Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[CH:14]([N:17]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)([CH3:16])[CH3:15].Cl>N1C(C)=CC(C)=CC=1C>[CH:27]1([N:17]([CH:14]([CH3:16])[CH3:15])[C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([NH:6][C:5]3[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:21][CH:20]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(Nc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyaniline (733 mg, 4.0 mmol) and p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.290 g, 3.98 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SC4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of methanol, methylene chloride and ammonium hydroxide as the eluents to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:8][Cl:9])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:13])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][CH2:2][C:3]([CH2:8][Cl:9])([CH3:7])[C:4]([Cl:13])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(CCl)(CCl)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(CCl)(CCl)C(=O)Cl
Temperature: 0 °C

Procedure:
DMF (1 drop) was added to a solution of 2,2-bis(chloromethyl)propanoic acid (1.4 g) in DCM (1.5 ml), the solution was cooled to 0° C. and oxalyl chloride (0.75 ml) added. After gas evolution had stopped the mixture was concentrated in vacuo to give the sub-title compound as a yellow oil (1.51 g) which was used directly in the next step.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([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:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:76][CH:77]1[C:108](=[O:109])[N:79]2[C:80]([C:92]([O:94][CH:95]([C:102]3[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=3)[C:96]3[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=3)=[O:93])=[C:81](/[CH:84]=[CH:85]\[C:86]3[S:90][N:89]=[N:88][C:87]=3[CH3:91])[CH2:82][S:83][C@H:78]12>C1COCC1.C(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)/[C:27]([NH:76][CH:77]2[C:108](=[O:109])[N:79]3[C:80]([C:92]([O:94][CH:95]([C:102]4[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=4)[C:96]4[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=4)=[O:93])=[C:81](/[CH:84]=[CH:85]\[C:86]4[S:90][N:89]=[N:88][C:87]=4[CH3:91])[CH2:82][S:83][C@H:78]23)=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1nnsc1/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nnsc1/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (1.58 g, 2.35 mmol) was dissolved in a mixed solvent of THF-methylene chloride (20 ml-10 ml) and cooled to 5° C. HOBT (0.32 g, 2.4 mmol) was added to this reaction solution, then DCC (0.50 g, 2.4 mmol) was added and the mixture was stirred at the same temperature for 2 hours. The reaction solution was filtered, then benzhydryl 7-amino-3-[(Z)-2-(4-methyl-1,2,3-thiadiazol-5-yl)vinyl]-3-cephem-4-carboxylate (0.98 g, 2.0 mmol) was added to the filtrate and it was stirred at 5° C. for 22 hours. The reaction solution was concentrated and then the concentrate was purified by column chromatography thereby benzhydryl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,2,3-thiadiazol-5-yl)vinyl]-3-cephem-4-carboxylate (1.38 g, 60.5% yield) was obtained as a yellow powdered compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].C([Mg]Cl)(C)C.[Cl-].[Li+].[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21]>O1CCCC1>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([C:20](=[O:21])[C:19]([F:26])([F:25])[F:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1c(Cl)cc(Cl)cc1I
Reactant: CCOC(=O)C(F)(F)F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cc(Cl)cc(Cl)c1O)C(F)(F)F
Temperature: -35 °C
Reaction time: 0.75 h
Yield: 67.1 %

Procedure:
2,4-Dichloro-6-iodophenol (2.0 grams (g), 6.9 millimoles (mmol)) was dissolved in dry tetrahydrofuran (THF; 20 milliliters (mL)), cooled to −30 to −40° C., treated in portions with isopropyl magnesium chloride-lithium chloride complex (1.3 M in THF; 7.3 mmol) and stirred for 45 minutes (min) as the temperature was allowed to rise to 0° C. The mixture was cooled to −30° C., treated with 8 mL (10 mmol) of the Grignard reagent and stirred for 30 min at −30° C. Ethyl trifluoroacetate (2.4 mL, 2.8 g, 20 mmol) was added, and the mixture was stirred for 15 min at −30° C., warmed to 25° C. and stirred for 2 hours (h). The reaction was quenched by addition of saturated (satd) ammonium chloride (NH4C1; 10 mL), diluted with ethyl acetate (EtOAc; 50 mL) and washed with 1 M hydrochloric acid (HCl; 20 mL), satd sodium chloride (NaCl; 10 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc/hexane to give the purified ketone (1.2 g): mp 50-52° C.; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=2.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 5.92 (s, 1H); EIMS m/z 258.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH:12](O)=[O:13]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:12]=[O:13])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=CO
Product: O=CNc1ccc(C(F)(F)F)cc1

