Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: c1c[nH]nn1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccnn2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 100 g (803 mmol) of p-fluorobenzaldehyde in 400 ml of DMF, 95 g (1377 mmol) of 1-H-1,2,3-triazole and 200 g (1449 mmol) of K2CO3 are added successively and the mixture is stirred for 4 h at 100° C. The mixture is cooled to r.t. and filtrated through celite. The filtrate is concetrated under reduced pressure to give crude crystals which are washed with AcOEt several times. The solid which is not well soluble in AcOEt is washed with water and dried in vacuo to give 4-[1,2,3]-triazol-1-yl-benzaldehyde (B). The filtrate is concentrated under reduced pressure, the obtained solid is solved in CH2Cl2 and then absorbed on silica gel for dry CC (n-Hexane:AcOEt=2:1˜1:2) to provide 4-[1,2,3]-triazol-2-yl-benzaldehyde (A) and further compound (B) as pale yellow solids; 1H-NMR (400 MHz, CDCl3): compound A, 7.88 (s, 2H), 8.01 (d, 2H, J=8.56 Hz), 8.29 (d, 2H, J=8.56 Hz), 10.06 (s, 1H); compound B: 7.90 (s, 1H), 7.98 (d, 2H, J=8.56 Hz), 8.07 (d, 2H, J=8.56 Hz), 8.13 (s, 1H), 10.09 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[CH3:24])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:27]([O-])=O.O.O.Cl[Sn]Cl>C(O)C.C(OCC)(=O)C>[NH2:27][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:2]=1[CH3:1])[C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:11]([N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH3:24])[CH:10]=1)=[O:7]
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The compound (27 g, 72.1 mmol) obtained in Step 2 of Preparation Example 6 was dissolved in ethanol (300 mL), SnCl2.2H2O (81 g, 360 mmol) was added thereto and stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with sat. NaHCO3 solution several times. The organic layer was dried with anhydrous MgSO4, filtered and concentrated to obtain the title compound without further purification.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].O.[C:14](OCC)(=O)[CH3:15]>C1COCC1>[OH:2][CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)[CH2:14][CH3:15]
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1ccc(-c2cccs2)s1
Reaction time: 1 h

