Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([CH3:37])[C:22](=[O:36])[CH2:23][NH:24][C:25](=[O:35])[CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:19][CH:18]=[C:17]([Cl:38])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.C(OC([N:46]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:47](=[NH:51])SOC)=O)(C)(C)C>C(O)C.[Hg]=O>[Cl:1][C:2]1[C:20]([N:21]([C:22](=[O:36])[CH2:23][NH:24][C:25](=[O:35])[CH:26]=[CH:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:47]([NH:46][C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])=[N:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[CH:32][CH:33]=2)[CH3:37])=[CH:19][CH:18]=[C:17]([Cl:38])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: COSC(=N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)cc4)c3Cl)c2n1
Agent: O=[Hg]
Solvent: CCO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc4)c3Cl)c2n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 165.8 %

Procedure:
to asolution of 8-[2,6-dichloro-3-[N-methyl-N-(4-aminocinnamoylglycyl)amino]benzyloxy]-2-methylquinoline (50 mg) in ethanol (2 ml) were added N,N-bis(tert-butoxycarbonyl)-S-methoxyisothiourea (28 mg) and mercury (II) oxide (21 mg) at ambient temperature and stirred for 1 hours at 40° C. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (8% solution of methanol in chloroform) to give 8-[2,6-dichloro-3-[N-[4-[2,3-bis(tert-butoxycarbonyl)guanidino]-cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline (60 mg) as an amorphous powder.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.CN(C)CCN(C)C.[F:22][C:23]([F:43])([F:42])[C:24]1[CH:41]=[CH:40][C:27]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[O:29])=[CH:26][CH:25]=1>O.O1CCCC1>[CH3:6][O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:28]([C:27]1[CH:40]=[CH:41][C:24]([C:23]([F:22])([F:42])[F:43])=[CH:25][CH:26]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=1)[OH:29]
Reactant: COCn1ccnc1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCn1ccnc1C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
9.1 Ml. (0.015 mol) of n-butyl lithium solution (15% in n-hexane) were added dropwise with stirring at -60° C. and under a nitrogen atmosphere to a solution of 1.7 g (0.015 mol) of 1-(methoxymethyl)imidazole and 1.8 g (0.015 mol) of N,N,N',N'-tetramethylethylenediamine in 75 ml. of anhydrous tetrahydrofuran. Stirring was continued for 1.5 hours and then 2.9 g (0.0091 mol) of 4,4'-bis(trifluoromethyl)benzophenone in 50 ml. of anhydrous tetrahydrofuran were added dropwise under the same conditions, which made the colour change from light red into very dark brown. The reaction mixture was kept standing overnight at room temperature and it was then decomposed by addition of 40 ml. of water. The mixture was extracted with diethyl ether and the extract was concentrated. The residue was extracted with a mixture of 2 N hydrochloric acid and diethyl ether. The ethereal phase was dried over sodium sulphate and the ether was distilled off. The residue was boiled a few times with petroleum ether (boiling range 40°-60° C.) to remove ketone starting material and it was then once crystallised from a mixture of toluene and petroleum ether (boiling range 28°-40° C.) twice from petroleum ether (boiling range 100°-140° C.). 1-(Methoxymethyl)-α,α-bis(p-trifluoromethylphenyl)imidazole-2-methanol was obtained. Melting point 160°-161° C.
Reaction SMILES: BrC1C=C2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].[NH:57]1CCOCC1.N1CCC1>>[N:7]1([S:53]([C:33]2[C:32]3[C:36](=[CH:37][CH:38]=[C:30]([Cl:29])[CH:31]=3)[NH:35][C:34]=2[C:48]([NH2:57])=[O:50])(=[O:54])=[O:55])[CH2:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: C1CNC1
Product: NC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)N1CCC1

Procedure:
The titled compound was prepared using the procedures described in Steps B and C of Example 2, followed by the procedure described in Step E of Example 1, replacing in Step B of Example 2 ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with azetidine. Proton NMR for the product was consistent with the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: Oc1ccccc1Cl
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cccc(Oc2ccccc2Cl)c1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
To a mixture of 3-cyanophenyl boronic acid (2.84 g, 19.3 mmol), 2-chlorophenol (1.24 g, 9.64 mmol), copper (II) acetate (1.75 g, 9.64 mmol) and 4 Å molecular sieves is added CH2Cl2 (30 mL). While stirring at 25° C., pyridine (3.89 mL, 48.2 mmol) of is added and the reaction mixture stirred at 25° C. for 48 hours. Once complete, the reaction is filtered, and the resulting filtrate is concentrated to afford a crude oil which is purified by column chromatography (5% ethyl acetate in hexanes) to provide 1.92 g of 3-(2-chlorophenoxy)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Temperature: 25 °C
Yield: 0.1 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.84 g, 18.6 mmol) in N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil, 1.08 g, 27.0 mmol) under cooling with ice for 1 hour. The reaction mixture was stirred with triisopropylsilyl chloride (6.0 mL, 28 mmol) at room temperature for one day. After addition of water, the reaction mixture was warmed to room temperature and extracted with hexane twice. The resulting organic layers were combined, washed with saturated aqueous sodium chloride dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the title compound as a reddish brown oil (5.74 mg, yield 99%).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C:31]([CH:41]=[O:42])([CH2:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C:31]([CH:41]([C:8]2[S:9][C:10]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=2)[OH:42])([CH2:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:30]1)=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(CC2CCOCC2)C1
Reactant: Fc1cccc2ccsc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC2CCOCC2)(C(O)c2cc3cccc(F)c3s2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
To a solution of 7-fluoro-benzothiophene (0.22 g, 1.44 mmoles) in anhydrous tetrahydrofuran (10 ml) at −78° C. was added dropwise a solution of n-BuLi in hexane (1.6M, 0.9 ml, 1.44 mmoles). The reaction mixture was stirred at −78° C. for one hour, and then a solution of 3-formyl-3-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g, 1.01 mmoles) in anhydrous tetrahydrofuran (5 ml) was then added. The reaction mixture was stirred at −78° C. for 3 hours, quenched with saturated aqueous ammonium chloride, and partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10 to 45% ethyl acetate in hexane) to yield 3-[(7-Fluoro-benzo[b]thiophen-2-yl)-hydroxy-methyl]-3-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless semisolid (0.138 g, 30%). MS=450 [M+H]+.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](O)[CH3:31]>>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]=4)[NH:20][CH:19]=3)[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Agent: Cl
Product: CCOC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1

Procedure:
HCl is passed into a boiling solution of 4.04 g of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylic acid in 50 ml of absolute ethanol for 2 hours. The mixture is boiled for a further hour and worked up in the customary manner to give ethyl 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylate. Rf 0.65 (silica gel; 8:2 CH2Cl2 /CH3OH).
Reaction SMILES: [OH:1][CH:2]([C:4]1([CH3:18])[CH2:8][NH:7][CH2:6][CH:5]1[C:9]1[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([OH:15])[CH:14]=1)[CH3:3].CCN(C(C)C)C(C)C.[CH3:28][C:29]1([CH3:37])[O:33][C@H:32]([C:34](Cl)=[O:35])[CH2:31][O:30]1>C(Cl)Cl>[CH3:28][C:29]1([CH3:37])[O:33][C@@H:32]([C:34]([N:7]2[CH2:6][C@@H:5]([C:9]3[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([OH:15])[CH:14]=3)[C@@:4]([C@H:2]([OH:1])[CH3:3])([CH3:18])[CH2:8]2)=[O:35])[CH2:31][O:30]1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: COc1ccc(C2CNCC2(C)C(C)O)cc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc([C@@H]2CN(C(=O)[C@H]3COC(C)(C)O3)C[C@@]2(C)[C@@H](C)O)cc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A round bottom flask equipped with a stir bar and rubber septum was charged with 5-[4-(1-hydroxy-ethyl)-4-methylpyrrolidin-3-yl)-2-methoxyphenol (2.4 g, 9.55 mmol), dry CH2Cl2 (50 mls), and DIEA (3.49 mls, 20.1 mmol) under a nitrogen atmosphere. The mixture was chilled to 0° C. and (S)-2.2-dimethyl-[1,3]dioxolane-4-carbonyl chloride (3.14 g, 19.1 mmol) in 15 ml of CH2Cl2 was added dropwise by syringe. The reaction mixture was allowed to gradually warm to room temperature over a 16-hour period. The mixture then was diluted with 50 ml of CH2Cl2, washed with 1N HCl (2×50 ml), saturated aqueous NaHCO3 (1×50 ml), dried over Na2SO4, and concentrated to 3.9 g of a tan foam. The material was taken up in 100 ml CH3OH and chilled to 0° C. Three equivalents of aqueous 1N LiOH then were added (29 ml, 29.0 mmol), the mixture was stirred at 0° C. for 2 hours, then warmed to room temperature for 2 hours. The reaction mixture next was concentrated under reduced pressure with the bath temperature at 30° C. to remove CH3OH. The remaining aqueous material was neutralized with saturated NH4Cl to pH 7 and extracted with EtOAc (2×100 ml). The extracts were dried over Na2SO4 and concentrated to 2.74 g of a tan foam (76%).
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([C:19]4[CH:23]=[C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:21][C:20]=4[S:28]([NH:31]C(C)(C)C)(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:48]>C(Cl)Cl.O>[CH2:50]([O:49][C:47]([NH:31][S:28]([C:20]1[S:21][C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:23][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1)(=[O:29])=[O:30])=[O:48])[CH2:51][CH2:52][CH3:53]
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccccc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3-[3-(2-phenylimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (31.2 mg, 0.0615 mmol; see step (a)) in CH2Cl2 (1 mL) was added BCl3 (0.2 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (29.3 mg, 0.277 mmol), water (2 mL) and butyl chloroformate (15.6 μL, 0.123 mmol), and the reaction mixture was stirred for 11 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound as a white solid in 87% yield, over two steps, (29.4 mg, 0.0533 mmol).
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)/[C:5](/Cl)=[C:6](\[O:8]C)/[CH3:7].[OH-].[Na+].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O>[CH:14](=[C:7]1/[C:6](=[O:8])[CH2:5][C:4](=[O:3])[NH:1]/1)\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: N
Reactant: COC(=O)/C(Cl)=C(/C)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CC(=O)/C(=C/c2ccccc2)N1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
133 g of concentrated aqueous ammonia solution was heated to 65° to 70° C. 75 g of (E)-2-chloro-3-methoxybut-2-enoic acid methyl ester was instilled for 3 hours with constant passing through of ammonia gas. The mixture was stirred another 45 minutes at this temperature, heated 30 minutes to reflux temperature and then cooled to room temperature. After the addition of 300 ml of water and 50 ml of 33 percent sodium hydroxide solution, 46.4 g of benzaldehyde was added. The mixture was heated for 6 hours at 60° C. under stirring and then cooled to room temperature. Then 688 ml of concentrated hydrochloric acid was added and the reaction mixture was stirred for 22 hours at 40° C. After cooling to room temperature, the yellow product was filtered off, washed with cold water and dried in a vacuum drying cabinet. The yield of the title compound was 74.66 g (88 percent of theory). The title compound had a melting point of 186° to 187° C. (THF/hexane).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:45])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1cccnc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Yield: 91 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 91% of theory, C28H30N6O3 (498.6) Rf value: 0.19 (silica gel; dichloromethane/ethanol=4:1) EKA mass spectrum: (M+H)+ =499
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[Br:24].IC>O1CCCC1>[Br:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[CH:16]([CH3:1])[C:15]([O:14][CH3:13])=[O:25]
Reactant: [Li]CCCC
Reactant: COC(=O)Cc1cc(Cl)ccc1Br
Solvent: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cc(Cl)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium (1.67 mL of a 2.5 M solution in hexanes, 4.17 mmol) was added dropwise via syringe to a stirred solution of diisopropylamine (0.61 mL, 4.36 mmol) in tetrahydrofuran (10 mL) at −78° C. After approximately 10 min, the reaction mixture was warmed to 0° C. and aged for another 10 min. After re-cooling to −78° C., a solution of methyl (2-bromo-5-chlorophenyl)acetate (1-2) (1.00 g, 3.79 mmol) in tetrahydrofuran (10 mL) was added dropwise via syringe and the resulting yellow mixture was stirred at −78° C. for approximately 30 min. Iodomethane (0.35 mL, 5.69 mmol) was added and after 1 h, the reaction mixture was warmed to ambient temperature and quenched with saturated aqueous ammonium chloride. The resulting mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-20% ethyl acetate/hexanes as eluent) furnished 2-1 as a colorless oil (1.00 g).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:13][C:14]([N:16]([CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17][C:18]([O:20]C)=[O:19])=[O:15])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Li+].[OH-].O>C1COCC1>[CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:13][C:14]([N:16]([CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Cc1cc2ccc(C)nc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2cc(CC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of methyl N-((7-methyl-1,8-naphthyridin-2(1H)-on-3-yl)acetyl)-N-(2-tert-butyloxycarbonylaminoethyl)glycinate (0.775 g, 1.79 mmol) in THF (10 mL, LAB-SCAN C2520, dried over molecular seives) was added LiOH (2M, aqueous) (2.0 mL). The resulting solution was stirred at rt for 30 min, additional water was added, and the THF removed in vacuo. The pH of the aqueous solution was adjusted to pH 3.0 and the precipitate collected, and washed (2×10 mL) by filtration, to yield the desired product (424 mg, 56%) as a colorless precipitate (mp 94-95° C.). 1H NMR (DMSO-d6; this compound exist as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 12.05 (s br, 1H), 7.90 (7.96) (d, 7.9 Hz, 1H), 7.78 (7.71) (s, 1H), 7.11 (d, 7.9 Hz, 1H), 6.90 (6,73) (m, 1H), 3.97 (4.23) (s, 2H), 3.59 (s, 2H), 3.44 (s, 3H), 3.04 (3.15) (m, 2H), 1.37 (1.36) (s, 9H). 13C NMR (DMSO-d6): δ 170.94 (171.22), 170.00 (170.16), 162.6, 159.1, 155.7, 148.8, 136.30 (136.57), 135.90 (136.09), 128.28 (128.62), 118.12, 111.96 (112.00), 77.9, 48.08 (48.29), 47.5, 38.39 (38.05), 33.44 (33.66), 28.3, 24.2. FAB+ HRMS (m/z): 417.1794, calc. C20H25N4O6 417.1774.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:45][NH2:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:47]1([CH:44]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:45][NH:46][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCC(c4ccccc4)c4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 61 %

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2,2-diphenylethylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound (61% yield) as a yellow powder, m.p. 129-132° C. MS [(+)ESI, m/z]: 632 [M+H]+
Reaction SMILES: NCC(O)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22]>O>[CH:12](=[C:26]1[NH:20][C:21](=[O:22])[NH:23][C:24]1=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccccc2)N1
Yield: 88.3 %

Procedure:
A 37.5 g amount of glycine and 26.5 g of sodium carbonate were dissolved in 200 ml of water in the flask. Then, 53.0 g of benzaldehyde and 50.0 g of hydantoin were added to the resultant solution. The mixture was allowed to react at a temperature of 100° C. for 1 hour while stirring. During the reaction, the pH of the reaction mixture was 9.7 to 9.4. After cooling, the precipitated 5-benzylidene hydantoin was separated and recovered from the reaction mixture. Thus, 83.0 g of 5-benzylidene hydantoin was obtained. The yield was 88% based on the hydantoin.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:21]=C)[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=1)(=[O:11])=[O:10].I([O-])(=O)(=O)=[O:24].[Na+].Cl>O1CCOCC1.N1C(C)=CC=CC=1C.O.[Os](=O)(=O)(=O)=O>[CH:21]([C:14]1[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=[C:12]([S:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])(=[O:10])=[O:11])[CH:13]=1)=[O:24]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(S(=O)(=O)Nc2ccccc2C)cc2ccoc12
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1NS(=O)(=O)c1cc(C=O)c2occc2c1

Procedure:
N-(2-Methylphenyl)-7-vinyl-1-benzofuran-5-sulfonamide (1.03 g, 3.3 mmol; Intermediate 59) was dissolved in dioxane (30 mL) and 2,6-lutidine (0.8 mL). Osmium tetroxide (84 mg, 0.33 mmol) was added with stirring followed by a solution of sodium periodate (2.82 g, 13.2 mmol) in water (10 mL). After stirring for 90 minutes, 1 M HCl (40 mL) was added followed by water (200 mL). The precipitated product was collected by filtration, washed with water and dried under vacuo. Yield: 0.95 g (91%) of an off white solid.