Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=3)[O:16][C:15]=2[CH3:26])[CH:8]=1)(=[O:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:36][C:37]1[S:38][C:39]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:40]=2[N:41]=1.Cl>CN(C)C=O.CCOCC.O>[F:28][C:2]([F:27])([F:1])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:36][C:37]4[S:38][C:39]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:40]=5[N:41]=4)[CH:21]=3)[O:16][C:15]=2[CH3:26])[CH:8]=1)(=[O:4])=[O:5]
Reactant: Cc1oc2ccc(O)cc2c(=O)c1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Reactant: Fc1ccc2sc(CCl)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Cc1oc2ccc(OCc3nc4cc(F)ccc4s3)cc2c(=O)c1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a stirred solution of 1.8 g (4.4 mmole) of the product from Example 126 in 50 mL dimethylformamide was added 2.4 g (17.4 mmole) potassium carbonate. The mixture was stirred at room temperature for 1 hour then 1.2 g (5.72 mmole) 2-(chloromethyl)-5-fluorobenzothiazole was added. The mixture was stirred for 18 hours, poured into water, acidified to ph 1-4 with 1N HCl, and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine and then dried (MgSO4), and concentrated to give a solid. Trituration with ether afforded 2.45 g (97%) of the title product as a solid, mp 218°-220° C. Analysis calculated for C26H18N2S2O5F4 : C, 53.98; H, 3.14; N, 4.84. Found: C, 53.94; H, 2.91; N, 4.55.
Reaction SMILES: C(C1C=[CH:42][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#N.[OH-:44].[K+].Cl.[CH2:47]([OH:50])[CH2:48][CH3:49]>O>[C:47]([C:48]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)=[CH:42][CH:49]=1)([OH:50])=[O:44]
Reactant: [OH-]
Reactant: CCCO
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCOc2ccc(F)cc2)Cc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCCOc2ccc(F)cc2)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A solution of 460 mg (0.80 mmol) of methyl 4-[(4E)-3-(4-cyanobenzyl)-5-{2-[4-(4-fluorophenoxy)butoxy]phenyl}pent-4-en-1-yl]benzoate in 15 ml of 1-propanol and 2 ml of water is mixed with 1340 mg (23.89 mmol) of potassium hydroxide and stirred at 110° C. for 12 h. After cooling, the mixture is acidified with 1 M hydrochloric acid, and the crystals which have separated out are filtered off with suction, washed several times with water and dried. 325 mg (0.52 mmol, 65% of theory, purity 93%) of the title compound are obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C([O:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:37]2[C:45]3[C:40](=[CH:41][C:42]([C:46](O)=[O:47])=[CH:43][CH:44]=3)[C:39]([CH3:49])=[C:38]2[CH3:50])=[CH:32][CH:31]=1)=[O:23])(C)(C)C>>[CH2:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:46]([C:42]2[CH:41]=[C:40]3[C:45](=[CH:44][CH:43]=2)[N:37]([CH2:36][C:33]2[CH:32]=[CH:31][C:30]([C:25]4[C:24]([C:22]([OH:23])=[O:21])=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:35][CH:34]=2)[C:38]([CH3:50])=[C:39]3[CH3:49])=[O:47])[CH2:3]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H]3CCN(C(=O)OCc4ccccc4)C3)cc12

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-benzyl 3-aminopyrrolidine-1-carboxylate and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 601 [M+1]+.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C([Si](C)(C)[O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])=[CH:24][CH:23]=1)(C)(C)C>C1COCC1>[OH:4][C:3]1[CH2:5][C:30]([CH2:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][CH:26]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:31][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 6 using 4.3 mL (40 mmol) of methyl acetoacetate, 1.64 g (41 mmol) of 60% sodium hydride, 25.6 mL (41 mmol) of 1.6 M n-butyllithium, 6.81 g (20 mmol) of 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1-phenyl-propan-1-one (from Example P) and 200 mL of THF. The product was carried on crude to the next step.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:14]=[C:13]3[CH:15]=[CH:16][C:17](C(Cl)=O)=[CH:18][C:12]3=[N:11]2)=[CH:6][CH:5]=1)=[O:3].[CH3:22][O:23]C(=O)C1C=CC(N)=CC=1.C1(N)C=CC=C([NH2:39])C=1>N1C=CC=CC=1>[CH3:22][O:23][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:14]=[C:13]3[CH:15]=[CH:16][C:17]([NH2:39])=[CH:18][C:12]3=[N:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(Cl)c1ccc(-n2nc3ccc(C(=O)Cl)cc3n2)cc1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Nc1cccc(N)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-n2nc3ccc(N)cc3n2)cc1

