Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]3[C@H:19]([CH3:20])[C@H:18]4[N:15]([C:16](=[O:24])[C@@H:17]4[C@H:21]([OH:23])[CH3:22])[C:14]=3[C:25]([O:27]CC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:9][N:8]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[N:6]=1.P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]3[C@H:19]([CH3:20])[C@H:18]4[N:15]([C:16](=[O:24])[C@@H:17]4[C@H:21]([OH:23])[CH3:22])[C:14]=3[C:25]([OH:27])=[O:26])[CH2:9][NH:8]2)[N:6]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](c4csc(N)n4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](c4csc(N)n4)C3)[C@H](C)[C@H]12
Yield: 45.7 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2- (2-aminothiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)-pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate (900 mg), 20% palladium hydroxide on carbon (350 mg), 0.05M phosphate buffer (pH 6.5, 20 ml) and tetrahydrofuran (30 ml) was stirred at room temperature for 3 hours under atmospheric pressure of hydrogen. After the catalyst was filtered off, the filtrate was concentrated to remove the organic solvent. The residue was washed with ethyl acetate, adjusted to pH 6.2 with aqueous potassium carbonate and concentrated in vacuo to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (60 ml) eluting in turn with water (250 ml) and 5-7% aqueous acetone (200 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl) -pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid (233 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[S:18](=[O:36])(=[O:35])[NH:19][C@H:20]([C:29](=[O:34])[N:30]([O:32][CH3:33])[CH3:31])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:38]1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:25]([O:24][C:22](=[O:23])[CH2:21][CH:20]([NH:19][S:18]([C:17]1[CH:16]=[CH:15][C:11]([C:12](=[O:13])[NH2:38])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:35])=[O:36])[C:29]([N:30]([O:32][CH3:33])[CH3:31])=[O:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(=O)O)cc1OCc1ccccc1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(N)=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of 3-benzyloxy-4-[(S)-2-tert-butoxycarbonyl-1-(methoxy-methyl-carbamoyl)-ethylsulfamoyl]-benzoic acid (8.0 g, 15.3 mmol) in tetrahydrofuran (150 ml) at 0° C. was added 4-methyl morpholine (2.5 ml, 22.9 mmol), 1-hydroxybenzotriazole (3.09 g, 22.90 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.40 g, 22.90 mmol). The reaction was stirred for 1 h at 0° C., then concentrated ammonium hydroxide was added (3.1 ml, 22.9 mmol). The reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was then diluted with ethyl acetate and washed sequentially with 5% citric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a pale oil. The crude residue was chromatographed (silica gel with a gradient of 50% ethyl acetate/49% hexane/1% acetic acid to 99% ethyl acetate/1% acetic acid) to give 3-(2-benzyloxy-4-carbamoyl-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a white foam (6.57 g, 82%). 1H NMR(300 MHz, DMSO) 8.12 (s, 1H), 7.76 (d, 1H), 7.38 (m, 9H), 5.34 (dd, 2H), 4.60 (m, 1H), 3.50 (bs, 3H), 2.58 (bs, 3H), 2.55 (dd, 1H), 2.34 (dd, 1H), 1.30 (s, 9H). MS(APCI) m/z 522.2 (M+1), 520.2 (M−H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]>CC(O)C.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([CH2:12][N:5]([CH2:4][CH2:3][N:2]([CH3:22])[CH3:1])[C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])[CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)CCN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CC(C)O
Product: CN(C)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
To a solution of N-[2-(dimethylamino)ethyl]-2,2,2-trifluoro-N-[(3-nitrophenyl)methyl]acetamide (204 mg, 0.64 mmol) in 2-propanol (15 mL) was added 10% palladium on carbon (20 mg). The reaction was stirred at rt under a hydrogen atmosphere (1 atm) for 17 h. The reaction mixture was filtered through Celite, adsorbed to silica, and purified by column chromatography to generate the title compound in 62% yield (115 mg, 0.40 mmol). 1H NMR (400 MHz, CDCl3): δ 7.10 (t, J=7.6 Hz, 1H), 6.68-6.70 (m, 2H), 6.58 (d, J=7.9 Hz, 1H), 3.76 (s, 2H), 2.75 (t, J=6.0 Hz, 2H), 2.49 (t, J=6.0 Hz, 2H), 2.24 (s, 6H). MS (ESI) m/z=290 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:15]([CH3:16])[C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.C(OCC)(=O)C>[CH3:16][N:15]1[C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:3][CH2:4]3)=[CH:12][CH:13]=[C:14]1[C:17]#[N:18]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)CCN2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)CCN2S(C)(=O)=O
Reaction time: 3 h
Yield: 33.2 %

Procedure:
5-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile hydrochloride (100 mg, 0.38 mmol) was dissolved in methylene chloride (5 mL) and triethylamine (0.17 mL, 1.14 mmol) was added. The mixture was treated with methanesulfonyl chloride (0.033 mL, 0.42 mmol) and stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, 2N HCl, water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 20-60% ethyl acetate in hexane) to afford 1-methyl-5-[1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1H-pyrrole-2-carbonitrile (38 mg). MS (ES) m/z 301.8; HPLC purity 100.0% at 210-370 nm, 8.8 min.; the Xterra® column RP18, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:5](NN)=[N:6][C:7]([F:10])=[CH:8][CH:9]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:4]([F:3])=[CH:9][CH:8]=[C:7]([F:10])[N:6]=1
Reactant: BrBr
Reactant: NNc1nc(F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(F)c(Br)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
Bromine (0.30 mL, 6 mmol) was added dropwise to a stirred solution of (3,6-difluoro-pyridin-2-yl)-hydrazine (435 mg, 3 mmol) in CHCl3 (6 mL) at room temperature. The mixture was stirred at 60° C. for 1 hour. The mixture was cooled at 0° C. and a saturated solution of NaHCO3 was added dropwise. DCM was added, the organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield 2-bromo-3,6-difluoro-pyridine (600 mg, 88% yield) as a dark oil.