Procedure:
Was prepared according to Example 2 from 4-(trifluoromethyl)aniline and formic acid.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:49][C:50]([F:56])([F:55])[S:51](Cl)(=[O:53])=[O:52]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:51]([C:50]([F:56])([F:55])[F:49])(=[O:53])=[O:52])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)C(F)(F)F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 49 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added trifluoromethylsulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 49% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]=[CH:5]2.CS(C)=O.[C-:15]#[N:16].[Na+]>CC(OC)(C)C>[C:15]([CH2:2][CH2:3][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]=[CH:5]2)#[N:16]
Reactant: [C-]#N
Reactant: ClCCC12C=CC(CC1)C2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: N#CCCC12C=CC(CC1)C2
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A 1 L, 4 neck RBF was equipped with a thermowell, condenser with a nitrogen inlet, stopper and mechanical stirrer. The RBF was charged with chloroethylnorbornene (100 g, 0.64 mol), 300 mL DMSO and solid NaCN (43.8 g, 0.89 mol). An extra 20 mL DMSO was added to rinse in the NaCN. The reaction mixture was stirred at ˜80° C. for 2 hours. GC analysis of an aliquot indicated all starting material had been consumed and the reaction was completed. The reaction mixture was cooled to room temperature. Approximately 200 mL water was poured into the flask and diluted with 100 mL MTBE. The organic phase was separated and the aqueous layer was re-extracted with (3×200 mL) MTBE. The organic phases were combined and washed with (3×500 mL) tap water until the aqueous wash reached pH=6. The MTBE solution was dried over anhydrous sodium sulfate overnight, filtered, and rotary evaporated to give 93.5 g (99.5% yield) with 99.3% purity by GC. NMR analysis indicated the material contained ˜1% MTBE. The crude product was used for the next reaction without further purification. Data: GC analysis done on a DB5 Column, 30 meters, 0.32 mm ID, 0.25 μm film, 75° C. to 300° C. at 25° C./min., hold for 2 min at 300° C., Injector temperature: 275° C., Detector temperature: 350° C.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].C[O-].[Na+].C[O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18]C(CBr)=[CH:16][CH:15]=1.Cl>CC(O)=O>[O:3]=[C:1]([CH3:2])[CH2:4][CH2:5][C:6]1[CH:18]=[CH:19][C:14]([C:13]([OH:22])=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(=O)CC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of acetyl acetone (5.0 ml, 49 mmol) at room temperature NaOMe (25% wt, 10.8 ml, 47.3 mmol) was added followed by 4-bromomethyl-benzoic acid methyl ester 2 (9.0 g, 39.3 mmol). The reaction mixture refluxed 3 hours, cooled to the room temperature and acidified with HCl (pH 1-2). Evaporation of the resultant solution yielded a residue, which was refluxed in a mixture of glacial AcOH (50 ml) and conc. HCl (25 ml) for 4 hours. Acids were removed in vacuum and the residue was triturated with water to form a crystalline material, which was collected by filtration and dried to afford 278 (6.72 g, 80% yield). [M−1] 191.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[C:30]([F:36])[C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[C:34]2[C:29]=1[CH2:28][CH2:27][N:26]2[C:24]([C:22]1[CH:23]=[CH:18][N:19]=[C:20]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:21]=1)=[O:25]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2c1ccc(F)c2F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccnc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c1)N1CCc2c1ccc(F)c2F

