Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]3[CH:20]=[C:21]([C:23]([OH:25])=O)[O:22][C:16]=3[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][CH2:27][CH2:28]O.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[O:25]1[CH2:28][CH2:27][N:26]=[C:23]1[C:21]1[O:22][C:16]2[CH2:15][N:14]([C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:19][CH2:18][C:17]=2[CH:20]=1
Reactant: O=C(O)c1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Reactant: NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCCCCc1ccccc1)N1CCc2cc(C3=NCCO3)oc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.884 g (2.590 mmol) of 6-(6-phenylhexanoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-carboxylic acid, 0.16 g (2.59 mmol) of 2-aminoethanol, 1.08 ml (7.77 mmol) of triethylamine and 2.50 ml (25.9 mmol) of carbon tetrachloride in 50 ml of acetonitrile, 2.04 g (7.77 mmol) of triphenylphosphine was added under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel flush column chromatography (ethyl acetate to ethyl acetate/methanol=20/1) to yield the desired product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:21][CH:20]=3)[N:18]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+]>CO>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:14]([C@@H:4]3[CH2:3][C@H:2]([CH3:1])[CH2:6][N:5]3[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[NH:15][CH:16]=2)=[CH:24][CH:23]=1)#[CH:26]
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(C#C[Si](C)(C)C)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2c[nH]c([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of tert-butyl (2S,4S)-4-methyl-2-[4-[4-(2-trimethylsilylethynyl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (57 mg, 0.1346 mmol) in MeOH (2 mL) is added K2CO3 (37.2 mg, 0.27 mmol). The mixture is stirred at rt for 2 hours. After removal of the solvent under reduced pressure, the residue is purified by flash column chromatography on silica gel using 0-5% MeOH/CH2Cl2 to provide tert-butyl (2S,4S)-2-[4-(4-ethynylphenyl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (47 mg, 99%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23].O.CCCC(C)C.CCOC(C)=O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:11]=1
Reactant: COc1ccccc1CN
Reactant: O=Cc1cccc(CCOC2CCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Solvent: O
Product: COc1ccccc1CNCc1cccc(CCOC2CCCCO2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a solution of 3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzaldehyde (10 g) and 2-methoxybenzylamine (6 g) in toluene (150 mL) was added TsOH (100 mg). The mixture was heated at reflux in a Dean-Stark apparatus for a couple of hours. About 1 mL water was displaced. The reaction was checked by TLC, iso-hexane/EtOAc (4/1, Rf ˜0.5). The mixture was cooled and washed with aqueous bicarbornate, then concentrated in vacuo. The residue was azeotroped twice with toluene and was taken up in ethanol (150 ml). The solution was cooled to 0° C. and sodium borohydride (1.65 g) was added slowly. The reaction was left to warm to room temperature and was stirred overnight. Water was added (150 mL) and ethanol removed under vacuum. The residue was partitioned between aqueous bicarbonate and ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo to give a yellow oil (6.5 g). The material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][N:6]=1.[NH4+:11].[OH-]>CCN(CC)CC>[Cl:1][C:2]1[S:3][C:4]([S:7]([NH2:11])(=[O:9])=[O:8])=[CH:5][N:6]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1cnc(Cl)s1
Agent: [OH-]
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cnc(Cl)s1
Yield: 61.4 %

Procedure:
Prepared by general procedure III from 2-Chloro-thiazole-5-sulfonyl chloride (1.1 g, 5 mmol) and NH4OH (0.42 mL, 6 mmol) with Et3N (0.77 mL, 6 mmol to give the title compound as alight-brown solid (610 mg, 61%). MS (ISN) 197[(M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]3[NH:30][CH:31]=[N:32][C:28]=3[CH:27]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:35].C(N1C=CN=C1)([N:38]1C=CN=C1)=O.N>CN(C)C=O>[NH2:1][C:2]1[C:3]([Cl:35])=[CH:4][C:5]([S:9]([NH:12][CH:13]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]3[NH:30][CH:31]=[N:32][C:28]=3[CH:27]=2)[C:14]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([NH2:38])=[O:24])[CH2:20][CH2:21]2)=[O:15])(=[O:11])=[O:10])=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCC(C(=O)O)CC2)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Reaction time: 12 h

