Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10].[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2>CN(C)C=O.C(Cl)(Cl)Cl>[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19]([O:10][C:9](=[O:11])[C:8](=[O:7])[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH2:18]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(=O)c1ccco1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution of oxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide (one drop) in 150 ml of chloroform (etanol free) at 01 C. The mixture was stirred and allowed to warm at room temperature. After five hours the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHCl3 (150 ml) and a solution of 3(R)-quinuclidinol (10.90 g, 0.086 mol) in CHCl3 (150 ml) was added to this at 01 C. The mixture was stirred and allowed to warm at room temperature. After 15 h at r.t., the mixture was washed with 10% aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 9.34 g (52.5%) of the title compound as a dark oil. Structure confirmed by NMR.
Reaction SMILES: [OH-].[K+].[N+:3]([CH2:5][C:6]([NH2:8])=[O:7])#[C-:4].[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CO>[F:9][C:10]([F:19])([F:20])[C:11]1[CH:12]=[CH:13][C:14]([C@H:15]2[O:16][CH:4]=[N:3][CH:5]2[C:6]([NH2:8])=[O:7])=[CH:17][CH:18]=1
Reactant: [C-]#[N+]CC(N)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)C1N=CO[C@@H]1c1ccc(C(F)(F)F)cc1
Temperature: 12.5 °C
Reaction time: 2 h

Procedure:
To a cooled (˜10° C.) solution of KOH (13.2 g, 235 mmol) in MeOH (50 mL) was added the solution of 2-isocyanoacetamide (LXXIV) in MeOH (60 mL) dropwise while maintaining the temperature at 10-15° C. A solution of 4-(trifluoromethyl)benzaldehyde (40.9 g, 235 mmol) in MeOH (50 mL) was then added and the reaction was stirred for an additional 2 h. The reaction mixture was cooled to −20° C. causing a white solid to precipitate. The solid was filtered and dried to give crude (5R)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole-4-carboxamide (LXXV) (62 g). The crude product was used for the next step without purification.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]1[CH2:15][S:14][C:13]2[C:16]([NH2:20])=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:21])(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[NH2:8][C@H:9]1[CH2:15][S:14][C:13]2[C:16]([NH2:20])=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSc2c(N)cccc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc2c1SC[C@H](N)C(=O)N2
Temperature: 25 °C
Yield: 99 %

Procedure:
Hydrogen chloride gas was bubbled for 1 min. into a solution of ((R)-9-amino-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepin-3-yl)-carb amic acid tert-butyl ester (560 mg, 1.8 mmol) in dioxane (15 mL) at 0° C. and the reaction was warmed to RT. After 1 h the mixture was concentrated and the residue was triturated with Et2O. The resulting solid was filtered, washed with hexanes and dried to give (R)-3,9-diamino-2,3-dihydro-5H-benzo[b][1,4]thiazepin-4-one dihydrochloride (500 mg. 99%).
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:25])[NH:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][C:28]=2[O:36][CH3:37])=[CH:7]1)=[O:5])[CH3:2].ClCCCl.[C:44]1([CH3:54])[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([NH2:53])(=[O:52])=[O:51]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:25])[NH:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:53][S:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH3:54])(=[O:51])=[O:52])=[O:33])=[CH:29][C:28]=2[O:36][CH3:37])=[CH:7]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)n1cc(Cc2ccc(C(=O)O)cc2OC)c2cc(C(=O)NCC(C)CC(F)(F)F)ccc21
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CC)C(=O)n1cc(Cc2ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc2OC)c2cc(C(=O)NCC(C)CC(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
To a solution of 4-[1-diethylcarbamoyl-5-(4,4,4-trifluoro-2-methylbutylcarbamoyl)-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (0.12 grams, 0.22 mmol), 4-dimethylaminopyridine (0.040 grams, 0.33 mmol) and 1,2-dichloroethane (0.063 grams, 0.33 mmol) in methylene chloride (15 mL) was added o-tolylsulfonamide (0.038 grams, 0.22 mmol). The resulting solution was stirred, at room temperature, for 12 hours. The reaction mixture was then diluted with methylene chloride and washed with 1 M hydrochloric acid (aq). The organics were dried over magnesium sulfate and concentrated in vacuo. Recrystallization from wet ether gave the titled compound (0.115 grams, 75% yield), m.p.=153-154° C. Anal calcd. for C35H39H4O6SF3 : C, 59.92; H, 5.60; N, 7.99. Found: C, 60.18; H, 5.68; N, 8.41.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:14][NH2:15].O>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:15][CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a chilled (0° C.) stirred solution of 4-(bromomethyl)-benzenesulfonylchloride (3.0 g, 11 mmol) in DCM (100 mL) was added methylamine hydrochloride (1.2 g, 12 mmol). After 30 minutes, water (100 mL) was added. The organic layer was separated, washed with brine (30 mL), and dried over sodium sulfate and concentrated in vauco to afford 4-bromomethyl-N-methyl-benzenesulfonamide.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[CH3:14][NH:15][C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19]>>[CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:16]([NH:15][CH3:14])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:6][CH:5]=1
Reactant: CNCc1ccc(CSCCN)o1
Reactant: CNC(=C[N+](=O)[O-])SC
Product: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])NC)o1

