Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>N1C=CC=CC=1>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:16](=[O:17])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cnc(-c2ccc(O)cc2)cn1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cnc(-c2ccc(O)cc2)cn1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-(4-hydroxyphenyl)pyrazine (283 mg) in pyridine (20 mL) was added under ice-cooling phenyl chloroformate (199 μL) and the mixture was stirred for 1 hour. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with diethyl ether (10 mL) to give the subject compound (314 mg).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:6])[CH2:4][CH3:5].[H-].[Na+].C(O[C:12](=O)[CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C.O>CN(C=O)C>[C:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][C:12]1[O:1][N:2]=[C:3]([CH2:4][CH3:5])[N:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Reactant: CCC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-Hydroxy-propionamidine (0.10 g, 1.15 mmol) in DMF (2 ml) is added to a stirred suspension of sodium hydride (0.05 g of a 60% dispersion in oil, 1.26 mmol) in DMF (20 ml) in the presence of molecular sieves (0.1 g). The reaction flask is then immersed in a pre-heated oil bath at 50° C. and stirring continued for 5 min. 3-tert-Butoxycarbonylamino-propionic acid ethyl ester (0.25 g, 1.15 mmol) in DMF (2 ml) is added over 5 minutes. After 3 hours at 50° C. the mixture is cooled to 0° C. and water (3 ml) is added. The mixture is allowed to warm to room temperature then filtered through Celite™ filter material, washing with ethyl acetate, and the solvent is removed. Purification by chromatography, eluting with hexane:ethyl acetate (3:1) affords the titled compound.
Reaction SMILES: C(OC([O:11][C:12]1[N:13]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([Cl:21])=[CH:16][CH:15]=2)=O)C1C=CC=CC=1.N.O1CCOCC1>[Cl-].[Na+].O>[Cl:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C:12](=[O:11])[CH2:20]2
Reactant: O=C(OCc1ccccc1)Oc1cc2cc(Cl)ccc2n1C(=O)OCc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Cc2cc(Cl)ccc2N1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 59 %

Procedure:
Benzyl 2-{[(benzyloxy)carbonyl]oxy}-5-chloro-1H-indole-1-carboxylate, intermediate 37 (5.00 g; 11.47 mmol) was treated with a solution of ammonia in dioxane (25.2 ml; 0.50 M; 12.6 mmol) and stirred overnight. Brine was added and the mixture extracted with ethyl acetate. The organic phase was dried (MgSO4) and removed in vacuo, to give a solid residue which was purified by recrystallisation (ethyl acetate), to give the title compound in 59% yield (HPLC purity 88%). MS (ESI+): 302.1; MS (ESI−): 300.1
Reaction SMILES: BrC1SC(Cl)=C(Cl)C=1C(=O)CCl.[Br:13][C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]([Br:21])[CH:15]=1.[Br:22][CH2:23][C:24](Br)=[O:25]>>[Br:22][CH2:23][C:24]([C:19]1[C:14]([Br:13])=[CH:15][C:16]([Br:21])=[CH:17][C:18]=1[Br:20])=[O:25]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: O=C(Br)CBr
Agent: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Product: O=C(CBr)c1c(Br)cc(Br)cc1Br
Yield: 45 %

Procedure:
General procedure described for compounds 1 and 2 starting from 1,3,5-tribromobenzene and bromoacetyl bromide. Purified by column chromatography column (hexane:ethyl acetate 6:1), yield 45% m.p.: 86-87° C., 1H-NMR (CDCl3): δ7.7 (s, 2H, Ar), 4.44 (s, 2H, CH2); 13C-NMR (CDCl3): δ193.4 (CO), 139.4 (C—CO), 134.5 (CH), 124.7 (C—Br), 119.4 (C—Br), 34.6 (CH2); M/z (EI): 440, 438, 436, 434, 432 (M+, 1, 3, 5, 3, 1%), 345, 343, 341, 339 (M-CH2Br, 35, 96, 100, 41%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 98%, r.t.=3.40 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.
Reaction SMILES: BrBr.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Cu](C#N)[C:15]#[N:16].Cl>ClCCl.O.CN(C)C=O>[C:15]([C:7]1[CH:6]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:10]=[CH:9][C:8]=1[OH:11])#[N:16]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: N#C[Cu]C#N
Agent: BrBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1O
Reaction time: 38 h
Yield: 77.4 %