Procedure:
5-Formyl-2,2'-bithiophene (3 g) was dissolved in THF (50 ml) and ethyl-magnesium bromide Grignard reagent (9.3 ml) was added dropwisely under nitrogen gas atmosphere in ice bath and stirred for 1 hour. The mixture was stirred for 1 hr. and then continuously stirred at room temperature. The reaction was monitored by thin layer chromatography. After the reaction was completed, water (30 ml) and ethyl acetate (200 ml) were added to the mixture and extracted and purified by column chromatography, eluted with ethyl acetate/n-hexane (1/9). Light yellowish product was thus obtained.
Reaction SMILES: Cl[O-].[Na+].Cl.[CH2:5]([O:12][C:13]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:14]=1[C:15]1[C:16]([CH2:39][O:40][CH3:41])=[C:17]([CH:36]=[N:37][OH:38])[N:18]=[CH:19][C:20]=1[N:21]2S(C1C=CC(C)=CC=1)(=O)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:42][O:43][CH2:44][C:45]#[CH:46]>O1CCCC1>[CH2:5]([O:12][C:13]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:14]=1[C:15]1[C:16]([CH2:39][O:40][CH3:41])=[C:17]([C:36]3[CH:46]=[C:45]([CH2:44][O:43][CH3:42])[O:38][N:37]=3)[N:18]=[CH:19][C:20]=1[NH:21]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COCc1c(C=NO)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: C#CCOC
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: COCc1cc(-c2ncc3[nH]c4cccc(OCc5ccccc5)c4c3c2COC)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature under a protective gas, 1.4 ml of sodium hypochlorite solution is added dropwise to 155 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carbaldehyde oxime hydrochloride in 6 ml of absolute tetrahydrofuran. The mixture is stirred until the oxime has disappeared (TLC control) for one hour at room temperature, then 210 mg of methylpropargyl ether is added dropwise and the mixture is agitated overnight at room temperature. After the solvent has been removed by distillation, the mixture is distributed in ethyl acetate/water, and the organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue is dissolved in 8 ml of methanol, combined with 54 mg of sodium methylate, and heated to reflux for one hour. After concentration and distribution in ethyl acetate/concentrated sodium chloride solution, the organic phase is dried, filtered, and concentrated. The residue is chromatographed over silica gel with toluene+ethyl acetate in a ratio of 1:1. The corresponding fractions are combined and crystallized from ethyl acetate, thus obtaining 70 mg, melting point 133°-135° C. (ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:15])=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[N:3][C:4]2[C:9](=[CH:8][C:7]([CH3:14])=[C:6]([CH3:15])[CH:5]=2)[N:10]=1
Reactant: CCOC(=O)Cl
Reactant: COc1nc2cc(C)c(C)cc2nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
2-Amino-3-methoxy-6,7-dimethylquinoxaline (2.34 g, 11.5 mmol) and ethyl chloroformate (2.50 g, 23.0 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (1.82 g, 23.0 mmol) was added. The mixture was stirred at room temperature for 12 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 2.65 g of the titled compound (yield, 84%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([CH3:28])[CH:22]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:24]1[CH:26]=[CH:27][C:21]([O:20][CH3:19])=[CH:22][C:23]=1[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: COc1ccc(N)c(C)c1
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(OC)cc1C
Yield: 34.7 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (5.0 g, 0.019 mol) and 4-methoxy-2-methylaniline (3.0 g, 0.022 mol) were heated under reflux in 1,4-dioxan (50 ml) for 30 minutes. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with dilute hydrochloric acid, sodium bicarbonate solution, water and brine. The solution was dried and evaporated to an oil, which crystallised on standing. The crystals were triturated with ether and recrytallised from ethyl acetate to give 3-butyryl-4-(4-methoxy-2-methylphenylamino)-8-methoxyquinoline (2.4 g, 34.8%), m.p. 161°-3°.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35]>>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][S:34]([N:33]([CH3:38])[CH3:32])(=[O:36])=[O:35])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Product: COc1ccc(NC(=O)c2ccc(NS(=O)(=O)N(C)C)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 30 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide (500 mg, 1.20 mmol) was reacted with dimethylaminosulfonyl chloride to yield 190 mg (30%) of title compound as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]([CH2:16][CH3:17])[C:11]([N:13]([CH3:15])[CH3:14])=[N:12][C:8]=2[CH:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[C:5]=1[Cl:22])([O-])=O.C(COC)OC>[Pt]=O.CO>[NH2:1][C:4]1[C:9]2[N:10]([CH2:16][CH3:17])[C:11]([N:13]([CH3:14])[CH3:15])=[N:12][C:8]=2[CH:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[C:5]=1[Cl:22]
Reactant: CCn1c(N(C)C)nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c21
Agent: O=[Pt]
Solvent: CO
Solvent: COCCOC
Product: CCn1c(N(C)C)nc2cc(C(F)(F)F)c(Cl)c(N)c21
Reaction time: 3 h

Procedure:
7-nitro-6-chloro-2-dimethylamino-1-ethyl-5-trifluoromethylbenzimidazole (2 g.) in 50 ml. of a 50:50 mixture of dimethoxyethane and methanol was hydrogenated in the presence of 100 mg. of platinum oxide catalyst at an initial pressure of 40 psi. for 3 hours. Filtration to remove the catalyst was followed by solvent removal by evaporation under reduced pressure. The residue was passed through a silica gel column with chloroform as eluent to give 1.1 g. of the desired product melting at 99° - 100°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.ClC1C=CC=C2C=1N([CH2:21][CH2:22][C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])N=C2>>[Cl:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:21][CH2:22][C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2cn[nH]c12
Reactant: C[Si](C)(C)C#CCCn1ncc2cccc(Cl)c21
Product: C[Si](C)(C)C#CCCn1cc2cccc(Cl)c2n1
Yield: 63 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(A), from 7-chloro-1H-indazole (220 mg, 1.44 mmol) to yield 250 mg (0.90 mmol, 63%) of 7-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and 7-chloro-1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([C:6]1[CH:19]=[CH:18][C:9]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([N+:20]([O-])=O)[CH:7]=1)=[O:5])[CH3:2]>CCOC(C)=O.[Pd]>[NH2:20][C:8]1[CH:7]=[C:6]([C:4]([N:3]([CH2:23][CH3:24])[CH2:1][CH3:2])=[O:5])[CH:19]=[CH:18][C:9]=1[NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCNc1ccc(C(=O)N(CC)CC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNc1ccc(C(=O)N(CC)CC)cc1N
Reaction time: 8 h
Yield: 115.5 %

Procedure:
Following general procedure 2C: A mixture of ethyl 3-{4-[(diethylamino)carbonyl]-2-nitroanilino}propanoate (0.150 g, 0.445 mmol) and 10% Pd/C in EtOAc (15 mL) was hydrogenated overnight at 40 psi. Usual work-up provided the title compound (0.158 g) which was used without further purification. 1H-NMR (CDCl3): δ 6.86 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.46 (t and overlapping br s, J=5.6 Hz, 6H), 2.66 (t, J=6.8 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H), 1.18 (t, J=6.8 Hz, 6H). MS (ESI) (M+H)+=308.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[C:8]([N:11]1[CH2:15][CH2:14][CH2:13][O:12]1)(=[NH:10])[NH2:9].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[N:31]=[C:32]=[O:33].[N-]=C=O.[ClH:37].Cl.O1CCCN1>O1CCCC1.CO.C(OCC)(=O)C>[ClH:37].[CH3:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[C:25]=1[NH:31][C:32]([NH:10][C:8]([N:11]1[CH2:15][CH2:14][CH2:13][O:12]1)=[NH:9])=[O:33]
Reactant: N=C(N)N1CCCO1
Reactant: Cc1cccc(C)c1N=C=O
Agent: C1CNOC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1NC(=O)NC(=N)N1CCCO1

Procedure:
To 2.9 g. (36.0 mmol) of fifty percent (w/w) sodium hydroxide suspended in tetrahydrofuran (50 ml.) is added 6.0 g. (18.0 mmol) of N-amidinoisooxazolidine sulfate and the mixture stirred for one hour. Five (5.0) grams of anhydrous sodium sulfate are added and the mixture stirred for an additional hour. To this mixture are added 5.4 (36.0 mmol) of 2,6-dimethylphenylisocyanate and the mixture stirred for three hours. Thin layer chromotography (ethyl acetate) shows no starting isocyanate so the tetrahydrofuran is removed under vacuum. The residue is partitioned between water and chloroform. The layers are separated and the aqueous layer extracted with chloroform (1×100 ml.). The combined chloroform extracts are dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil which is dissolved in methanol and acidified (pH=1) with metholic hydrochloric acid. The methanol is removed to give an oil which is triturated with diethyl ether to give a solid which is crystallized from tetrahydrofuran/hexane to give N-[(2,6-dimethylphenylcarbamoyl)amidino] is isooxazolidine hydrochloride, m.p. 147°-8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:15][CH:14]2[NH:16][CH:11]([CH2:12][CH2:13]2)[CH:10]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:15][CH:14]2[NH:16][CH:11]([CH2:12][CH2:13]2)[CH2:10]1
Reactant: COc1ccccc1C1=CC2CCC(C1)N2
Solvent: CO
Product: COc1ccccc1C1CC2CCC(C1)N2
Temperature: 60 °C

Procedure:
Crude 10b from above (1.223 g) was dissolved in methanol (20 mL) and the solution purged with nitrogen gas for several minutes. 10% Palladium on carbon (500 mg, wet) was added and the flask flushed with nitrogen, followed by hydrogen (balloon). The reaction was heated at 60° C. for 1 h under a hydrogen balloon, then filtered through a pad of Celite and rinsed with methanol (3×25 mL). The filtrate was concentrated in vacuo to afford 1.030 g crude 3-(2-methoxyphenyl)-8-azabicyclo[3.2.1]octane 10c as a pale amber oil, which was taken to the next step without further purification. A small sample was purified via reverse-phase HPLC for analysis. 1H-NMR (400 MHz, DMSO-d6) δ 8.66 (br s, 2H), 7.33 (d, J=9.0 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.93 (t, J=7.5 Hz, 1H), 4.00 (m, 2H), 3.80 (s, 3H), 3.34 (m, 1H), 2.35 (m, 2H), 1.99 (m, 2H), 1.86 (m, 2H), 1.78 (m, 2H). LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 218.2 [M+H]+, retention time 1.81 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]3=[N:12][CH2:13][CH2:14][CH2:15][N:9]3[C:8]=2[CH:16]=1)([O-])=O.N.[H][H]>[Pd].CO>[N:12]1[CH2:13][CH2:14][CH2:15][N:9]2[C:8]3[CH:16]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[S:11][C:10]=12
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCCN=C1S2
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Product: Nc1ccc2c(c1)N1CCCN=C1S2

Procedure:
A mixture of 18 parts of 3,4-dihydro-7-nitro-2H-pyrimido[2,1-b]benzothiazole and 240 parts of methanol, previously saturated with gaseous ammonia is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 8.6 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine; mp. 197° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:20])[C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C>[NH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:20])=[O:19]
Reactant: CN(Cc1ccccc1)C(=O)c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a solution of N-benzyl-N-methyl-3-nitro-benzamide (320 mg, 1.18 mmol) in ethyl acetate (10 ml) was added stannous chloride dihydrate (1.34 g, 5.95 mmol) and then stirred for 3 hr at room temperature. The reaction mixture was washed with dilute sodium hydroxide solution, then water. The organic layer was separated, dried and then evaporated to give 3-amino-N-benzyl-N-methyl-benzamide (270 mg, 95%) as solid.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[O:13]=[C:14]1[NH:18][CH2:17][CH:16]([C:19](O)=[O:20])[CH2:15]1>C(OCC)(=O)C>[F:1][C:2]1[C:7]([O:8][C:19]([CH:16]2[CH2:15][C:14](=[O:13])[NH:18][CH2:17]2)=[O:20])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: O=C1CC(C(=O)O)CN1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: O=C1CC(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)CN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 212.3 %

Procedure:
To a suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (18.5 mg, 0.096 mmol) in 2 mL ethyl acetate was added pentafluorophenol (35.6 mg, 0.193 mmol) at 0° C. After 10 minutes, 5-oxo-pyrrolidine-3-carboxylic acid 16 (33.9 mg, 0.064 mmol) was added at 0° C. and the reaction mixture was stirred for 1 hour at room temperature. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (ethyl acetate:hexane=1:2) to yield the corresponding 5-oxo-pyrrolidine-3-carboxylic acid pentafluorophenyl ester 17 as a colourless oil (40.1 mg, 89.80%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:7]=1)(=[O:4])=[O:3].CO[C:20](OC)([CH3:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][C:20]([CH3:22])([CH3:21])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:8]=2[CH:7]=1)(=[O:4])=[O:3]
Reactant: COC(C)(C)OC
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OCC(C)(C)c2cc(OS(C)(=O)=O)ccc2O1

Procedure:
A mixture of 4-hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methylsulphonate (10 parts) (from Example 1), 2,2-dimethoxypropane (17 parts) and p-toluenesulphonic acid (0.1 parts) was heated in toluene (90 parts) with distillation of low boiling fraction and slow addition of further 2,2-dimethoxypropane (17 parts) for 1 hour. The resulting solution was cooled, washed with aqueous sodium hydroxide solution and with water, dried over magnesium sulphate and the solvent evaporated off under reduced pressure. The crude product was distilled yielding 9 parts of 4,5-dihydro-2,2,5,5-tetramethyl-1,3-benzodioxepin-7-yl methanesulphonate, boiling point 130°-142° C./0.2 mm Hg. Recrystallisation from aqueous ethanol gave the pure product (4.8 parts), melting point 65°-67° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24]O)[CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([O:12][CH2:24][CH2:23][CH2:22][C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: OCCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCCCc1cccnc1
Yield: 99 %

Procedure:
A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (3.0 g; 13.9 mmol); 3-(3-Pyridyl)-1-propanol (2.90 g; 20.9 mmol), dicyclohexylcarbodiimide (4.59 g; 22.24 mmol), camphorsulfonic acid (1.08 g; 4.63 mmol), and 4-dimethylaminopyridine (0.60 g; 4.63 mmol) in dry methylene chloride (100 mL) was stirred overnight. The reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL), and the layers were separated. The organic phase was washed with water (3×100 mL), dried over magnesium sulfate, and concentrated, and the crude residue was purified on a silica gel column eluting with ethyl acetate to obtain 4.60 g (95%) of the ester as a thick oil, 1H NMR (300 MHz, CDCl3): δ 1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32 (m, 1H); 2.71 (t, 2H); 3.50 (m, 2H); 4.15 (m, 2H); 4.18 (m, 1H); 7.24 (m, 1H); 7.51 (m, 1H); 8.48 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C=O.N.S(=O)(=O)(O)[OH:15]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: C=O
Agent: N
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
13.2 g of p-cyanobenzylamine, 51 g of a 35% aqueous formalin solution and 24 g of a 28% aqueous ammonia solution were reacted at 90° C. for 2 hours while stirring in a solvent of which pH was adjusted to 3 by sulfuric acid. The reaction solution was cooled to room temperature and then cooled on ice for 2 hours. The crystals precipitated were collected by filtration, washed with water and dried to obtain 5.2 g (yield: 40%) of p-cyanobenzaldehyde. The p-cyanobenzaldehyde obtained had a purity of 99.5% or more determined by the analysis of high performance liquid chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C(OCC)C>[CH2:1]([O:3][C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([OH:10])[CH3:9])[CH3:2]
Reactant: CCOC(C)(C)CCCC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCOC(C)(C)CCCC(C)O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 43 g. of 6-ethoxy-6-methyl-2-heptanone in 100 ml. of absolute diethyl ether is slowly added dropwise with ice cooling to a suspension of 4.5 g. of lithium aluminum hydride in 400 ml. of absolute diethyl ether. The mixture is subsequently stirred for a further one hour at ca. 5° C. and then hydrolyzed by the cautious addition of a dilute aqueous ammonium chloride solution. The mixture is filtered through diatomaceous earth and the organic phase washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. By distillation there is obtained pure 6-ethoxy-6-methyl-2-heptanol of boiling point 100° C./10 mmHg; nD20 = 1.4372.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Yield: 93.2 %

Procedure:
Diethyl 2-aminomalonate hydrochloride (12.7 g) and benzyloxycarbonyl chloride (11.9 g) are treated in the same manner as described in Reference Example 19-(3) to give diethyl 2-(N-benzyloxycarbonylamino)malonate (17.3 g), m.p. 36.5°-37° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[NH:29][CH:28]=[N:27][C:26]=2[CH:30]=1>>[N:27]1[C:26]2[CH:30]=[C:22]([NH:21][C:16](=[O:17])[C:15]3[CH:19]=[C:11]([N:10]=[N:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:12]=[CH:13][C:14]=3[OH:20])[CH:23]=[CH:24][C:25]=2[NH:29][CH:28]=1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc4[nH]cnc4c3)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride and 6-aminobenzimidazole were reacted together as described for Preparation 7. The product was crystallized in aqueous pyridine, m.p. 274°, λmax (methanol)=350 nm.