Procedure:
0.59 g (2.7 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.80 g (2.7 mmol) (2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone and 0.39 g (2.8 mmol) potassium carbonate were stirred in 3 mL of NMP for 4 h at 130° C. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:32]=[CH:31][C:25]([CH:26]=[CH:27][C:28](O)=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:32]=[CH:31][C:25]([CH:26]=[CH:27][C:28]([N:4]3[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N+:2]([O-:1])=[N:3]3)=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCc1ccc(-c2ccc(C=CC(=O)O)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ccc(C=CC(=O)n3n[n+]([O-])c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.9 %

Procedure:
To a suspension of 1-hydroxybenzotriazole (0.20 g) and 4-(4-pentylphenyl)cinnamic acid (0.40 g) in dichloromethane (12.0 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.33 g) (WSCD.HCl), and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was diluted with dichloromethane, and washed with brine, and dried over magnesium sulfate. After magnesium sulfate was filtered off, evaporation of the filtrate and trituration with acetonitrile gave 1-[4-(4-Pentylphenyl)cinnamoyl]benzotriazole 3-oxide (0.24 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][C:6](=[O:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.N1C(C)=CC=CC=1C.N#N.FC(F)(F)S(O[Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])(=O)=O>C(Cl)Cl>[O:29]=[C:6]1[CH:5]=[C:4]2[C@:24]([CH3:27])([CH2:25][CH2:26][C@H:2]([O:1][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])[CH2:3]2)[C@@H:23]2[C@@H:7]1[C@H:8]1[C@:20]([CH3:28])([CH2:21][CH2:22]2)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#N
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of methyl 3β-hydroxy-7-oxochol-5-en-24-oate (2) (5.02 g, 12.5 mmoles) and 2,6-lutidine (3.32 ml, 28.5 mmoles) in CH2Cl2 (23 ml) cooled in an ice bath in a N2 atmosphere was added dropwise with magnetic stirring triisopropylsilyl trifluoromethanesulfonate (4.56 g, 17 mmoles). After 2 hrs, the reaction was diluted with CH2Cl2 (150 ml). It was then washed with cold 2N HCI, washed twice with H2O and then with saturated brine before drying with MgSO4. Evaporation in vacuo and purification of the residue by flash chromatography on silica gel with hexane-EtOAc (10:1) gave 5.88 g of 3 as a colorless syrup. NMR (CDCl3): δ 0.67 (s, 3H, 18-Me); 0.93 (d, 3H, 20-Me); 1.06 (s, 18H, TIPS Me); 1.19 (s, 3H, 19-Me); 3.66 (s, 3H, CO2Me); 3.68 (m, 1H, 3-H); 5.66 (s, 1H, 6-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[CH2:27][O:26][CH3:25])=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: COC[C@@H]1CCCN1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC[C@@H]1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, (S)-2-methoxymethylpyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.56 minutes; C22H22Cl2N4O3 (461.35); mass spectrum: (M+H)+=461.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]C1)[CH:5]=O.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:12][CH:13]([CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:14][CH2:15]1
Reactant: C1CCNC1
Reactant: Cc1cc(C=O)ccc1N1CCC(CN2CCCC2)CC1
Product: Cc1cc(CN2CCCC2)ccc1N1CCC(CN2CCCC2)C1

Procedure:
Prepared from the product of Example 66 and pyrrolidine.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[C:9]([F:16])[CH:8]=1.[S-:19][C:20]#[N:21].[K+].Cl>C(O)C.O>[F:16][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([F:13])[C:10]=1[O:14][CH3:15])[CH2:6][N:5]1[CH:4]=[CH:3][N:21]=[C:20]1[SH:19]
Reactant: N#C[S-]
Reactant: COc1c(F)cc(CNCC(OC)OC)cc1F
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1c(F)cc(Cn2ccnc2S)cc1F
Yield: 45.8 %

