Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[C:11](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CC(=O)CC(c2ccc(Cl)cc2)C1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-cyclohexane-1,3-dione (1.0 g, 4.5 mmol) was suspended in N,N-dimethylformamide dimethylacetal (5 ml) and heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature and the precipitate was filtered, washed with diethyl ether and dried under air suction. The required product was obtained as a yellow solid which was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[O:12])=[CH:6][CH:5]=1.[C:23]([Mg]Br)#[C:24][CH3:25]>COCCOC.C1COCC1>[F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[C:11]([C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([CH:16]([OH:17])[C:23]#[C:24][CH3:25])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(C(=O)C(=O)c2ccc(OC(F)F)cc2)c1
Reactant: CC#C[Mg]Br
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC#CC(O)c1cccc(C(=O)C(=O)c2ccc(OC(F)F)cc2)c1
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A stirred solution of 3-[2-(4-difluoromethoxyphenyl)-2-oxo-acetyl]-benzaldehyde (0.1 g, 0.33 mmol) in dry DME at 0° C. under nitrogen was treated over 10 min with 0.5 M 1-propynyl magnesium bromide in THF. The reaction was stirred for 0.5 h, quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by flash chromatography (20% to 40% ethyl acetate/petroleum ether) gave 1-(4-difluoromethoxyphenyl)-2-[3-(1-hydroxybut-2-ynyl)phenyl]ethane-1,2-dione as a clear oil, 55 mg (49% yield). Using essentially the same procedure described as described in Example 1, step c, and employing 1-(4-difluoromethoxyphenyl)-2-[3-(1-hydroxy-but-2-ynyl)phenyl]-ethane-1,2-dione (0.055 g, 0.16 mmol), the title product was obtained as a slight yellow foam, 0.044 g (69% yield), identified by NMR and mass spectral analyses. MS (ES+): 400 (M+H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH:15]=[CH2:16])[CH3:14])(=[O:11])[CH3:10].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>C1COCC1>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]([CH2:10][C:9]([O:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])([CH:15]=[CH2:16])[CH3:14])=[O:11])=[O:34]
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide in the amount of 101.0 mL (2.0 M, 0.202 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is placed in a dry ice-acetone bath. Linalyl acetate in the amount of 18.66 g (0.095 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of 17.43 g (0.090 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (53 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 5% ethyl acetate dissolved in petroleum ether) to give an oil. Purity of the product is determined by thin layer chromatography and GC analysis and the structure confirmed by mass spectrometry, 1 and 13C NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(CCC1CCC(=O)N1)Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCC(CCC(O)Cc2ccc(F)cc2)N1
Reaction time: 20 h
Yield: 75.5 %

Procedure:
Following the procedure described for Preparation 8, Step B, 5-[4-(4-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.64 g, mmol) was reduced with NaBH4 (400 mg, mmol) at room temperature for 1 h. Additional NaBH4 (150 mg) was added and the reaction was stirred for 20 h. Purification by medium pressure chromatography using a solvent gradient (CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 5-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (2.01 g). 1H NMR (CDCl3) δ7.14 (m, 2H), 6.98 (m, 2H), 6.78 (m, 1H), 3.76 (m, 1H), 3.65 (m, 1H), 2.76 (m, 1H), 2.64 (m, 1H), 2.32-2.18 (m, 4H), 1.72-1.47 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:16]([C:17](O)=[O:18])[CH2:15][C:14]2([CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].C1C2(OCCCO2)C[C@@H](C2NC=C([C:42]3[CH:47]=[CH:46][C:45]([C:48]4[CH:53]=[CH:52][C:51]([C:54]5[N:55]=[C:56]([C@@H:59]6[CH2:63][CH2:62][CH2:61][N:60]6[C:64]([C@@H:66]([NH:70][C:71](=[O:74])[O:72][CH3:73])[CH:67]([CH3:69])[CH3:68])=[O:65])[NH:57][CH:58]=5)=[CH:50][CH:49]=4)=[CH:44][CH:43]=3)N=2)N1>>[CH3:68][CH:67]([CH3:69])[C@H:66]([NH:70][C:71](=[O:74])[O:72][CH3:73])[C:64]([N:60]1[CH2:61][CH2:62][CH2:63][C@H:59]1[C:56]1[NH:57][CH:58]=[C:54]([C:51]2[CH:50]=[CH:49][C:48]([C:45]3[CH:44]=[CH:43][C:42]([C:10](=[O:11])[CH2:6][NH:5][C:17]([CH:16]4[CH2:15][C:14]5([CH2:20][CH2:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24]5)[CH2:13][N:12]4[C:10](=[O:11])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:9])[CH3:8])=[O:18])=[CH:47][CH:46]=3)=[CH:53][CH:52]=2)[N:55]=1)=[O:65]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1C(=O)NCC(=O)c1ccc(-c2ccc(-c3c[nH]c([C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)n3)cc2)cc1)C(C)C
Yield: 49 %

Procedure:
Prepared in 49% yield from 2-{N-[(methyloxy)carbonyl]-L-valyl}-8-thia-2-azaspiro[4.5]decane-3-carboxylic acid 8,8-dioxide (107) (100 mg, 0.26 mmol) and methyl {(1S)-1-[((2S)-2-{4-[4′-(aminoacetyl)-4-biphenylyl]-1H-imidazol-2-yl}-1-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate dihydrochloride (1) (148 mg, 0.26 mmol), in an analogous fashion as described in Example 15.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.CO>[Fe].O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:10][C:4]=1[NH2:1]
Reactant: Nc1ccc(SCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CO
Product: Nc1ccc(SCC(F)(F)F)cc1N
Reaction time: 2 h

Procedure:
4.1 G. of 2-nitro-4-(2,2,2-trifluoroethylthio) aniline in 60 ml. of methanol and 12 ml. of water is treated with 1.25 g. of ferrous sulfate and 3.3. g. of iron powder at reflux. After 2 hours, 1.25 g. of ferrous sulfate and 3.3 g. of iron powder are added and heating is continued for 4 hours. The mixture is poured into 600 ml. of hot tetrahydrofuran and filtered. 1,2-Diamino-4-(2,2,2-trifluoroethylthio) benzene is obtained from the filtrate by evaporation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6](N)=[CH:5]2.[FH:13].N1C=CC=CC=1.N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([F:13])=[CH:5]2
Reactant: F
Reactant: Nc1cc2cc(Br)ccc2cn1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1cc2cc(Br)ccc2cn1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
To a mixture of 6-bromoisoquinolin-3-amine (0.710 g, 3.18 mmol) in pyridine hydrofluoride (10 mL, 3.18 mmol) at −78° C. was carefully added sodium nitrite (0.26 g, 3.82 mmol). The reaction mixture was stirred at −78° C. for 5 minutes. The reaction mixture was warmed to room temperature over 40 minutes. The mixture was poured into an ice bath, and the pH was adjusted to >9 with Na2CO3. The mixture was filtered to recover a yellow-purple solid. The solid was dissolved in EtOAc-water with stirring. The mixture was extracted with EtOAc (3×200 mL). The EtOAc was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was taken up in DCM-MeOH and adsorbed onto silica gel. Purification by chromatography on silica gel (EtOAc 0-7% in hexane) provided the product (500 mg, 70%). LCMS (API-ES) m/z: 226, 228 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25][OH:26])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCCNC(=O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: COC(=O)CCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(5-methoxycarbonylpentyl)propanamide (507 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(5-methoxycarbonylpentyl)propanamide (483.5 mg).
Reaction SMILES: [CH:1]1([C:6]2([CH2:26][CH2:27][C:28]3[CH:44]=[CH:43][C:31]([O:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)=[C:30]([CH2:45][CH3:46])[CH:29]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)[C:8](=[O:25])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[NH2:35][CH2:34][CH2:33][O:32][C:31]1[CH:43]=[CH:44][C:28]([CH2:27][CH2:26][C:6]2([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[O:7][C:8](=[O:25])[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)=[C:10]([OH:12])[CH2:11]2)=[CH:29][C:30]=1[CH2:45][CH3:46]
Reactant: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1OCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 111.6 %

Procedure:
tert-Butyl 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethylcarbamate (Example A(70)) (250 mg) was dissolved in 4N HCl in dioxane (10 ml) and stirred at room temperature for 12 hrs. Upon completion the mixture was concentrated and azeotroped several times with dichloromethane to afford the title compound as a white solid (235 mg). 1H NMR (300 MHz, MeOD): δ 1.18 (t, J=7.56 Hz, 3H) 1.32-2.35 (m, 11H), 2.59-2.85 (m, 15H), 2.92 (dd, J=16.54 Hz, 1H), 4.05 (t, J=7.54 Hz, 2H), 6.55 (d, J=1.56 Hz, 1H), 6.65 (d, J=1.56 Hz, 1H), 6.95 (s, 1H), 6.99 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([CH2:21][C:22]([CH3:24])=[CH2:23])=[C:9]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:8]=[C:9]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:10]([CH2:21][C:22]2([CH3:24])[CH2:23][O:42]2)=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)Cc1c(OCc2ccccc2)cc(C(=O)OC(C)(C)C)cc1OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2(C)CO2)c(OCc2ccccc2)c1
Yield: 48250.3 %

Procedure:
To a solution of 3,5-bis-benzyloxy-4-(2-methyl-allyl)-benzoic acid tert-butyl ester (227a) (80 g, 0.18 mmol) in CH2Cl2 (500 mL) was added m-CPBA (62 g, 0.36 mol) portion-wise. The mixture was refluxed overnight. The solid was filtered and washed with CH2Cl2. The filtrate was washed with saturated aqueous Na2S2O4 (250 mL) and brine (250 mL). The organic layer was separated, dried over Na2SO4 and concentrated to give a brown oil. The crude oil was quickly purified by column chromatography (EtOAc/petroleum ether=1/10) to give the title compound (40 g, 48.2% yield) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[C:15]([Cl:16])=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([O:17][CH3:18])[CH:9]=1>>[Cl:1][CH2:2][CH2:3][C:4]([NH:7][C:8]1[CH:9]=[C:10]([O:17][CH3:18])[C:11]([CH:12]=[O:13])=[CH:14][C:15]=1[Cl:16])=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: COc1cc(N)c(Cl)cc1C=O
Product: COc1cc(NC(=O)CCCl)c(Cl)cc1C=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
3-Chloropropionyl chloride (98.4 ml, 1.0 mol) was added over 30 minutes to a stirred suspension of 4-amino-5-chloro-2-methoxybenzaldehyde (47.4 g, 0.26 mol) ensuring the reaction temperature did not exceed 20° C. After the addition was complete the reaction was stirred at 20° C. for a further 2 hours and then filtered. The filtrate was concentrated to 150 ml under reduced pressure and then diluted with ethyl acetate (100 ml) and water (400 ml). The mixture was stirred at 20° C. for 1 hour and then filtered to give 3-chloro-N-[2-chloro-4-formyl-5-(methyloxy)phenyl]propanamide as an off-white solid which was not isolated but suspended in tetrahydrofuran (730 ml) and treated with diisopropylethylamine (154 ml, 0.88 mol). The resulting mixture was stirred at 45° C. for 46 hours and then concentrated under reduced pressure to leave a residue which was diluted with ethyl acetate (300 ml), washed with 2M hydrochloric acid (4×100 ml) and concentrated under reduced pressure to give N-[2-chloro-4-formyl-5-(methyloxy)phenyl]-2-propenamide (37.8 g, 62%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[C:2]#[CH:3].C(O[C:21](=[O:27])[C:22]([O:24]CC)=O)C>>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:21](=[O:27])[C:22]1=[O:24])[C:2]#[CH:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: C#CCNCCNc1cccc(C(F)(F)F)c1
Product: C#CCN1CCN(c2cccc(C(F)(F)F)c2)C(=O)C1=O

Procedure:
Condensation of N-propargyl-N'-(3-trifluoromethyl-phenyl)-ethylenediamine, obtainable according to 3.2, with diethyloxalate gave 1-propargyl-4-(3-trifluoromethyl-phenyl)-piperazin-2,3-dione. This compound was reduced to the title compound with lithium aluminum hydride or borane and was processed according to Example 5. White crystals, melting point 218°-219° C. (decomposition).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH:9]1[CH3:29])=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:28][CH:17]1[N:16]2[C:21]([CH2:22][O:23][C:24]3[C:15]2=[CH:14][C:13]([NH:12][CH:10]2[CH2:11][NH:8][CH:9]2[CH3:29])=[CH:26][CH:25]=3)=[N:20][NH:19][C:18]1=[O:27]
Reactant: CC1C(Nc2ccc3c(c2)N2C(=NNC(=O)C2C)CO3)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1NCC1Nc1ccc2c(c1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 2-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.016 g, 0.040 mmol) in DCM (2 mL) was added TFA (0.4 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 4-methyl-6-(2-methyl-azetidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.012 g, 100%) LC/MS (Table 1, Method 5) Rt=1.582 min.; MS m/z: 302 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1.[F:14][C:15]([F:30])([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2)[C:16]([NH:18][NH2:19])=O.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:30][C:15]([F:14])([C:16]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2
Reactant: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 130 °C
Yield: 61.8 %

