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1
Reactant: C[n+]1ccn(C(=O)N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A solution of 5-(5-trifluoromethyl-pyridin-2-yloxy)-pyridin-2-ol (180 mg, 0.70 mmol), 3-[4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carbonyl]-1-methyl-3H-imidazol-1-ium iodide (317 mg, 0.70 mmol) and triethylamine (98 μL) in acetonitrile (10 mL) was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was redissolved in some dichloromethane, chloromethane, filtered over a short pad of silicagel and washed with ethyl acetate:heptane 50:50. The solvent was evaporated in vacuo and the residue was dissolved in 3.2N HCl in ether (10 mL). After stirring for 1 hour at room temperature the solvent was evaporated in vacuo and the residue was dissolved in dichloromethane. Triethylamine (0.5 mL) was added and the solution was extracted with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound (174 mg, 65% yield) as a thick oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:18])[CH:9]=2)=[CH:6][C:5]([C:24]2[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=2)=[CH:4][N:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(-c3cnn(C)c3)cnc2N)cc1C
Temperature: 120 °C
Yield: 79.7 %

Procedure:
To methyl 4-(2-amino-5-bromopyridin-3-yl)-2-methylbenzoate (500 mg, 1.557 mmol) in 20 mL MW vial was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (421 mg, 2.024 mmol), PdCl2(dppf)DCM (114 mg, 0.156 mmol), DME (11.7 mL) and 2 M Na2CO3 solution (3.892 mL). The reaction mixture was heated at microwave synthesizer (12 min, 120° C.). The reaction mixture was diluted with EtOAc and washed with water three times, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography eluting with 0-100% of EtOAc (containing 10% of MeOH)/heptane to provide crude product which was triturated with ether to provide 400 mg of pure product in 80% yield. LCMS (m/z): 323.4 (MH+), 0.60 min.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:49]([N+:53]1[N:57]=[C:56]([CH3:58])[S:55][C:54]=1[CH3:59])[CH2:50][CH2:51][CH3:52]>>[CH2:49]([N:53]1[N:57]=[C:56]([CH3:58])[S:55]/[C:54]/1=[CH:59]\[C:4]([C:3]1[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:50][CH2:51][CH3:52]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-chloro-5-(trifluoromethyl)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.26-1.36 (m, 2 H) 1.69-1.76 (m, 2 H) 2.50 (s, 3 H) 4.17 (t, 2 H) 6.29 (s, 1 H) 7.69-7.76 (m, 1 H) 7.77-7.82 (m, 2 H); MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14](=[O:26])[NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=O)(C)(C)C.C(OC)(C)(C)C>O1CCOCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][NH:15][C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:9]2)=[O:26])=[CH:19][CH:20]=1
Reactant: COc1ccc(CCNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: COc1ccc(CCNC(=O)[C@@H]2CCCN2)cc1

Procedure:
4N HCl solution in 41 ml of dioxane is added to a fine suspension of 16.78 g of (S)-2-[2-(4-Methoxy-phenyl)-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester in 40 ml of dioxane. After stirring under poor cooling with an ice-bath for 2.5 hours, solvent is evaporated, the residue obtained is cooled over night at 0° and resulting crystals are stirred with 150 ml of tert-butylmethylether, filtered and dried to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl.N1CCCCC1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH:19]2[O:21][CH2:20]2)=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1F
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: Fc1cc(OCc2ccccc2)ccc1OCC1CO1
Reaction time: 1 h

Procedure:
4.0 g of 4-benzyloxy-2-fluorophenol is reacted with 10 g epichlorhydrin and 0.2 ml piperidine for 90 minutes at 100°. After removal of the volatile material, 40 ml tetrahydrofuran and 20 ml 2M NaOH is added. After 1 hour stirring the solvent is evaporated and the residue partitioned between methylenechloride and water. The organic phase is purified over silica gel with toluene giving 4-benzyloxy-1-(2,3-epoxypropoxy)-2-fluorobenzene (colourless oil).
Reaction SMILES: [NH4+].[Cl-].[CH3:3][O:4][C:5](=[O:18])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[I:17]>O.CO.[Fe]>[CH3:3][O:4][C:5](=[O:18])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[I:17]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)COc1ccc(N)cc1I
Temperature: 90 °C
Yield: 26.1 %

Procedure:
NH4Cl (4.49 g, 84.00 mmol) in water (105 ml) was added to a suspension of Fe (powder, 2.85 g, 51.00 mmol) in water (18 ml), the treated with (2-iodo-4-nitro-phenoxy)-acetic acid methyl ester (5.06 g, 15.00 mmol) in MeOH (105 ml). The reaction was heated at 90° C. for 28 h, filtered and extracted with brine/EtOAc (3×). The organic phase was washed with brine, dried over Na2SO4 and evaporated to give 1.2 g of (4-amino-2-iodo-phenoxy)-acetic acid methyl ester, MS: 308.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([O:28][CH3:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>C(#N)C.O>[CH:30]([NH:33][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([O:28][CH3:29])[CH:11]=2)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:32])[CH3:31]
Reactant: COc1cc(-c2nc3c(C)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: CC(C)N
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)Nc2c(C)cc3cn[nH]c3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of 4:1 (v/v) mixture of acetonitrile/water is added 1.0 mL (12.2 mmol) of isopropylamine. The reaction mixture is stirred during 1 hour at ambient temperature and for 2.5 hours at 60° C. and then concentrated in vacuo. The residue is taken-up with brine and tert-butylmethylether. The phases are separated and the aqueous layer is washed with tert-butylmethylether. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:7) affords 118 mg (19% over two steps) of the product as white solid; LC/MS:468/470 (M+H)+, m.p.: 148-151° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:21]COC)[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH:10]([CH2:25][Cl:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([OH:21])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH:10]([CH2:25][Cl:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1c2c(cc3ccccc13)N(C(=O)OC(C)(C)C)CC2CCl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc1ccccc1c2O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
A solution of 28 (18 mg, 47.5 μmol) in 1.5 mL of 1:1 i-PrOH/THF was treated with 12 N HCI (0.20 mL, 0.38 mmol) and the mixture was stirred at 25° C. for 6 h before the volatiles were removed in vacuo. Flash chromatography (SiO2, 1.5×15 cm, 0-20% EtOAc/hexane gradient) provided 30 (14.5 mg, 90%) as a pale yellow oil: 1H NMR (CDCl3, 250 MHz) δ7.85 (d, J=8.0 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.43-7.30 (m, 2H), 5.67 (s, 1H), 4.09-3.86 (m, 4H), 3.65 (dd, J=8.0, 10.0 Hz, 1H), 1.59 (s, 9H);13C NMR (CDCl3, 6.25 MHz) δ147.9, 135.8, 132.7, 128.8, 128.0, 126.6, 123.7, 121.2, 119.5, 119.5, 104.4, 77.2, 52.6, 46.4, 34.7, 28.5; IR (film) νmax3368, 2976, 1668, 1477, 1450, 1369, 1145, 978, 746 cm−1; FABHRMS (NBA/CsI) m/z 466.0197 (C18H20CINO3+Cs+requires 466.0186). (−)-(3S)-30: [α]D25 −54 (c 0.25, CH3OH); (+)-(3R)-30: [α]D25+51 (c 0.30, CH3OH).