Procedure:
Bromine (15.9 ml) was added to a solution of 4-trifluoromethylphenol (50 g) in dichloromethane (300 ml) at room temperature and the mixture was stirred for 38 hours. The reaction mixture was successively washed with aqueous sodium bisulfite solution and saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain crude 2-bromo-4-trifluoromethylphenol (78.5 g) as oil. N,N-dimethylformamide (250 ml) was added to the crude product and copper cyanide (I) (27.6 g), and the mixture was heated to reflux for 2 hours under Ar. This hot reaction mixture was poured into a solution of ferric chloride hexahydrate (137.5 g) and hydrochloric acid (35 ml) in water (400 ml), and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate, and the ethyl acetate was successively washed with dilute hydrochloric acid and saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane to obtain 2-cyano-4-trifluoromethylphenol (34.6 g, mp. 149.5°-151° C.).
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@@H:6]2[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH3:10])[C@H:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[SH:66][CH2:67][CH2:68][NH:69][C:70](=[O:72])[CH3:71]>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)(=O)C>[C:70]([NH:69][CH2:68][CH2:67][S:66][C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@@H:6]2[C:9]([CH3:10])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:13])[CH3:25])[C:3]=1[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])(=[O:72])[CH3:71]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CC(=O)NCCS
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 4-nitrobenzyl (2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (47.8 mg) and 4-(N,N-dimethylamino)pyridine (1.08 mg) in acetonitrile (2.39 ml) was added dropwise a solution of di-isopropylethylamine (18.5 μl) in acetonitrile (166.5 μl) followed by addition of a solution of diphenyl chlorophosphate (19.2 μl) in acetonitrile (172.8 μl) at 0° C. After stirring for an hour at 0° C., a solution of di-isopropylethylamine (61.5 μl) in acetonitrile (553.5 μl) was added followed by addition of a solution of N-(2-mercaptoethyl)acetamide (11.05 mg) in acetonitrile (99.45 μl) at -15° C. The mixture was allowed to stand overnight at -15° C. The resulting solution was diluted with ethyl acetate (34 ml) and washed with dilute aqueous sodium chloride and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil (76.4 mg) was chromatographed on silica gel (1.5 g) eluting with a mixture of methylene chloride and acetone (20:1 to 2:1) to give 4-nitrobenzyl(5R,6S)-3-(2-acetamido-ethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate (54.0 mg) as an amorphous solid.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>CS(C)=O>[NH2:2][C:1](=[O:27])[CH2:3][C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC#N)C1
Reactant: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(cyanomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (1 g) in DMSO (10 mL) were added potassium carbonate (0.502 g) and 30% aqueous hydrogen peroxide (1.22 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hr. Diluted aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (746 mg).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.C[O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:4]([C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:29][C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[C:22]([OH:30])=[O:21])=[CH:11][CH:12]=1)([OH:3])=[O:19]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2cccc(C(=O)O)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 3-hydroxy-benzoic acid methyl ester via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=2[F:41])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]=C(C)O[N:26]=3)=[CH:21][CH:20]=2)=[N:12]1)=[O:5])[CH3:2].O.C(O)(=O)C>CO.[Fe]>[C:4]([OH:5])(=[O:3])[CH3:6].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:29])=[CH:23][CH:24]=2)[C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=2[F:41])=[N:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c(OC)cc2F)[nH]c1=O
Agent: [Fe]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)c(OC)cc2F)[nH]c1=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 115.6 %