Procedure:
540 mg (1 mMol) of 4-amino-N-[1-(1H-benzimidazol-5-yl-methyl)-2-(4-carboxy-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide are dissolved in 10 ml of absolute dimethylformamide and combined, with stirring, with 180 mg (1.1 mMol) of carbonyldiimidazole. After about one hour 2 ml of ethanolic ammonia solution are added dropwise and the mixture is stirred for a further 12 hours. It is then evaporated down, the residue is mixed with water and extracted twice with ethyl acetate. The organic phase is washed twice with aqueous saline solution, dried with sodium sulphate and evaporated down. The residue is purified over a silica gel column, the evaporated eluate is triturated with ether and suction filtered.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[C:15]([NH2:17])=[O:16].[O:18]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.CN1C(=O)CCC1>[O:18]([C:25]1[N:26]=[CH:27][C:28]([CH2:29][NH:9][C:10]2[N:14]=[CH:13][NH:12][C:11]=2[C:15]([NH2:17])=[O:16])=[CH:31][CH:32]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)c1nc[nH]c1N
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CO
Product: NC(=O)c1[nH]cnc1NCc1ccc(Oc2ccccc2)nc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (0.47 mL, 3.38 mmol) was added to 5-aminoimidazole-4-carboxamide hydrochloride (0.50 g, 3.1 mmol) in anhydrous methanol (12 mL). The reaction mixture was stirred for 10 min and 6-phenoxynicotinaldehyde (0.74 g, 3.7 mmol) and acetic acid (0.09 mL, 1.57 mmol) were added. The dark solution was stirred over night and sodium cyanoborohydride (0.23 g, 3.7 mmol) was added. More sodium cyanoborohydride (0.15 g, 2.4 mmol) was added after 40 min and the mixture was stirred for another 3 h. The reaction mixture was heated at 50° C. for 3 h, sodium cyanoborohydride (0.15 g, 2.4 mmol) was added and the mixture was heated at 50° C. over night. Sodium borohydride (0.12 g, 3.2 mmol) was added and the mixture was heated at 50° C. for 1 h, more sodium borohydride (0.15 g, 4.0 mmol) and NMP (1.0 mL) were added and the mixture was heated at 60° C. for 3.5 h. After cooling, NaHCO3 (sat., 20 mL) was added and some of the methanol was removed in vacuo. The mixture was extracted with EtOAc, the organic phase was extracted with 1N HCl (2×30 mL) and the acidic phase was made basic with 2N NaOH and was extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica (0 to 10% MeOH in DCM+NH3) to yield 0.25 g (0.81 mmol, 26%) of a slightly green syrup.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=O.Cl>C1C=CC=CC=1.O1CCOCC1>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[Cl:14])[C:4]([CH2:8][CH2:9][CH3:10])=[N:3]1
Reactant: CCCc1cc(=O)n(C)[nH]1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: CCCc1nn(C)c(O)c1Cc1ccccc1Cl
Temperature: 50 °C
Yield: 9.2 %

Procedure:
1.4 g. of 1-methyl-3-n-propyl-5-pyrazolone is dissolved in 10 ml. of dioxane with heating and then 1.5 g. of calcium hydroxide is added to the resulting solution. 1.75 g. of 2-chlorobenzoyl chloride is added dropwise with stirring at 50° C. After completion of the dropwise addition, the mixture is heated under reflux for 1 hour. After completion of the reaction, the reaction mixture is allowed to cool and 100 ml. of a 2 N hydrochloric acid solution is added thereto. The mixture is extracted with 70 ml. of chloroform and an organic layer is separated. The layer is washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off from the layer to give 2 g. of brown oily residue. The residue thus obtained is dissolved in a small amount of benzene and adsorbed on a silica gel column, which is then eluted with benzene: ethanol (50:1) to give 0.6 g. of crystals. The crystals are recrystallized from methanol-water (7:3) to give 0.25 g. of the desired product as colorless columns having a melting point of 125°-126° C. Yield 9.2%
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:32])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:23]=[N:24][N:25]([CH2:27][C:28]([O:30]C)=[O:29])[CH:26]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.Cl>C(#N)C>[ClH:1].[C:28]([CH2:27][N:25]1[CH:26]=[C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:3][CH2:4]3)=[O:32])[CH2:19][CH2:18][CH:17]\2[SH:20])[N:23]=[N:24]1)([OH:30])=[O:29]
Reactant: COC(=O)Cn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)nn1
Agent: Cl
Solvent: CC#N
Product: O=C(O)Cn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)nn1
Yield: 94.5 %

Procedure:
Following a procedure similar to that described in Example 134, (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl]methylidene}-4-sulfanylpiperidine hydrochloride (82.8 mg) was treated with hydrochloric acid and the residue obtained by concentration of the reaction mixture was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 25/75, v/v) to afford the title compound (76.0 mg, yield: 95%) as a colourless amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[C:5]#[N:6].[Cl-].[Na+].O.[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:15]([O:10][C:9]1[C:2]([Br:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[Br:11])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC(=O)Cl
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCC(=O)Oc1c(Br)cc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A mixture of 3,5-dibromo-4-hydroxybenzonitrile (27.69 g) sodium hydroxide (4.08 g), sodium chloride (43.4 g) and water (125 ml) was stirred at room temperature for 15 minutes. Toluene (30 ml) and benzyltributyl ammonium chloride (1.57 g) was added, and a solution of octanoyl chloride (17.06 g) in toluene (30 ml) was slowly added to the stirred mixture over a half an hour while the temperature was maintained at 20° C. After addition was completed, the mixture was stirred for 1 hour and the phases allowed to separate. After removing the aqueous phase, the organic phase was washed with water, then with 5% aqueous Na2O3 and again with water. The solution was dried over Na2O3 and evaporated to dryness, yielding 2,6-dibromo-4-cyanophenyl octanoate (40.08 g, 99.5%) as a brown crystalline solid.
Reaction SMILES: CC1N=CC2C=COC=2C=1.Cl[C:12]1[C:17]2[CH:18]=[CH:19][O:20][C:16]=2[C:15]([CH3:21])=[CH:14][N:13]=1.ClC1C2C=COC=2C=C(C)N=1>>[CH3:21][C:15]1[C:16]2[O:20][CH:19]=[CH:18][C:17]=2[CH:12]=[N:13][CH:14]=1
Reactant: Cc1cnc(Cl)c2ccoc12
Agent: Cc1cc2occc2c(Cl)n1
Agent: Cc1cc2occc2cn1
Product: Cc1cncc2ccoc12

Procedure:
The title compound was prepared according to the procedure described for 6-methylfuro[3,2-c]pyridine (Example 12, step C) except 4-chloro-7-methylfuro[3,2-c]pyridine was substituted for 4-chloro-6-methylfuro[3,2-c]-pyridine. Title compound was obtained pure in 81% yield after distillation under vacuum, b.p. 74° C./2.2 mm Hg. This material crystallized, m.p. 41°-43° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH3:10])=[CH:7][C:2]=1[CH3:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (5.0 g) in dry acetonitrile (50 ml) was treated with potassium carbonate (5.06 g) and benzyl bromide (3.96 ml) and the reaction mixture heated at 40° C. After 3 hours the reaction was allowed to cool and was concentrated. The residue was partitioned between water and ethyl acetate; the aqueous layer separated and extracted twice more with ethyl acetate. The organic solutions were combined and were dried with brine and over magnesium sulfate and concentrated to give the title compound as a colourless oil
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6])[CH3:3].[Li]C(C)(C)C.CN([CH:33]=[O:34])C>C1COCC1>[OH:34][CH:33]1[C:24]2[CH:23]=[C:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:9]3=[CH:8][C:7]=2[C:5](=[O:6])[N:4]1[CH:2]([CH3:1])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)NC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)N1C(=O)c2cc3c(cc2C1O)CCN(C(=O)OC(C)(C)C)CC3
Temperature: -40 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 1,1-dimethylethyl 7-{[(1-methylethyl)amino]carbonyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.95 g, 1 eq) in THF (50 ml), cooled to −78° C. under nitrogen atmosphere, t-BuLi (1.7 M pentane solution, 3.7 ml) was added over a 20 min period, then the mixture was allowed to warm to −40° C. and stirred for 1 h at that temperature. Anhydrous DMF (0.27 ml) was added dropwise, then the mixture was allowed to warm to room temperature and quenched with a saturated aqueous solution of NH4Cl (5 ml). After removal of THF, the residue was dissolved in ethyl acetate and the solution washed with 1 N HCl, 5% aqueous NaHCO3 and brine, then dried over Na2SO4 and concentrated to afford a white solid (1.0 g, 97% yield).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:24].[C:31]1([C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[CH2:39]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:37]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][N:9]1[C:10]2[C:16]3[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:24]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccc([N+](=O)[O-])cc43)c2=O)c(OC)c1
Reactant: BrCc1ccccc1-c1ccccc1
Product: O=c1c2sc3ccc([N+](=O)[O-])cc3c2n(Cc2ccccc2-c2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-8-nitro-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-phenylbenzyl bromide and subsequently deprotected to provide the title compound as a light yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.53 (s, 2H); 7.20-7.57 (m, 9H); 8.29 (dd, J1=9 Hz, J2=2 Hz, 1H); 8.36 (d, J=2 Hz, 1H); 8.40 (d, J=9 Hz, 1H); Ret. time=3.14 min., m/z=444.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40]>CN(C)C=O>[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH:40][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)CCN
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.03 h

Procedure:
24.9 g of benzyloxycarbonyl-L-proline were dissolved in 200 ml of dimethylformamide, cooled to -20° C and treated with 11.1 ml of N-methylmorpholine and 13.0 ml of chloroformic acid isobutyl ester. The suspension was stirred for a further 2 minutes at -° C and then treated with a suspension, pre-cooled to -20° C, prepared from 14.0 g of β-alanine methyl ester hydrochloride and 11.1 ml of N-methylmorpholine in 100 ml of dimethylformamide. The mixture was stirred for 30 minutes at a temperature below -10° C and for a further 30 minutes at room temperature, filtered and the filtrate concentrated in vacuo. The oily residue was dissolved in 1.2 liters of ethyl acetate and washed three times, each time with 1-N hydrochloric acid, water, 10% sodium carbonate solution and saturated sodium chloride solution, and dried over sodium sulphate. The organic phase was concentrated in vacuo and the oily residue crystallised from ethyl acetate/hexane. Yield: 22.8 g; melting point 55° C; [α]D25 = -50.7° (c = 1 in methanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=[N:14][OH:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:16])[C:4](=[N:14][O:15][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13]
Reactant: COC(=O)C(Cc1ccc(Cl)cc1Cl)=NO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CON=C(Cc1ccc(Cl)cc1Cl)C(=O)OC
Temperature: 20 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a stirred suspension of 3-(2,4-dichloro-phenyl)-2-(hydroxyimino)-propionic acid methyl ester (2.0 g; 7.6 mmol) and potassium carbonate (3.2 g; 23 mmol) in N,N-dimethylformamide (15 ml) under argon at 20° C., was added drop wise methyl iodide (4.3 ml; 23 mmol). The mixture was stirred for 2 hours at 20° C. Water (300 ml) was added to the mixture which was extracted with ethyl acetate (3×150 ml). Combined organics were concentrated, the residue dissolved in 20 ml of dichloromethane, washed twice with water (150 ml), dried over sodium sulfate and evaporated under reduced pressure to afford 2.0 g (95% of theory) of 3-(2,4-dichloro-phenyl)-2-(methoxyimino)-propionic acid methyl ester (mixture of E/Z-isomers) as a clear yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>O.C([O-])([O-])=O.[Na+].[Na+]>[OH:1][CH:2]1[CH2:6][N:5]([S:20]([C:11]2[CH:12]=[CH:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)(=[O:22])=[O:21])[CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC(O)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
2.62 g of (2S,4R)-4-hydroxyproline are dissolved in 15 ml of water containing 5.9 g of Na2CO3 and 5.21 g of 2-naphthalenesulphonyl chloride are added. After vigorous stirring for 18 hours at RT, the mixture is drained and the filtrate is then acidified to pH=1. The resulting mixture is again drained, washed with water and dried in order to obtain 4.1 g of the expected compound.
Reaction SMILES: [C:1](=[O:4])([O-])[OH:2].[K+:5].[CH3:6][S:7][CH2:8][CH2:9][CH:10]1[NH:14]C(=O)NC1=O.N.C(=O)=O>O>[NH2:14][C@H:10]([C:1]([O-:2])=[O:4])[CH2:9][CH2:8][S:7][CH3:6].[K+:5]
Reactant: CSCCC1NC(=O)NC1=O
Reactant: O=C([O-])O
Agent: N
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: CSCC[C@H](N)C(=O)[O-]
Temperature: 180 °C

Procedure:
Using pump pressure, a solution of 100 kg of potassium hydrogen carbonate in aqueous solution and 41 kg of 5-(2-methylmercaptoethyl)-hydantoin in 400 l of water is fed hourly into a continuously operating pressurised column 8 made of special steel (compare FIG. 2) operated with steam. The reaction mixture is heated to 180° C. and has an average residence time of about 15 minutes at about 8 bar. Ammonia and carbon dioxide liberated is drawn off at the top of the reactor column by means of a pressure-maintaining valve. The reaction solution is depressurised at the bottom of the pressurised reactor and cooled with the heat exchanger 9. A quantity of 41.9 kg per hour of potassium methioninate in solution is obtained (94.5% of the theoretical).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:38]=[C:37]([C:39]([N:41]2[CH2:50][C:49]3[CH:48]=[N:47][N:46]([CH3:51])[C:45]=3[NH:44][C:43]3[CH:52]=[CH:53][CH:54]=[CH:55][C:42]2=3)=[O:40])[CH:36]=[CH:35][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33].Cl.Cl.[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:63][CH2:64][N:65]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][O:28][C:27]2[CH:35]=[CH:36][C:37]([C:39]([N:41]3[CH2:50][C:49]4[CH:48]=[N:47][N:46]([CH3:51])[C:45]=4[NH:44][C:43]4[CH:52]=[CH:53][CH:54]=[CH:55][C:42]3=4)=[O:40])=[CH:38][C:26]=2[CH3:25])[CH2:66][CH2:67]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)O
Reactant: CC(C)(C)CCN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
HBTU (101 mg, 0.27 mmol) was added to a solution of 4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butyric acid from E76.2 (71 mg, 0.17 mmol) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (54 mg, 0.22 mmol) in dichloromethane (10 ml) and DIEA (0.15 ml, 0.86 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 6% methanol:94% dichloromethane) to give a white powder identified as the title compound (52 mg, 53%).