Procedure:
the 2-(4-chlorocarbonylphenyl)-5-chlorocarbonylbenzotriazole used in Examples 1 to 9 was prepared in the following way: p-aminobenzoic acid methyl ester is diazotised in the customary manner and the diazo compound is coupled with m-phenylenediamine. The resulting crude azo dyestuff is oxidised in hot pyridine with Cu-II acetate to give 2-(4-methoxycarbonylphenyl)-5-aminobenztriazole with a melting point of 240° C, 135 g of this amine are dissolved in 375 ml of concentrated sulphuric acid and diazotised at 15° to 20° C with nitrosylsulphuric acid. The diazonium salt solution is discharged onto 2.5 kg of ice; the diazonium salt is filtered off and suspended in 800 ml of ice water. This suspension is added in small portions to a solution of 50 g of copper-I cyanide, 75 g of sodium cyanide, 500 ml of water and 250 ml of dimethylformamide. A brown product separates out, with vigorous evolution of gas, and this product can be purified by recrystallisation from o-dichlorobenzene and dimethylformamide; melting point 265° C, blue-fluorescent. The product has the formula ##STR16## and is subjected to alkaline saponification in aqueous glycol monomethyl ether. The product of the formula ##STR17## which melts at 146°-148° C is obtained by boiling in a large excess of thionyl chloride.
Reaction SMILES: Cl[CH2:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[NH3:12].CO>>[S:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:2][NH2:12]
Reactant: N
Reactant: ClCc1cc2ncccc2s1
Solvent: CO
Product: NCc1cc2ncccc2s1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
2-(Chloromethyl)thieno[3,2-b]pyridine (C-5) (183 mg, 1 mmol) was dissolved in NH3/methanol (7 N, 10 mL). The resulting mixture was stirred at 50° C. for 16 hours and concentrated. The residue was purified by chromatography. MS (m/z): 165 (M+1)+.
Reaction SMILES: N#N.[C:3]1([S:12]([NH:15][CH2:16][C:17]([NH2:19])=O)(=[O:14])=[O:13])[S:4][CH:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.[H-].[Na+].Cl[C:23]([O:25][CH3:26])=[O:24].[OH2:27]>CN(C)C=O>[C:3]1([S:12]([NH:15][C:16](=[O:27])[CH2:17][NH:19][C:23]([O:25][CH3:26])=[O:24])(=[O:14])=[O:13])[S:4][CH:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: COC(=O)Cl
Reactant: O
Reactant: NC(=O)CNS(=O)(=O)c1scc2ccccc12
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)NCC(=O)NS(=O)(=O)c1scc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product obtained in Step 1 (0.45 g) in N,N-dimethylformamide (5 ml) was added slowly 60% sodium hydride (75 mg) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. Methyl chloroformate (0.14 ml) was added to the above-mentioned mixture followed by stirring for 20 minutes at room temperature. 60% sodium hydride (75 mg) was added to the solution, and the mixture was stirred for 1.5 hours at room temperature, then 15 minutes at 70° C. After cooling to room temperature, water (20 ml) was added to the resultant mixture and this aqueous solution was extracted with ethyl acetate (20 ml×3). The organic layer was washed with water, then saturated aqueous NaCl solution. After drying over anhydrous magnesium sulfate, ethyl acetate was removed in vacuo and the residue was purified by silica-gel columun chromatography to give 0.18 g of the objective compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH2:25]1[CH:29]2[CH2:30][NH:31][CH2:32][CH:28]2[CH2:27][N:26]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C(O)CCCC>[NH2:24][C:20]1[CH:19]=[C:18]([C:8]2[N:6]3[N:7]=[C:2]([N:31]4[CH2:30][CH:29]5[CH2:25][N:26]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:27][CH:28]5[CH2:32]4)[CH:3]=[CH:4][C:5]3=[N:10][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Nc1cc(-c2c(-c3ccc(Cl)cc3)nc3ccc(Cl)nn23)ccn1