Reaction SMILES: [Na].[CH2:2]([C:9]([CH3:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12](O)(=O)[CH3:13]>CO>[C:3]1([CH:2]([C:9](=[O:10])[CH2:11][CH2:9][CH2:2][CH2:3][CH2:4][CH2:12][CH3:13])[CH2:5][CH2:6][CH3:7])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: CC(=O)O
Agent: [Na]
Solvent: CO
Product: CCCCCCCC(=O)C(CCC)c1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution prepared from 3 g sodium metal in 100 ml absolute methanol there was added 45 g methyl benzyl ketone. The resulting solution was refluxed for 30 minutes, cooled to 0° C. and 39 g 2-methylene-3-quinolidinone was added. The solution was stirred at ambient temperature during 48 hours, netralized by the addition of 3 ml acetic acid and the solvents were removed under reduced pressure. There was obtained a crude oil which was extracted with chloroform. After evaporation of the solvent there was obtained 52 g (a yield of 60%) of the desired product, M.P. from acetone, 125.7° C. Treatment with hydrochloric acid gave the corresponding hydrochloride salt, M.P. above 300° C. (dec.).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13](C3CCCCO3)[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([C:36]1[NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=2[N:37]=1)[CH3:35].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:17]=[C:16]([N:37]2[C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=[C:36]2[CH2:34][CH3:35])[N:15]=3)[CH2:7][CH2:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: CC(C)(C)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C2CCCCO2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)[nH]c2n1
Temperature: 145 °C
Yield: 38.3 %

Procedure:
Into a vial was added 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (126 mg, 0.264 mmol), 2-ethyl-1H-benzo[d]imidazole (40.4 mg, 0.277 mmol), Xphos (16.3 mg, 0.0343 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.4 mg, 0.0179 mmol), and cesium carbonate (172 mg, 0.527 mmol;). The mixture was dissolved in N,N-dimethylformamide (2.02 mL, 0.0261 mol) and heated at 145° C. under pressure for 30 minutes in a microwave reactor. The reaction mixture was filtered and concentrated. The crude residue was dissolved in MeOH (5.0 mL) and para-toluenesulfonic acid (90.8 mg, 0.527 mmol) was added. The reaction was heated overnight at 40° C. The reaction mixture was concentrated to dryness and purified by reverse phase HPLC to give 401 (50.9 mg, 38.3%). [M+H]+=504.3
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5][N:6]=1.ClC1C=C(Cl)C=C(Cl)C=1[O:24][C:25](=O)[CH:26]([CH3:39])[C:27](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:28].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:27]([OH:28])=[C:26]([CH3:39])[C:25](=[O:24])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CCCCCCCSc1nnc(N)s1
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCSc1nn2c(=O)c(C)c(O)nc2s1
Reaction time: 0.75 h
Yield: 78 %

Procedure:
A mixture of 19.7 g of the thus obtained 2-amino-5-heptylthio-1,3,4-thiadiazole, 40.9 g of bis(2,4,6-trichlorophenyl)-2-methyl-malonate and 55 ml of chlorobenzene was stirred at 140°~144° C. for 45 minutes. After cooling, n-hexane was added thereto, the precipitate was collected by filtration. Further n-hexane was added to the filtrate, and the precipitate was collected The collected precipitates were combined. The combined precipitate was washed with n-hexane and thus 21.2 g of 2-heptylthio-7-hydroxy-6-methyl-5H-1,3,4-thiadiazolo-[3,2-a] pyrimidin-5-one was obtained. m.p. 141°~143° C. Yield 78%.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[O:30][CH:29]([OH:34])[CH2:28][CH2:27]2>O1CCCC1.CCCCCC>[OH:34][CH:29]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][N:16]=1)[CH2:28][CH2:27][C:26]1[CH:25]=[C:24]([O:23][CH3:22])[CH:33]=[CH:32][C:31]=1[OH:30]
Reactant: c1cnccn1
Reactant: COc1ccc2c(c1)CCC(O)O2