Procedure:
A mixture of 2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethanamine (0.9 g) and N-methyl-1-methylthio-2-nitro-etheneamine was heated at 100°-120° for 30 mins under water pump pressure. The residue was purified by column chromatography (silica/methanol:0.88 ammonia) to give N-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine which was crystallised from acetonitrile m.p. 106°-108° (0.65 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[N:21]=[C:20]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:19]=1.C(=O)(O)[O-].[Na+].O>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[N:21]=[C:20]([C:34]2[CH:35]=[CH:36][C:37]([NH:38][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:39][CH:40]=2)[N:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccncc2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccncc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
Phenyl chloroformate (0.029 mL, 0.23 mmol) was added to a solution of 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(pyridin-4-ylsulfonylmethyl)pyrimidin-2-yl]aniline (0.097 g, 0.23 mmol) and sodium bicarbonate (0.029 g, 0.34 mmol) in dioxane at RT. The resulting slurry was stirred at RT for 2 hours. Additional phenyl chloroformate (2×0.005 mL) was added to drive the reaction to completion. Water was then added to the reaction and the solid filtered, and dried in a vacuum oven to give the desired material as an off-white solid (0.098 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f61) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][NH:16][C:12]=2[N:13]=[CH:14][N:15]=1.O>CN(C=O)C>[Cl:9][C:10]1[C:11]2[C:18]([I:1])=[CH:17][NH:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncnc2[nH]ccc12
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2[nH]cc(I)c12
Reaction time: 1 h
Yield: 99.2 %

Procedure:
N-Iodosuccinimide (11.6 g) was added to a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (7.52 g) in DMF (49 ml) at room temperature. The mixture was stirred at the same temperature for 1 hour, and water (150 ml) was added to the reaction mixture. The resulting precipitate was collected by filtration, washed with water, and dried to obtain the title compound as a light-yellow solid (13.57 g).
Reaction SMILES: C[C@@H:2]1CCC[CH2:4][NH:3]1.[C:8]([C:12]1[CH:13]=[C:14]([NH:27][C:28]([NH:30][C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:34]([O:41][C:42]3[CH:43]=[CH:44][C:45]4[N:46]([C:48]([N:51]5[CH2:56][CH2:55][CH2:54][CH2:53][C@@H:52]5[CH3:57])=[N:49][N:50]=4)[CH:47]=3)[CH2:33][CH2:32]2)=[O:29])[N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25]O)[CH:18]=2)[N:16]=1)([CH3:11])([CH3:10])[CH3:9]>>[C:8]([C:12]1[CH:13]=[C:14]([NH:27][C:28]([NH:30][C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:34]([O:41][C:42]3[CH:43]=[CH:44][C:45]4[N:46]([C:48]([N:51]5[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]5[CH3:57])=[N:49][N:50]=4)[CH:47]=3)[CH2:33][CH2:32]2)=[O:29])[N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][N:3]([CH3:4])[CH3:2])[CH:18]=2)[N:16]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Reactant: C[C@@H]1CCCCN1
Product: C[C@@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared from (R)-2-methyl piperidine using analogous procedures to those described for the preparation of Intermediate 95e. LCMS (Method 3): Rt 3.63 min, m/z 679 [MH+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][S:2]([O:12][CH2:11][CH:8]1[CH2:9][CH2:10][O:6][CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCOC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOC1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Methanesulfonyl chloride (18 mmol, 1.39 mL) was added to a flask containing (±)-tetrahydro-3-furanmethanol (1.53 g, 15.0 mmol) in tetrahydrofuran (25 mL) and triethylamine (3.13 mL, 22.5 mmol) at 0° C. under a nitrogen atmosphere. The cooling bath was removed and the reaction mixture was stirred overnight. A saturated solution of NaHCO3 (15 mL) was added to the reaction mixture followed by extraction with diethyl ether (3×15 mL). The combined organic extracts were dried over anhydrous magnesium sulfate. Filtration followed by concentration on a rotary evaporator yielded the product as a pale yellow solid (2.13 g) which was used in the next step without further purification.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[C:13]([NH2:32])=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH3:21])[N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][Cl:30])=[CH:24][CH:23]=3)[C:16]=2[CH:31]=1>C1COCC1>[Cl:11][C:12]1[C:13]([NH:32][CH:5]=[O:7])=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH3:21])[N:17]([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][Cl:30])=[CH:26][CH:27]=3)[C:16]=2[CH:31]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCc1nc2cc(N)c(Cl)cc2n1-c1ccc(CCCl)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: CCc1nc2cc(NC=O)c(Cl)cc2n1-c1ccc(CCCl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of acetic anhydride (0.14 ml) in THF (5 ml) was added formic acid (0.06 ml, 1.65 mmol) at 0° C. under nitrogen and the mixture was stirred at 60° C. for 2 h. Then the mixture was recooled to 0° C. and was added 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine(Example 110, step 6, 100 mg, 0.3 mmol) in THF (2 ml). The mixture was stirred at room temperature for 2 h. The volatile component was removed under reduced pressure, and the residue was dissolved with ethyl acetate (100 ml). The organic layer was washed with 2N aqueous NaOH (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1:10) to afford 68 mg (67%) of the title compound as pale yellow solids.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]#[CH:27]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:27]#[C:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2Cl)cc1[N+](=O)[O-]
Yield: 96.6 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (1.82 g, 5.0 mmol) and 2-chlorophenylacetylene (1.02 g, 7.5 mmol) according to the general procedure F. Obtained as a yellow solid (1.8 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C-:32]#[N:33].O>CS(C)=O>[C:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:33]
Reactant: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: [C-]#N
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
1-(7-Bromoheptyl)-2,4,5-triphenylimidazole (7 g) in dry dimethylsulphoxide (15m1) was added over 20 minutes to a mixture of sodinto cyanide (0.87 g) in dimethyl-sulphoxide (25 ml ). The reaction was stirred at 40° C. for 1 hour. The cooled reaction mixture was poured into water (800 ml) and extracted with diethyl ether (4×100 ml). The extracts were combined, washed with water, dried over anhydrous magnesinm sulphate and evaporated to dryness in vacuo. Recrystallisation from dichloro-methane/hexane gave 1-(7-cyanoheptyl)-2,4,5-triphenylimidazole (3.7 g,60%) as a white solid, m.p. 93°-94°; Found: C, 82.35; H, 6.90; N, 9.96%; C29H29N3 1% CH2Cl2 requires C, 82.43; H, 6.91; N, 9.91%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[C@H:13]([NH2:14])[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:26]1[N:27]=[N:28][C:29]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:30]([NH:32][C:33]2[C:41]3[CH:40]=[CH:39][S:38][C:37]=3[CH:36]=[CH:35][CH:34]=2)[N:31]=1>C1COCC1>[S:38]1[CH:39]=[CH:40][C:41]2[C:33]([NH:32][C:30]3[N:31]=[C:26]([NH:14][C@@H:13]4[CH2:12][CH2:11][O:10][CH2:9][C@@H:8]4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[N:27]=[N:28][C:29]=3[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:34][CH:35]=[CH:36][C:37]1=2
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: CCOC(=O)c1nnc(Cl)nc1Nc1cccc2sccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(N[C@@H]2CCOC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc2sccc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate (26 mg) and diisopropylethylamine (0.050 ml) were added to a solution of ethyl 3-chloro-5-(benzo[b]thiophen-4-ylamino)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 1 (34 mg) in THF (1 mL), and the reaction solution was stirred at 80° C. for 30 minutes. The solvent was evaporated under vacuum, and the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain ethyl 5-(benzo[b]thiophen-4-ylamino)-3-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-1,2,4-triazine-6-carboxylate.
Reaction SMILES: [OH-].[Na+].[C:3]([S:6][CH2:7][C:8]1[NH:9][C:10](=[O:13])[S:11][CH:12]=1)(=O)N.ClC[C:16]([NH2:18])=[O:17]>O>[C:16]([CH2:3][S:6][CH2:7][C:8]1[NH:9][C:10](=[O:13])[S:11][CH:12]=1)(=[O:17])[NH2:18]
Reactant: NC(=O)SCc1csc(=O)[nH]1
Reactant: NC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)CSCc1csc(=O)[nH]1
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
9.0 ml of 10N (40%) sodium hydroxide solution are added dropwise to a suspension containing 5.7 g (0.03 mol) of 4-carbamoylmercaptomethyl-2(3H)-thiazolone [compound of the formula (Ib)] in 27 ml of water and 18 ml of ethanol at 25° to 30° C. while bubbling an inert gas through the mixture. After 15 minutes, 3.0 g (0.032 mol) of chloroacetamide are added to the reaction mixture which is then stirred for 16 hours. After filtering off the insoluble material, the filtrate is acidified by adding 5 ml of glacial acetic acid. The crystalline product is filtered, washed with isopropanol and dried to obtain 4.04 g (66.0%) of the named compound, m.p.: 151°-153° C. The active ingredient content of the substance is 99.4% based on titration with alkaline metal hydroxide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[O:26])=[C:15](/[CH:18]=[CH:19]\[C:20]4[N:21]=[N:22][S:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:36][CH2:37][CH2:38]Br)(=[O:35])[CH3:34]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH:37]([O:36][C:33](=[O:35])[CH3:34])[CH3:38])=[O:26])=[C:15](/[CH:18]=[CH:19]\[C:20]4[N:21]=[N:22][S:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(/C=C\c4csnn4)CS[C@H]23)cs1
Reactant: CC(=O)OCCBr
Agent: [Na+]
Product: CC(=O)OC(C)OC(=O)C1=C(/C=C\c2csnn2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 23.1 %