Solvent: CCCCCO
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc4nc(-c5ccc(Cl)cc5)c(-c5ccnc(N)c5)n4n3)CC2C1
Temperature: 135 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
A mixture of 0.15 g (0.42 mmol) of 4-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]pyrid-2-ylamine and 0.36 g (1.7 mmol) of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate in 7 mL of pentanol is stirred at 135° C. for 20 hours. The solvent is then evaporated off under reduced pressure and the oily residue is chromatographed on a column of silica gel, eluting with a stepwise gradient of methanol and aqueous ammonia in dichloromethane (0:0:100 to 2:1:98). 0.16 g of product is isolated after trituration in diisopropyl ether, filtering off and drying under reduced pressure.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH3:31]>CO.O1CCOCC1>[NH2:31][C:2]1[CH:7]=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4ccnc(F)c4)n4ccnc34)cc2)CC1
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccnc(N)c4)n4ccnc34)cc2)CC1
Temperature: 120 °C
Reaction time: 96 h
Yield: 16 %

Procedure:
A solution of [5-(2-fluoro-pyridin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.0272, 0.067 mmol) (from Example 125) in a mixture of aq. NH3 (2.5 mL):1M NH3 in MeOH (2.5 mL) is stirred at 100° C. overnight. Additional aq. NH3 (5 mL) and 0.5M NH3 in dioxane (2 mL) are added and the mixture stirred at 120° C. for 4 days. The mixture is concentrated in vacuo and purified by reverse phase HPLC affording the title compound (4.2 mg, 16%). LCMS: Rt 3.76 min (95%) m/z (APCI) 401 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.49-2.53 (4H, t), 3.12-3.15 (4H, m), 6.18 (2H, br s) 6.76 (1H, s), 6.81 (1H, d), 6.97 (2H, d), 7.51 (1H, s), 7.72 (1H, s), 7.88 (2H, d), 8.04 (1H, s), 8.09 (1H, d), 9.55 (1H, s).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]([NH:22][C:23]#[N:24])=[N:18][CH2:19][CH2:20][NH2:21])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>CO.CCOCC>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]([NH:22][C:23]#[N:24])=[N:18][CH2:19][CH2:20][NH:21][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[Cl:25])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N#CNC(=NCCN)NC1CCCC(c2csc(NC(=N)N)n2)C1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CCOCC
Product: N#CNC(=NCCNC(=O)c1ccccc1Cl)NC1CCCC(c2csc(NC(=N)N)n2)C1
Reaction time: 16 h

Procedure:
To a solution of 2-guanidino-4-{3-[3-cyano-2-(2-aminoethyl)guanidino]cyclohexyl}thiazole (0.5 g.) in methanol (30 ml.) was added o-chlorobenzoyl chloride (0.4 g.) and the mixture allowed to stand at room temperature for 16 hours. The residue obtained by evaporation of the solvent was partitioned between ethyl acetate (100 ml.) and water (20 ml.) The organic layer was isolated, washed with water (20 ml), dried (magnesium sulphate) and evaporated. The residue was subjected to preparative thin layer chromatography on Merck 60 F-254 plates using chloroform/methanol/aqueous ammonia (s.g. 0.88) 80:20:0.1 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform 50:50 v/v (200 ml.) and the residue obtained on evaporation of the solvents was dissolved in methanol. To this solution was added an excess of maleic acid in ether followed by a further amount of ether until precipitation began. The white powder precipitate (0.2 g.) was washed with ether to give 2-guanidino-4-{ 3-[3-cyano-2-(2-(2-chlorobenzoylamino)ethyl)guanidino]cyclohexyl}thiazole hydrogen maleate, m.p. 158°-165° (decomp.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([NH2:17])[N:3]=1.[C-:18]#[N:19].[K+]>CS(C)=O.CCOC(C)=O>[NH2:17][C:4]1[N:5]=[C:6]([N:8]([CH2:15][CH3:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([C:18]#[N:19])[N:3]=1
Reactant: CCN(c1ccccc1)c1nc(N)nc(Cl)n1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCN(c1ccccc1)c1nc(N)nc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-N-ethyl-N-phenyl-[1,3,5]triazine-2,4-diamine (Intermediate 37, 400 mg, 1.60 mmol) was dissolved in anhydrous DMSO (5 mL) before the addition of potassium cyanide (200 mg, 3.07 mmol). The reaction mixture was stirred at 120 C in a pressure tube for 2 h before allowing to cool to room temperature. The product mixture was diluted with EtOAc (20 mL), extracted with water (2×10 mL), saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The desired product was obtained and used directly without further purification (300 mg, 78%). Method C HPLC-MS: MH+ requires m/z=241. Found: m/z=241, Rt=1.27 min (89%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH:8]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][C:3]=1[C:21]#[N:22].ClC1C(C#N)=CC=C2C=1C1CC(NC(=O)C(C)C)CCC=1N2.[F:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49]Br>>[Cl:1][C:2]1[C:3]([C:21]#[N:22])=[CH:4][CH:5]=[C:13]2[C:14]=1[C:10]1[CH2:9][CH:8]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH2:7][CH2:6][C:11]=1[N:12]2[CH2:49][C:48]1[CH:51]=[CH:52][CH:53]=[C:46]([F:45])[CH:47]=1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3cc(Cl)c(C#N)cc3c2C1
Reactant: Fc1cccc(CBr)c1
Agent: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)c(Cl)c3c2C1
Product: CC(C)C(=O)NC1CCc2c(c3c(Cl)c(C#N)ccc3n2Cc2cccc(F)c2)C1
Yield: 5 %

Procedure:
Prepare the title compound by essentially following the procedure as described in Example 96 with N-(7-chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide and N-(5-chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (50:50 mixture—Preparation 17) and 3-fluorobenzyl bromide, to obtain a mixture of regioisomers. Separate the title compound from this mixture of regioisomers using silica gel chromatography (0-20% EtOAc/CHCl3), to afford the title compound in 5% yield. MS (ES): m/z 424 (M+1), 422 (M−1); HPLC (Method B): Rt=6.87 min, (97%).
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].C=O.O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:8][OH:9])[CH2:6][O:7][CH2:13][O:5][CH2:4]1)[CH3:2]
Reactant: CCC(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(CO)COCOC1
Reaction time: 3 h

Procedure:
In a one-liter three neck flask were placed 405 grams of 2-ethyl-2-hydroxymethyl-1,3-propanediol, 90 grams of paraformaldehyde, 0.9 grams of p-toluene sulfonic acid monohydrate and 150 ml of toluene. The flask was equipped with a Dean-stark trap and a condenser. The reaction mixture was stirred at a bath temperature of 120° C. to 170° C. for three hours. The toluene-water was collected, and after removing the toluene, the crude product was distilled under vacuum at 10-11 mm Hg and 115° C. to 117° C. 410 grams of 5-ethyl-5-hydroxymethyl-1,3-dioxane (EHMDO) were collected. The product was then dried by molecular sieve and had a water content of about 350 ppm. NMR spectra confirmed that EHMDO was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.O[CH2:52][C:53]([N:55]([CH3:57])[CH3:56])=[O:54]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:52][C:53](=[O:54])[N:55]([CH3:57])[CH3:56])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Reactant: CN(C)C(=O)CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCC(=O)N(C)C)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 3c from 100 mg (0.15 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 16 mg (0.16 mmol) 2-hydroxy-N,N-dimethyl-acetamide. After purification by HPLC the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][N:2]1[CH2:40][CH2:39][CH2:38][C@@:3]1([CH3:41])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:16]([O:32][CH3:33])[CH2:17][C:18](=[O:31])OC1C(F)=C(F)C(F)=C(F)C=1F)[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].C(N(C(C)C)CC)(C)C.Cl.