Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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]>[CH2:15]([N:12]([CH2:13][CH3:14])[C:10]([C:9]1[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:11])[CH3:16]
Reactant: CCN(CC)C(=O)c1ccccc1Br
Reactant: C1CNCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccccc1N1CCNCC1
Temperature: 100 °C
Yield: 46.5 %

Procedure:
Piperazine (489 mg, 4.8 mmol), 2-bromo-N,N-diethyl-benzamide (1 g, 3.95 mmol), Pd2(dba)3 (235 mg, 0.2 mmol), BINAP (442 mg, 0.6 mmol), and cesium carbonate (3 g, 5.53 mmol) were mixed together in toluene (20 mL). The mixture was degassed and heated to 100° C. for about 72 hours. The mixture was diluted with ether (100 mL) and filtered over celite. The filtrate was concentrated and then subjected to chromatography on silica gel to give the title compound (480 mg, 47%) as a brown oil. LRMS (ESI+): 262.2 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:24][N:25]=1)[NH:6]2.C[N:31](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:14])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27]([NH2:31])=[O:29])[CH2:24][N:25]=1)[NH:6]2
Reactant: CN(C)C=O
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(N)=O)S3)cc12
Temperature: 25 °C
Yield: 92 %

Procedure:
To a mixture of (2-{4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.25 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (0.11 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.14 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=9:1-10:0), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (228 mg, yield: 92%) as colorless crystals. MS: 449 (MH+). melting point 120-121° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[CH2:11]([CH:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)=[O:26])[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2cn[nH]c2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 6-aminoindazol (Aldrich) and (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) according to the method described in Example 1c. Melting Point: 160-164° C. (diethylether).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH:13]=[CH2:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(NC(C)=O)cc1

Procedure:
Commercially available 4-acetamido phenol (1 molar equivalent), allyl bromide (1 molar equivalent) and potassium carbonate (1 molar equivalent) in butan-2-one were heated at reflux for 18 hours with stirring. The mixture was cooled, filtered and the solid residue washed with ether. The combined filtrates were evaporated and the solid residue was further purified by crystallisation from ethyl acetate-hexane to give 4-acetamido-1-allyloxy benzene as a colourless solid, m.p. 85°-86° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1N.N([O-])=O.[Na+].[C-:16]#[N:17].[K+]>Cl.O>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Reactant: [C-]#N
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])cc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Compound 489A (10.0 g, 37.9 mmol) was dissolved in a mixture of 20 mL 12 N HCl/40 mL water and then cooled to 0° C. To this mixture was slowly added a solution of sodium nitrite (5.23 g, 75.8 mmol) in 10 mL water while maintaining the reaction temperature at 0° C. The reaction was stirred for 1 h at 0° C. and then slowly added to a mechanically stirred solution of freshly prepared cuprous cyanide (3.0 g, 33 mmol, prepared as described in Vogel's Textbook of Practical Organic Chemistry, 5th edition, pg. 429) and potassium cyanide (6.30 g, 96.7 mmol) in water (50 mL) at 50° C. The reaction was stirred for 1 h at 50° C., cooled to 25° C. and extracted with methylene chloride (2×200 mL). The organic portion was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel eluting with 4:1 hexane:ethyl acetate to yield 4.6 g (44%) of compound 489B as an orange solid. HPLC: 98% at 2.647 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([CH:25]([CH3:45])[CH2:26][C:27]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH2:3]1.[H][H]>[Pd].CO>[OH:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH2:6][CH2:5][N:4]([CH:25]([CH3:45])[CH2:26][C:27]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:28]([N:30]([CH3:31])[CH3:32])=[O:29])[CH2:3]1
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2ccccc2OCc2ccccc2)[C@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2ccccc2O)[C@H](O)C1
Yield: 63 %

Procedure:
A mixture of 2.7 parts of trans-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-4-[[2-(phenylmethoxy)benzoyl]amino]-1-piperidinebutanamide and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in methylbenzene and the solvent was evaporated again. The residue was suspended in a mixture of 2,2'-oxybispropane and a few drops of acetonitrile. The product was filtered off and dried in vacuo at 70° C., yielding 1.3 parts (63.0%) of trans-3-hydroxy-4-[(2-hydroxybenzoyl)-amino]-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 154.3° C. (compound 77).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[C:5]([N+:23]([O-:25])=[O:24])[C:4]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C1COCC1.[H-].[Na+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>O>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][N:9]([C:7](=[O:8])[C:6]1[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[C:4]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:5]=1[N+:23]([O-:25])=[O:24])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[CH3:45]
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccc([N+](=O)[O-])cc2)c1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCOc1c(OC)ccc(C(=O)N(CCc2ccc([N+](=O)[O-])cc2)CC(=O)OCC)c1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 68 %

Procedure:
4-Methoxy-2-nitro-N-[2-(4nitrophenyl)ethyl]-3-pentyloxybenzamide obtained in Example 2-47, THF (1 ml) and sodium hydride (13.3 mg, 0.556 mmol) were mixed, and the mixture was stirred for 5 minutes. Ethyl bromoacetate (0.0617 ml, 0.556 mmol) was added, and the mixture was stirred at 90° C. for 5.5 hours. Then, sodium hydride (6.7 mg, 0.278 mmol) and ethyl bromoacetate (6.7 mg, 0.278 mmol) were further added, and the mixture was stirred at 90° C. for 6.5 hours. To the mixture was added water (3 ml) to stop the reaction, and the organic layer was extracted 3 times with ethyl acetate (5 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. The drying agent was fitered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1-2/3) to give ethyl{ (4-methoxy-2-nitro-3-pentyloxybenzoyl)-[2-(4nitrophenyl)ethyl]amino}acetate (0.137 g, 68%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu](C#N)[C:14]#[N:15].O>CN1CCCC1=O>[F:10][C:5]1[C:6]([CH:7]=[O:8])=[CH:9][C:2]([C:14]#[N:15])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: COc1cc(F)c(C=O)cc1Br
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(F)c(C=O)cc1C#N
Temperature: 180 °C
Reaction time: 5.5 h
Yield: 25.8 %

Procedure:
5.33 g of 5-bromo-2-fluoro-4-methoxy-benzaldehyde was dissolved in 73 ml of 1-methyl-2-pyrrolidone, 2.46 g of copper cyanide was added under stirring at 180° C. for 5.5 hours. After cooling to room temperature, water was added to the reaction mixture. The mixture was extracted with ethyl acetate and filtered through Celite. Then, the resulting organic layer was washed with water and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography, to give 0.983 g of the title compound as pale yellow crystals.
Reaction SMILES: [Si]([O:8][CH:9]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14][C:15](=[C:21]1[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1)[C:16]2=[O:20])(C(C)(C)C)(C)C.O.C(O)(=O)C.O1CCCC1>[Cl-].[Na+]>[CH:32]1([CH:9]([OH:8])/[CH:10]=[CH:11]/[CH:12]2[CH2:19][CH2:18][CH:17]3[CH:13]2[CH2:14][C:15](=[C:21]2[CH2:22][CH2:23][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]2)[C:16]3=[O:20])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CCOC(=O)C1CCC(=C2CC3C(/C=C/C(O[Si](C)(C)C(C)(C)C)C4CCCCC4)CCC3C2=O)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(=C2CC3C(/C=C/C(O)C4CCCCC4)CCC3C2=O)CC1
Yield: 73.1 %

Procedure:
(E)-6-(3-tert-Butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)-3-(4-ethoxycarbonylcyclohexylidene)bicyclo[3,3,0]octan-2-one (15 mg), prepared as described in Reference Example 36 and in the form of (±)-(E)-6β-(3α-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl)-3-(4-ethoxycarbonylcyclohexylidene)bicyclo[3,3,0]-octan-2-one, otherwise known as (±)-ethyl(13E)-(9S,15S)-6a-oxo-2,5-ethano-6,9-methano-15-tert-butyldimethylsilyloxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoate and a solution of water, glacial acetic acid and tetrahydrofuran (0.59 ml; 7:13:2 by volume) were stirred together at 45° C. for 5 hours. After cooling, the mixture was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The extract was washed with aqueous sodium carbonate solution (2M) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The residue was subjected to medium pressure, short column chromatography on silica gel, using a mixture of ethyl acetate and hexane (2:1 v/v) as eluant, to give (E)-6-(3-cyclohexyl-3-hydroxyprop-1-enyl)-3-(4-ethoxycarbonylcyclohexylidene)bicyclo[3,3,0]octan-2-one (8.6 mg), in the form of (±)-(E)-6β-(3-cyclohexyl-3α-hydroxyprop-1-enyl)-3-(4-ethoxycarbonylcyclohexylidene)bicyclo[3,3,0]octan-2-one, otherwise known as (±)-ethyl(13E)-(9S,15S)-6a-oxo-2,5-ethano-6,9-methano-15-hydroxy-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoate [NMR (in deuterochloroform): multiplets at 5.4-5.6, 3.6-4.3 and 0.8-3.0 p.p.m⟧
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:18][NH:19][CH3:20]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:19]([CH3:20])[CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CNC
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCC2c1ccccc1
Yield: 100.3 %

Procedure:
A solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.754 mmol) and excess dimethylamine (3.77 mL, 7.54 mmol) in MeOH (2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum to afford 2-chloro-N,N-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (207 mg, 0.756 mmol, 100% yield). LC-MS (M+H)+=274.2.
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:32][C:33]1[S:37][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[S:37][C:36]([S:38]([N:7]2[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]5[CH:23]=[CH:22][NH:21][C:17]=5[N:18]=[CH:19][N:20]=4)[CH:12]=[N:11]3)[CH3:1])[CH2:9][CH2:8]2)(=[O:40])=[O:39])=[CH:35][CH:34]=1
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Product: CC(CN1CCN(S(=O)(=O)c2ccc(Cl)s2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1

Procedure:
This compound was prepared according to the procedure of Example 92, using 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine and 5-chlorothiophene-2-sulfonyl chloride as the starting materials. 1H NMR (300 MHz, DMSO-D6): δ 12.05 (s, 1H); 8.62 (s, 1H); 8.60 (s, 1H); 8.22 (s, 1H); 7.54 (d, 1H); 7.48 (d, 1H); 7.28 (d, 1H); 6.90 (d, 1H); 4.63 (m, 1H); 2.85 (m, 5H); 2.61 (m, 3H); 2.41 (m, 2H); 1.41 (d, 3H); LCMS calculated for C20H23CIN7O2S2(M+H)+: m/z=492.0.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][C@H:9]2[C:8]2=[C:13]([C:16]([O:18]CC)=[O:17])[N:14]=[CH:15][N:7]2[C:6]2[CH:21]=[CH:22][S:23][C:5]1=2>C(O)C.O>[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][C@H:9]2[C:8]2=[C:13]([C:16]([OH:18])=[O:17])[N:14]=[CH:15][N:7]2[C:6]2[CH:21]=[CH:22][S:23][C:5]1=2
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Yield: 88.2 %

Procedure:
13.9 ml (55.6 mmol) of 4N sodium hydroxide solution were added dropwise to a suspension of 13.5 g (44.5 mmol) of ethyl (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylate in 10 ml of ethanol and 16 ml of water. The mixture was heated at reflux for 30 minutes and the ethanol was subsequently distilled off. The aqueous phase was washed twice with methylene chloride and adjusted to pH=3 with 4N hydrochloric acid. The resulting precipitate was filtered off and washed with water, ethanol and subsequently with diethyl ether. There were obtained 10.8 g (88%) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid as a colourless powder of m.p. 260° (dec.).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:7]([S:15]([CH3:17])=[O:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=1[S:12][CH3:13])=[O:4].[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:19]=1[S:27]([CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:19]=1[S:27]([CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]([NH:5][C:6]2[C:7]([S:15]([CH3:17])=[O:16])=[N:8][C:9]([CH3:14])=[CH:10][C:11]=2[S:12][CH3:13])=[O:4])[CH2:33][CH2:32]1)=[O:28]
Reactant: CSc1cc(C)nc(S(C)=O)c1NC(=O)CBr
Reactant: O=S(CCN1CCNCC1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(C)nc(S(C)=O)c1NC(=O)CN1CCN(CCS(=O)c2nc3ccccc3[nH]2)CC1
Reaction time: 12 h
Yield: 49.6 %

Procedure:
To a solution of this sulfoxide (21.4 mg, 0.063 mmol) in DMF (1 ml) were added 1-[2-(benzimidazol-2-ylsulfinyl)ethyl]piperazine (17.6 mg, 0.063 mmol) obtained in Example 146 and potassium carbonate (17.5 mg, 0.127 mmol), and stirred for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=5:1) to provide 16.7 mg (yield 49%) of the desired compound as pale yellow oil. IR (KBr) cm−1: 3190, 2993, 1674, 1571, 1484. 1H-NMR (CD3OD) δ: 2.15-2.65 (14H, m), 2.63-2.84 (5H, m), 2.89 (2H, s), 3.34 (1H, dt, J=12.0, 6.0 Hz), 3.43 (1H, dt, J=12.0, 6.0 Hz), 7.22 (1H, s), 7.23-7.28 (2H, m), 7.55-7.59 (2H, m).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[N:5]1[C:12](Cl)=[N:11][C:9](Cl)=[N:8][C:6]=1Cl>O>[N:1]1([C:6]2[N:8]=[C:9]([N:1]3[CH2:4][CH2:3][CH2:2]3)[N:11]=[C:12]([N:1]3[CH2:4][CH2:3][CH2:2]3)[N:5]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1CNC1
Solvent: O
Product: C1CN(c2nc(N3CCC3)nc(N3CCC3)n2)C1
Yield: 78 %

Procedure:
Compound LXXVI was prepared after the method of Schaefer (J Am Chem Soc (1955) 77 p592B). The hydrochloride salt of azetidine was reacted with cyanuric chloride in water to give compound LXXVI as a white solid (yield 78%) having a melting point of 225°-238° C. The 1Hnmr of this compound indicated that its identity was correct and that its purity was adequate for subsequent reactions without further purification.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:30]([O:34][C:35]([NH:37][C:38]1[S:42][C:41]([C:43]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:44]=2[F:50])=[N:40][C:39]=1[C:51](O)=[O:52])=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:51]([C:39]3[N:40]=[C:41]([C:43]4[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:44]=4[F:50])[S:42][C:38]=3[NH:37][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[O:52])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1NC(=O)OC(C)(C)C)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (13.0 mg, 0.032 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (13.7 mg, 0.040 mmol), HATU (30.5 mg, 0.080 mmol) in DMF (0.09 mL) and DIPEA (12.5 mg, 0.096 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (12.4 mg, 52%). LCMS calc. for C36H45F2N6O7S (M+H)+: m/z=743.3. Found: 743.3.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].I[CH2:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][C:43](=O)[CH2:44][C:39]=2[NH:38][C:37]1=[O:46].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:33][CH2:34][CH2:35][N:36]3[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[NH:38][C:37]3=[O:46])[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: O=C1C=Cc2c([nH]c(=O)n2CCCI)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Temperature: 65 °C
Yield: 77.3 %

Procedure:
A mixture of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (500 mg, 1.19 mmol, 1 equiv), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one-one (358.8 mg, 1.19 mmol, 1 equiv), and potassium carbonate (493.4 mg, 3.57 mmol, 3 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. After cooling to ambient temperature, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using preparatory thin layer chromatography in 10% methanol in dichloromethane to afford the title compound (548 mg, 77.4%); 1H NMR (400 MHz, DMSO-d6): δ 1.52 (s, 9H); 1.61 (d, 2H, J=12.8 Hz), 1.83 (t, 2H, J=6.8 Hz); 2.36 (t, 2H, J=6.8 Hz); 2.54-2.73 (m, 6H); 3.86 (t, 2H, J=6.8 and 6.4 Hz); 4.58 (s, 2H); 4.61 (s, 2H); 6.77 (t, 1H, J=7.6 and 7.2 Hz); 6.85 (d, 2H, J=8 Hz); 6.97 (d, 1H, J=2.8 Hz); 7.18-7.25 (m, 3H); 7.48-7.55 (m, 2H); 7.79-7.84 (m, 2H); 10.81 (s, 1H); MS for C35H41N5O4 m/z 596.16 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH2:10]Br)=[CH:8][CH:7]=[CH:6][C:5]=1[Br:12].C[N+]1([O-])CC[O:18]CC1>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH:10]=[O:18])=[CH:8][CH:7]=[CH:6][C:5]=1[Br:12]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)c1c(Br)cccc1CBr
Solvent: CC#N
Product: COC(=O)c1c(Br)cccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2-bromo-6-bromomethyl-benzoic acid methyl ester (21.8 mmol), N-methylmorpholine N-oxide (43.6 mmol) and 35 g powdered 4 Å molecular sieves in 350 mL acetonitrile was stirred for 1.5 h at room temperature. The reaction was filtered through a bed of silica, and the filtrate was purified on silica.