Procedure:
In like manner as in Example 20 sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (0.5 g) was reacted with DL-2-bromoethyl acetate (0.23 g) thereby DL-1-acetyloxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (0.13 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: BrCc1cccs1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3cccs3)c3ccccc23)CC1
Reaction time: 15 h

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 4 g (15 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 30 mL of a freshly prepared 2-bromomethyl-thiophene 0.61M solution in anhydrous ethyl ether. After standard work-up, 5.6 g (100% of yield) of the expected product was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Cl[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[N:21][CH:22]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc(CCl)cn1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c3c(c4ccccc42)CN(C)CC3)cn1
Yield: 10.3 %

Procedure:
A solution of 2, 3,4,5-Tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (186 mg, 1 mmol), 5-(chloromethyl)-2-methylpyridine (324 mg, 2.3 mmol) and 60% NaH (120 mg, 3 mmol) in DMF (3 ml) were heated at 120° C. for 16 h to obtain 30 mg of 2, 3,4,5-tetrahydro-2-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indole after purification by silica gel chromatography (230-400 mesh) using methanol-dichloromethane gradient.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4].C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:46](Cl)(=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48]>O>[CH3:48][C:47]([CH3:50])([CH3:49])[C:46]([NH:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4])=[O:51]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C)ccc1OC
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)C(C)(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The stirred solution of 0.025 g of tert-butyl {1(S)-(2-amino-1(S)-hydroxyethyl)-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}carbamate (Example 36b) and 0.230 ml of ethyl acetate is admixed at 0° C. successively with 0.230 ml of 2M sodium carbonate solution and 0.007 ml of pivaloyl chloride, and stirred at room temperature over another 4 hours. The reaction solution is admixed with water and extracted with ethyl acetate (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.61 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.05 (gradient I).