Procedure:
To a solution of 0.152 g of 5-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-1H-pyrazole-4-carboxylic acid ethyl ester in 15 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 0.150 g of iron powder, and the mixture was heated and stirred at 60° C. for 20 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 0.091 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>CCO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:23][C:22]3[CH:25]=[CH:26][C:19]([N:18]([CH3:27])[CH3:17])=[CH:20][CH:21]=3)[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Solvent: CCO
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=Cc1ccc(N(C)C)cc1
Temperature: 25 °C

Procedure:
A slurry composed of 1-(4-carboxyphenyl)-3-methyl-2-pyrazolin-5-one (21.8 g, 0.10 mol), 4-dimethylamino-benzaldehyde (14.9 g, 0.10 mol) and EtOH (250 ml) was heated at reflux for two hours. The reaction mixture was cooled to room temperature, resulting in a crude orange product which was isolated by filtration. The product was then washed with ether and dried. The product was purified further by making a slurry of the solid in EtOH (700 ml) at refluxing temperature and filtering the slurry to recover the dye. The treatment was repeated. The mp of the product was above 310° C. The NMR and IR spectra were consistent with the structure assigned. The C, H, and N elemental analyses were in agreement with those calculated for the empirical formula.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([C:9](C(O)=O)=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.O.[NH3:15]>C(O)C>[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][CH3:1])(=[O:10])[NH2:15]
Reactant: CNc1ccccc1C(=O)C(=O)O
Reactant: N
Solvent: CCO
Solvent: O
Product: CNc1ccccc1C(N)=O
Temperature: 80 °C
Yield: 84.8 %

Procedure:
N-Methylisatic acid (10.0 g) is added gradually to water (140 ml) at room temperature and thereto is added dropwise aqueous ammonia (9.6 g). The mixture is warmed to 80° C. during 45 minutes, and ethanol is added thereto until the reaction mixture becomes colorless. Then, the reaction mixture is cooled to room temperature and the precipitated crystals are collected by filtration to give 2-carbamoyl-N-methylaniline (7.11 g) as colorless crystal.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3](=[O:21])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=1)([CH3:7])[CH3:6].[CH2:24]1[CH2:28]OC[CH2:25]1>C(OCC)C>[CH3:20][S:17]([C:10]1[CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([C:2]([F:1])([F:22])[F:23])([OH:21])[CH2:28][C:24]#[CH:25])[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=1)(=[O:18])=[O:19]
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(S(C)(=O)=O)cc2c1OCC2
Reactant: C1CCOC1
Solvent: CCOCC
Product: C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of 1,1,1-trifluoro-4-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-4-methylpentan-2-one (5.4 g, 15.4 mmol) in a mixture of 10 mL of anhydrous diethyl ether and 10 mL of anhydrous THF was treated with the organoaluminum reagent at −78° C. After 1 hour at −78° C. and 1 hour at room temperature, the reaction mixture was quenched with saturated ammonium chloride solution and diluted with water. The aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 6.3 g of the title product as a solid, which was used without further purification (quantitative yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29](/[C:43](/[NH:46]O)=[N:44]/[H])[CH:30]=[C:31]2[C:35]=1[NH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:44]=[C:43]([C:29]3[CH:30]=[C:31]4[C:35](=[C:27]([F:26])[CH:28]=3)[NH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32]4)[N:46]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: [H]/N=C(\NO)c1cc(F)c2[nH]c(CCC(=O)OCC)cc2c1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (150 mg) in tetrahydrofuran (30 mL) stirred at room temperature was added EDC (280 mg) and HOBT (223 mg). The reaction mixture was stirred at room temperature for 0.5 h. Then ethyl 3-{7-fluoro-5-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D163) (214 mg) was added. The reaction mixture was stirred at room temperature for an hour, and then TBAF (763 mg) was added. The reaction mixture was sealed and heated in Biotage Initiator using initial high to 120° C. for 2 hrs. After cooling the reaction, the solvent was removed. The residue was diluted with EtOAc (30 mL). The organic phase was washed with water (25 mL×4) and dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D165) (180 mg) as a white solid. MS (ES): C25H23FN4O4 requires 462; found 463.2 (M+H+).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([Cl:16])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([N:23]([CH3:31])C(=O)OC(C)(C)C)[CH2:18]1)[C:2]#[C:3][CH3:4].Cl.[NH2:33][CH:34]1CCCN(C2N(CC#CC)C3C(=O)N(CC4C=CC=CC=4C#N)C(C#N)=NC=3N=2)C1>>[ClH:16].[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([C:34]#[N:33])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:23][CH3:31])[CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc2nc(Cl)n(C)c(=O)c21
Reactant: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Agent: Cl
Product: CC#CCn1c(N2CCCC(NC)C2)nc2nc(C#N)n(C)c(=O)c21