Procedure:
A mixture of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-pyridazine (step d) (4.57 g, 23.6 mmol) and difluoro-quinolin-6-yl-acetic acid hydrazide (step c) (5.60 g, 23.6 mmol) in n-butanol (125 mL) was heated to 130° C. overnight. The mixture was cooled to room temperature, followed by aqueous work up using AcOEt and a solution of K2CO3. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography (first chromatography: CH2Cl2 100% and CH2Cl2/MeOH: 88/12 followed by another column with toluene/iPrOH/NH4OH: 85/15/2) to give the title compound (5.5 g, 62%). M.p=199.7° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([O:15][P:16]([C:21]([NH2:24])([CH3:23])[CH3:22])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14].C(N(CC)CC)C>C(#N)C>[CH2:18]([O:17][P:16]([C:21]([NH:24][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:22])[CH3:23])(=[O:20])[O:15][CH2:13][CH3:14])[CH3:19]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCOP(=O)(OCC)C(C)(C)N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(OCC)C(C)(C)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
83 g of 3-nitrobenzoyl chloride in 150 ml of acetonitrile are added dropwise to a solution of 105 g of 2-aminopropane-2-phosphonic acid diethyl ester and 45 g of triethylamine in 300 ml of acetonitrile at 0° C., with good stirring. After completion of the addition, the mixture is stirred for a further 3 hours at 0° C.; it is then filtered and the solvent is distilled off in vacuo. The residue is purified by extraction by shaking with ether and aqueous 2 normal sodium carbonate solution. 99 g of 2-(3'-nitrobenzamido)propane-2-phosphonic acid diethyl ester of melting point 95°-96° C. are obtained. This product is reduced with hydrogen as indicated in Example 2.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5].[BrH:17].OO>>[NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]([Br:17])=[CH:12][C:3]=1[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5]
Reactant: CCCCCOC(=O)c1cccc(C)c1N
Reactant: Br
Agent: OO
Product: CCCCCOC(=O)c1cc(Br)cc(C)c1N
Yield: 899.4 %

Procedure:
The above-described method (Example 1) was repeated to react pentyl 2-amino-3-methylbenzoate (2.28 g, 10 mmol) with hydrogen bromide (2.21 g, 13 1 mmol, 48% in water) and hydrogen peroxide (1.72 g, 15.0 mmol, 30% in water). Following working up similar to Example 1 and additional column chromatography, pentyl 2-amino-5-bromo-3-methylbenzoate (2.7 g, 88.3% of theory, >99 area% LC) was obtained as a yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:20])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH2:17][NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:20])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH2:17][NH:18][S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CNS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Glycyl-L-proline benzylester hydrochloride (1.49 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C., and then methylene chloride (10 ml) solution of benzenesulfonylchloride (0.86 g, 5 mmole) was added dropwise. The mixture was stirred for 1 hour at less than 0° C, and then for 5 hours at room temperature, and methylene chloride (60 ml) was added. The mixture thus obtained was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure to give N-benzenesulfonylglycyl-L-proline benzylester (yield: 1.91 g, 94.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=S)[CH2:13][N:14]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:12]1[CH2:13][N:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[N:11]=1)[NH2:23]
Reactant: NN
Reactant: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Solvent: CCO
Solvent: O
Product: CCc1cc2c(s1)N=C(NN)CN=C2c1ccccc1Cl

Procedure:
[d] 32.1 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e][1,4] diazepine-2-thione obtained in the above example [a] is suspended in 200 ml of ethanol, and to the suspension is added 8 g of hydrazine hydrate. Several minutes stirring turns the suspension into a homogeneous, red, transparent solution. Then crystals begin to precipitate. After stirring at room temperature for 2 hours and subsequent ice-cooling, the crystals are collected by suction filtration and washed well with methanol to give 28.6 g of almost pure 2-hydrazino-5-o-chlorophenyl-7-ethyl-3H-thieno[2,3-e][1,4]diazepine as yellowish crystals. The crystals, when recrystallized from a mixture of ethanol and diemethylformamide, show a melting point of 214° - 216°C (decomposition).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7]=2[CH:17]=1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:14]2[CH2:13][CH2:12][CH:11]([C:8]3[C:7]4[CH:17]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=4[O:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Clc1ccc2onc(C3CCNCC3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(Cl)cc34)CC2)CC1

Procedure:
The title compound, MS: m/e=462.3 (M+H+), was prepared in accordance with the general method of example 1, intermediate E from a mixture of 5-chloro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride and trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (Example 1, Intermediate C).