[CH3:52][O:53][C@@H:54]([C@@H:60]1[CH2:64][CH2:63][CH2:62][NH:61]1)[C@@H:55]([CH3:59])[C:56]([OH:58])=[O:57]>ClCCl>[CH3:1][N:2]1[CH2:40][CH2:39][CH2:38][C@@:3]1([CH3:41])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:16]([O:32][CH3:33])[CH2:17][C:18]([N:61]1[CH2:62][CH2:63][CH2:64][C@H:60]1[C@H:54]([O:53][CH3:52])[C@H:55]([C:56]([OH:58])=[O:57])[CH3:59])=[O:31])[CH3:14])=[O:12])[CH:8]([CH3:9])[CH3:10])=[O:5]
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.2 %

Procedure:
To a cooled solution (0° C.) of #204 (8.0 g, 10.77 mmol, 1 eq.) in dichloromethane (25 mL) was added dropwise diisopropylethylamine (5.6 g, 43.08 mmol, 4 eq.) followed by a solution of #103 (3.22 g, 10.77 mmol, 1 eq.) in dichloromethane (15 mL). After the addition, the mixture was stirred at room temperature for 16 hours and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (Gradient: 1 to 10% methanol in dichloromethane) to give #205 (2.2 g, 33%) as a yellow solid HPLC (Protocol X): m/z 597.42 [M+H+], retention time=8.729 minutes (purity >97%), Chiral HPLC retention time: 2.87 min (purity=89%) Column: Chiralcel OD-3, 150×4.6 mm, 3 μm; Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% over 12 minutes; Flow rate: 2.5 mL/minute.
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:17]=[C:16]([CH2:18][CH3:19])[S:15][C:10]=2[NH:11][CH2:12][CH2:13][N:14]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][C:30]([Cl:32])=[O:31])[CH2:22][CH2:21]1>N1C=CC=CC=1>[ClH:1].[ClH:32].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[C:16]([CH2:18][CH3:19])[S:15][C:10]=2[N:11]([C:30](=[O:31])[NH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][O:20][CH2:25][CH2:24]2)[CH2:12][CH2:13][N:14]=1
Reactant: O=C(Cl)NCCCN1CCOCC1
Reactant: CCc1cc2c(s1)NCCN=C2c1ccccc1Cl
Solvent: c1ccncc1
Product: CCc1cc2c(s1)N(C(=O)NCCCN1CCOCC1)CCN=C2c1ccccc1Cl
Product: Cl
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 5.8 g of 5-o-chlorophenyl-7-ethyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine in 50 ml of pyridine is added 4.5 g of 3-morpholinopropylcarbamoyl chloride and stirred for 24 hours at 60° C. Then pyridine is evaporated under reduced pressure, and to the residue is added acetone to crystallize. The crude crystals obtained are recrystallized from ethanol to give 5-o-chlorophenyl-7-ethyl-1-(3-morpholinopropylcarbamoyl)-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine dihydrochloride as yellow crystals, melting at 225°-238° C with decomposition.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1(C)[CH:8]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:7]2[C:17](=[O:29])[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:6]2[S:5]1.[N-:31]=[N+:32]=[N-:33].[Na+].CC(C)=O>O>[N:31]([C:3]1([CH3:2])[CH:8]([C:9]([O:11][CH2:12][C:13]([Cl:15])([Cl:14])[Cl:16])=[O:10])[N:7]2[C:17](=[O:29])[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:6]2[S:5][CH2:4]1)=[N+:32]=[N-:33]
Reactant: CC1(CCBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(N=[N+]=[N-])CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.4 %

Procedure:
A mixture of 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08 g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for 4 hours at room temperature. After acetone was distilled off under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, with saturated sodium bicarbonate aqueous solution and further with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and a small quantity of ether was added to the residue to give colorless crystals of 2,2,2,-trichloroethyl 3-azido-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (170 mg). This substance was recrystallized from carbon tetrachloride to give crystals melting at 136° to 140° C.