Procedure:
The title compound was synthesized by using t-butyl N-[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]-N-methylcarbamate according to the method described in Example 242 (f) and (g).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]([CH3:4])=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[N:21]1([CH:2]([CH3:4])[CH2:1][C:5]2[C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc(C2=C(CC(C)N3CCCC3)C(=O)NCCC2)c1

Procedure:
The solution of 1.36 g of 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 0.52 g of pyrrolidine and 0.1 g of p-toluenesulfonic acid hydrate in 10 ml of benzene is refluxed with water separation for 4 hours and evaporated. The residue is dissolved in 15 ml of ethanol and the solution hydrogenated over 0.1 g of platinum oxide at atmospheric pressure and room temperature. The mixture is filtered, the filtrate evaporated and the resulting oil dissolved in 2 N hydrochloric acid. The solution is washed with benzene, basified with 3 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, evaporated and the residue recrystallized from petroleum ether and hexane, to yield the 3-(2-pyrrolidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 94° to 96°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([O:10][CH3:11])[CH:3]=1.[C-:12]#[N:13].[Na+]>C1(C)C=CC=CC=1.O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]#[N:13])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CBr
Reactant: [C-]#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Cl)ccc1CC#N
Yield: 68 %

Procedure:
269 g of 4-chloro-2-methoxybenzyl bromide in 214 ml of toluene are reacted with 68.2 g of sodium cyanide in 69 ml of water and 1.8 g of Aliquat 336. 141 g of colorless oil are obtained (b.p. 107° C./0.08 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].[O:44]1[C:48]2([CH2:53][CH2:52][CH2:51][NH:50][CH2:49]2)[O:47][CH2:46][CH2:45]1>C(O)C>[O:44]1[C:48]2([CH2:53][CH2:52][CH2:51][N:50]([C:15](=[O:17])[C@@H:14]([NH:13][C:11]([C:9]3[NH:8][C:5]4=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]4[CH:10]=3)=[O:12])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:49]2)[O:47][CH2:46][CH2:45]1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: C1CNCC2(C1)OCCO2
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCO
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCCC2(C1)OCCO2)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 0.08 h

Procedure:
To a suspension of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 80 mg, 0.22 mmol) in ethanol (6 mL) was added DMTMM (78 mg, 0.27 mmol) and the reaction stirred for 5 min. To the mixture was added 1,4-dioxa-7-aza-spiro[4.5]decane (Preparation 94, 35 mg, 0.24 mmol) and stirring continued for 16 h. Solvent was removed in vacuo and the crude material partitioned between ethyl acetate and water. The organic layer was washed with NaHCO3 solution (2×20 mL) then brine (2×20 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography using dichloromethane/methanol (95:5) as the eluent gave the title compound as a pale yellow powder. m/z (ES+)=487.21 [M+H]+; RT=3.50 min.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:30][CH2:27][CH:28]=[CH2:29])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: C=CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: C=CCNCC1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), prop-2-en-1-amine (0.5 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. MS m/z (rel. intensity, 70 eV) 283 (M+, 4), 79 (4), 71 (6), 70 (bp), 68 (4).