Procedure:
To a solution of N-(3,5-difluoro-4-methoxybenzyl)-aminoacetaldehyde dimethyl acetal (4.94 g, 0.0189 mole) in ethyl alcohol (30 ml) was added potassium thiocyanate (2.10 g, 0.0216 mole) in water (48 ml) followed by 12 N hydrochloric acid (4 ml), and the reaction mixture was heated under reflux for 3.5 hours. The solvent was partially removed under reduced pressure, the mixture was cooled in ice, and the product was filtered. The product was recrystallized from ethyl alcohol - hexane to give 1-(3,5-difluoro-4-methoxybenzyl)-2-mercaptoimidazole as a solid melting at 160-161° (2.22 g, 46%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19](N(C)C)=[O:20].O=P(Cl)(Cl)Cl>>[C:19]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[NH:14][CH:13]=1)(=[O:20])[CH3:18]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
In a manner similar to that described in Reference example 1, 5-benzyloxyindole was reacted with DMA/POCl3 to give 3-acetyl-5-benzyloxyindole.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:29]([NH2:32])[CH:30]=[CH2:31]>C1COCC1>[N+:1]([C:4]1[N:5]([CH2:9][C:10]([NH:32][CH2:29][CH:30]=[CH2:31])=[O:12])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: C=CCN
Reactant: O=C(O)Cn1ccnc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=CCNC(=O)Cn1ccnc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
2-(2-nitro-1H-imidazol-1-yl)acetic acid (1.71 g, 10 mmol) was added to N-methylmorpholine (1.01 g, 10 mmol) in 150 ml of dry THF under nitrogen at 0° C. and stirred for 10 minutes until completely dissolved. Isobutyl chloroformate (1.43 mL 11 mmol) added. After 30 minutes, allylamine hydrochloride (1.03 g, 11 mmol) and N-methylmorpholine (1.21 g, 12 mmol) added to the solution and the mixture stirred at room temperature overnight. The solution was then filtered and the organic solvent was evaporated to give a pale yellow solid. Purification by chromatography (silica gel, CH3OH/CHCl3=10:1) gave a white solid (1 g, 48%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:17][C:18](=[O:37])[C@@H:19]([CH:24]([C:34](O)=[O:35])[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]([O:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:17][C:18](=[O:37])[C@@H:19]([CH:24]([C:34](=[O:35])[NH:50][O:49][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)NOCc1ccccc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of 1.15 g of 2′-(N-benzyloxycarbonyl-D-alanyl)-2(R)-[1(RS)-(carboxy)-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of dimethylformamide was cooled to 0° C. under a nitrogen atmosphere. The mixture was then treated with 1.25 g of O-benzylhydroxylamine and 0.467 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and left to warm to room temperature overnight. The mixture was diluted with water and extracted twice with ethyl acetate. The ethyl acetate layer was then washed with aqueous 2M hydrogen chloride, water and brine. Drying over anhydrous magnesium sulphate and evaporation of the solvent gave 0.820 g of 2′-(N-benzyloxycarbonyl-D-alanyl)-2(R)-[1(RS)-[(benzyloxy)carbamoyl)-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25](Br)([CH3:27])[CH3:26])=[O:24])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:25]([C:23]([C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=2)=[O:24])([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(Br)C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 87 g of 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C., in the course of approx. 2 hours. 28.7 g (0.53 mol) of sodium methylate are introduced at the same temperature, and the mixture is stirred for a further 12 hours and then concentrated. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 49 g (76% of theory) of crude 2-(4 chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane are obtained, and this compound is directly reacted further. ##STR158## 52 g (0.3982 mol) of p-chlorophenol and 55 g (0.3982 mol) of potassium carbonate in 400 ml of toluene are heated under reflux for 2 hours in a water separator. The mixture is cooled to 40° C., and a solution of 2-bromo-prop-2-yl 4-chlorophenyl ketone in 170 ml of toluene is added dropwise. This reaction mixture is stirred for a further 5 hours at 100° C. and then cooled, water is added and the organic phase is separated off. This is washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and concentrated. 87 g (85% of theory) of crude 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone are obtained, and this compound is directly reacted further. ##STR159## 1 ml of hydrogen bromide/glacial acetic acid is added to 65.5 g (0.36 mol) of 4-chlorophenyl isopropyl ketone in 200 ml of chloroform, and 57.5 g (0.36 mol) of bromine are then added dropwise at 30° C. The mixture is stirred for a further 30 minutes at room temperature, and thereafter concentrated in vacuo. 86.6 g (92% of theory) of crude 2-bromo-prop-2-yl 4-chlorophenyl ketone are obtained, and this compound is directly reacted further.