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(O)c(CCC(O)c2cnccn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (8.5 ml, 50.4 mmol) in 200 ml of anhydrous tetrahydrofuran was cooled to −30° C., n-butyllithium (20 ml of a 2.5 M solution in hexane, 50 mmol) was added dropwise, and the mixture stirred for 30 min at 0° C. After cooling at −70° C., a solution of pyrazine (4.0 g, 49.9 mmol) in 50 ml of anhydrous tetrahydrofuran was added dropwise. After 10 min at −70° C., 6-methoxy-chroman-2-ol (1.8 g, 10.0 mmol) was added and stirring was continued at −70° C. for 1.5 h. The reaction mixture was quenched with 20 ml of water and hydrochloric acid added until pH 5-6 was reached. After extraction with ethyl acetate, the organic layer was washed with water and brine, dried with sodium sulfate and concentrated. The obtained crude orange oil (960 mg) was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>CN(C=O)C>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:27]=2)[C:14]1=[O:22]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(Cc2cccc(C(F)(F)F)c2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.72 g. of NaH (80% suspension in mineral oil), 7 g. of 8-(2-oxo-benzimidazolin-1-yl)-caprylic acid methyl ester, 100 cc. of DMF, 4.7 g. of 3-trifluoromethylbenzylchloride and 0.72 g. of NaJ. Eluant for chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[C:16]([O:34][CH3:35])[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:37]1C=C(S(Cl)(=O)=O)C=C[C:42]=1Cl>>[CH2:37]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])=[C:16]([O:34][CH3:35])[CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:42]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)cc2c1CCN2S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC3)cc1F

Procedure:
4-{[1-(3,4-Dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 539.27 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-{[1-(3,4-dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[C:9]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[C:9]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:10]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(CC)c1ccc(-c2ccco2)c2[nH]c(=O)n(C)c12
Product: CCC(CC)c1ccc(-c2ccco2)c2nc(Cl)n(C)c12
Temperature: 120 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A mixture of 7-(1-ethylpropyl)-4-(2-furyl)-1-methyl-1,3-dihydro-2H-benzimidazole-2-one (79 mg, 0.278 mmol) in phosphorous oxychloride (0.78 ml, 8.33 mmol) was stirred at 120° C. for 2 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 1-30% ethyl acetate/n-hexane gradient mixture to give 44 mg (0.145 mmol, 52%) of the title compound.
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[C:9]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]2[O:14][CH:13]=[CH:12][C:11]=2[CH:15]=1)([O-])=O>[Ni].C(O)C.C1COCC1>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:9]2[C:10]3[O:14][CH:13]=[CH:12][C:11]=3[CH:15]=[C:7]([NH2:4])[CH:8]=2)[CH2:22][CH2:21]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])cc3ccoc23)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(N)cc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
Raney nickel (slurry in ethanol) and hydrazine hydrate (66 μL, 1.36 mmol) were added to tert-butyl 4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-carboxylate (123 mg, 0.34 mmol; obtained in Step 1) in ethanol:THF (4:1; 10 mL). The mixture was stirred at room temperature for 1 h. Unreacted starting material was still present and additional Raney nickel and hydrazine hydrate (33 μL, 0.68 mmol) were added with continuos stirring for 1 h. The mixture was filtered through a pad of Celite, which was rinsed several times with ethanol. Evaporation of the solvent gave 119 mg (quantitative) of the title amine as a green sticky oil which was used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH2:3][CH3:4].CN1CCOCC1.[C:13](Cl)(=[O:21])[O:14][CH2:15][O:16][C:17](=[O:20])[CH2:18][CH3:19]>C(Cl)(Cl)Cl>[C:13](=[O:21])([O:14][CH2:15][O:16][C:17](=[O:20])[CH2:18][CH3:19])[O:5][CH:2]([CH2:3][CH3:4])[CH3:1]
Reactant: CCC(C)O
Reactant: CCC(=O)OCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CCC(=O)OCOC(=O)OC(C)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 2-butanol (0.92 mL, 10 mmol) and 4-methylmorpholine (1.1 mL, 10 mmol) in CHCl3 (20 mL) at -70° C. is added 7c (1.7 g, 10 mmol) during 20 min with stirring. The temperature is kept at -70° C. for 1 h and then raised (1 h) to room temperature. Next day following evaporation the residue is triturated with Et2O (25 mL) and filtered. The filtrate is evaporated and distilled to give 1.0 g (50%) of the title compound with bp 66°-68° C./5 mbar.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([F:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-fluoroaniline (2.66 g) was treated in the same manner as described in Preparation Example 37 to give white crystalline powder of the title compound.
Reaction SMILES: [CH2:1]([CH:8](P(OCC)(=O)OCC)[CH:9]=[CH:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CCOCC>[C:2]1([CH2:1][CH:8]=[CH:9][CH2:10][CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=CC(Cc1ccccc1)P(=O)(OCC)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCC=CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
1.4 g (5 millimols) of diethyl 1-benzyl-2-butenephosphonate (a mixture of trans- and cis-forms) was dissolved in 10 ml. of dry ether, and the solution was stirred while being cooled with ice water. To the resulting solution was added 110 mg of lithium aluminum hydride, and the mixture was continued to be stirred. In about 2 hours, the reaction mixture was cooled with ice water, and with stirring, dilute hydrochloric acid was gradually added dropwise to decompose excess lithium aluminum hydride. the reaction mixture was extracted with ether, washed with an aqueous solution of sodium hydrogen carbonate and then with water, and dried. The solution was concentrated, and the residue was distilled at reduced pressure to afford 0.65 g (yield 89%) of 1-phenyl-2-pentene having a boiling point of 88° C. (14 torr). The analysis values of the product were as follows:
Reaction SMILES: [C:1]([C:4]1[C:5](Cl)=[C:6]2[NH:12][N:11]=[CH:10][C:7]2=[N:8][CH:9]=1)(=[O:3])[CH3:2]>C(N)C=C>[C:1]([C:4]1[C:5]([NH:8][CH2:7][CH:6]=[CH2:5])=[C:6]2[NH:12][N:11]=[CH:10][C:7]2=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2cn[nH]c2c1Cl
Solvent: C=CCN
Product: C=CCNc1c(C(C)=O)cnc2cn[nH]c12
Yield: 152.3 %

Procedure:
A solution of 6-acetyl-7-chloro-1H-pyrazolo[4,3-b]pyridine (D15, 340 mg, 1.7 mmol) in allylamine (5 ml) was stirred at room temperature for 16 h. Excess allylamine was removed in vacuo and the residue was dissolved in aqueous methanol. The solution was adjusted to pH 8 with 10% sodium carbonate solution, and extracted with ethyl acetate (4×50 ml). The extracts were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo to give a sticky solid. This was crystallised from ethyl acetate/ethanol to give the title compound (280 mg, 75%), m.p. 211°-213° C. Found: C, 60.49; H, 5.81; N, 25.55. C11H12N4O requires C, 61.10; H, 5.59; N, 25.91%.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[Cl:13][C:14]1[CH:15]=[C:16]([N:31]=[C:32]=[O:33])[CH:17]=[C:18]([Cl:30])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C>CC(C)=O>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[N:8][C:32]([NH:31][C:16]1[CH:17]=[C:18]([Cl:30])[C:19]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[C:14]([Cl:13])[CH:15]=1)=[O:33])[O:5][CH2:6][CH3:7]
Reactant: O=C=Nc1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Reactant: CCOC(=N)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=NC(=O)Nc1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-chlorobenzimidate hydrofluoroborate (1.90 g., 7.00 mmol), 3,5-dichloro-4-(4-nitrophenoxy)phenylisocyanate (2.28 g., 7.00 mmol) and triethylamine (0.72 g., 7.20 mmol) in acetone (20 ml) is stirred at room temperature for four hours under an atmosphere of dry nitrogen. The reaction mixture is concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase is washed sequentially with dilute hydrochloric acid, dilute sodium bicarbonate, and brine. After drying over sodium sulfate, the ethyl acetate solution is concentrated under reduced pressure and the residue chromatographed over silica gel eluting with 20% ethyl acetate in hexane. The product fractions are combined and concentrated under reduced pressure to leave the title compound as an amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][C:8]2([CH3:11])[CH3:10])[C:3]1=[CH:12][O:13][C:14](=[O:16])[CH3:15].O=[C:18]1N2C(CCOC2(C)C)C1>CN(C)C(=O)C>[O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][C:8]2([CH3:10])[CH3:11])[C:3]1=[C:12]([O:13][C:14](=[O:16])[CH3:15])[CH3:18]
Reactant: CC1(C)OCCC2CC(=O)N21
Reactant: CC(=O)OC=C1C(=O)N2C1CCOC2(C)C
Solvent: CC(=O)N(C)C
Product: CC(=O)OC(C)=C1C(=O)N2C1CCOC2(C)C

Procedure:
Following the procedure described for the preparation of 8-oxo-7-acetoxymethylene-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane from 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane and using N,N-dimethylacetamide instead of N,N-dimethylformamide one obtains 8-oxo-7-(1'-acetoxyethylidene)-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane.