Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Br.[CH3:4]I.[CH3:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH2:11][CH2:12][C:13](=[O:15])[CH3:14]>CCOCC>[CH3:14][C:13]([OH:15])([CH2:12][CH2:11][O:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([CH3:6])[CH:8]=1)[CH3:4]
Reactant: CI
Reactant: CC(=O)CCOc1cccc(C)c1
Agent: C[Mg]Br
Solvent: CCOCC
Product: Cc1cccc(OCCC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a solution of methyl magnesium bromide in ether (50 mL), prepared from Mg (572 mg, 23.56 mmol) and MeI (3.34 g, 23.56 mmol), was added 4(3-methylphenoxy)-2-butanone (2.1 g, 11.78 mmol) in 10 mL ether. The solution was stirred at room temperature for 30 minutes, after which it was quenched with water and dilute Hydrochloric acid. The organic layer was separated, dried over sodium sulfate, filtered through a silica plug to give a colorless syrup 1.91 g (83%) mass spectral analysis using APCI+ve 177 (M+—OH).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].[I:8][C:9]1[CH:10]=[C:11]([N:15]=[C:16]=[O:17])[CH:12]=[CH:13][CH:14]=1.C(O)C>ClCCl>[I:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([NH:3][NH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C=Nc1cccc(I)c1
Reactant: CCOC(=O)NN
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)NNC(=O)Nc1cccc(I)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A solution of ethyl carbazate (1.25 g) in dichloromethane (20 ml) was treated with 3-iodophenylisocyanate (1.7 g) at 0° C. The reaction mixture was allowed to warm to 20° C. and stirred for 2 h. Ethanol (2 ml) was added and the mixture was stirred for 0.5 h. The solvents were removed under reduced pressure and the residue was triturated in diethyl ether. The white solid was collected by filtration to give the title compound (2.4 g). LCMS RT=2.81 min
Reaction SMILES: [CH3:1][O:2][C:3](=[O:52])[NH:4][C@@H:5]([C@H:48]([O:50][CH3:51])[CH3:49])[C:6]([N:8]1[C@@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]1[C:27]2[C:32]([CH2:33][O:34][C:21]=1[CH:20]=3)=[CH:31][C:30]([C:35]1[NH:39][C:38]([C@@H:40]3[CH2:44][C@H:43]([CH2:45][O:46][CH3:47])[CH2:42][NH:41]3)=[N:37][CH:36]=1)=[CH:29][CH:28]=2)=[O:7].[CH3:53][O:54][C:55]([NH:57][C@@H:58]([CH:62]([CH3:64])[CH3:63])[C:59](O)=[O:60])=[O:56].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:53][O:54][C:55](=[O:56])[NH:57][C@@H:58]([CH:62]([CH3:63])[CH3:64])[C:59]([N:41]1[CH2:42][C@@H:43]([CH2:45][O:46][CH3:47])[CH2:44][C@H:40]1[C:38]1[NH:39][C:35]([C:30]2[CH:31]=[C:32]3[CH2:33][O:34][C:21]4[CH:20]=[C:19]5[C:24]([CH:25]=[CH:26][C:16]6[N:15]=[C:14]([C@@H:9]7[CH2:10][CH2:11][C@H:12]([CH3:13])[N:8]7[C:6](=[O:7])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:52])[C@H:48]([O:50][CH3:51])[CH3:49])[NH:18][C:17]=65)=[CH:23][C:22]=4[C:27]3=[CH:28][CH:29]=2)=[CH:36][N:37]=1)=[O:60]
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c65)cc3-4)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl{(2S,3R)-3-methoxy-1-[(2S,5S)-2-(9-{2-[(2S,45)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate (74.6 mg, 0.105 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (18.5 mg, 0.105 mmol), HATU (44 mg, 0.116 mmol) and 0.6 mL 10% DIPEA in DMF was stirred at room temperature for 1 hour. The product was purified by reverse phase HPLC. (48.1 mg)
Reaction SMILES: [CH2:1](N(C(C)C)C(C)C)[CH3:2].[CH2:10](Br)[CH3:11].[NH2:13][CH2:14][C:15]1[O:19][N:18]=[C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:29]4[CH:30]=[CH:31][S:32][C:28]=4[C:27](=[O:33])[N:26]([CH3:34])[CH2:25][C:24]=23)[N:16]=1>CN(C)C=O>[CH2:1]([N:13]([CH2:14][C:15]1[O:19][N:18]=[C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:29]4[CH:30]=[CH:31][S:32][C:28]=4[C:27](=[O:33])[N:26]([CH3:34])[CH2:25][C:24]=23)[N:16]=1)[CH2:10][CH3:11])[CH3:2]
Reactant: CCBr
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2ccsc2C1=O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)no1
Reaction time: 1 h
Yield: 47.5 %

Procedure:
2.35 ml (13.6 mmol) of N-ethyldiisopropylamine and 0.76 ml (10.2 mmol) of ethyl bromide were added to a solution of 0.54 g (1.7 mmol) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one in 20 ml dimethylformamide and the mixture was stirred at 70° for 1 hour. The reaction solution was subsequently evaporated, whereupon the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried over magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). There were obtained 301 mg (47%) of 3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as a colourless foam, Rf=0.66 (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1).
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26](N)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]1C=CC=CC=1.Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44].O>C1(C)C=CC=CC=1>[CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:17]([NH2:36])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccncc1
Reactant: NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=CC(=O)[C@H](C(N)c1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
A solution of 5 g of (2S)-2-(N,N-dibenzylamino)-5-amino-1,6-diphenyl-4-hexene-3-one in toluene (100 ml) was chilled with ice water. To the solution, 5 ml of pyridine and 5 ml of ethyl chloroformate were gradually added. The reaction mixture was stirred at 70° C. for 12 hours, and then chilled with ice water. 5 ml of water was added to the reaction mixture, and the mixture was held at the same temperature for 1 hour. The reaction mixture was then washed with 50 ml of water and 50 ml of a dilute solution of potassium hydrogensulfate, and further with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane-ethyl acetate (10:1) as an eluent, thereby obtaining 1.65 g (28.5%) of the title compound as pale yellow powder from the eluate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:24][C:25]3[C:30]([C:31]=2[CH:32]=O)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[NH:24][C:25]3[C:30]([C:31]=2/[CH:32]=[CH:14]/[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:15])=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:22]=1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)[nH]c2ccccc12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c(-c3ccc(Cl)cc3)[nH]c3ccccc23)cc(OC)c1OC
Yield: 169.9 %

Procedure:
Substantially the same procedure as in Example 12 was repeated using 3',4',5'-trimethoxyacetophenone (0.84 g) and 2-(4-chlorophenyl)indole-3-carboxaldehyde (2.56 g) to give Compound 14 (3.04 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCCC1>[CH2:3]([O:4][C:5](=[O:7])[CH2:6][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonate and 2.6 mL (30.0 mmol) of morpholine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroformn and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 2.75 g (53%) of the desired product as a tan oil. MS (ion spray) 174.2 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([CH2:14][N:15]2[C:23]3[C:18](=[C:19]([C:26]([F:29])([F:28])[F:27])[C:20]([C:24]#[N:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:30][CH2:31][CH3:32])[N:10]=1.[CH3:33][OH:34].CN([CH:38]=[O:39])C>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:33]([O:39][CH3:38])=[O:34])=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([CH2:14][N:15]2[C:23]3[C:18](=[C:19]([C:26]([F:28])([F:29])[F:27])[C:20]([C:24]#[N:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:30][CH2:31][CH3:32])[N:10]=1
Reactant: CN(C)C=O
Reactant: CO
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(I)ccc2Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)OC)ccc2Cl)n1
Temperature: 70 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
A solution containing 1-{[5-(2-chloro-5-iodophenyl)-1,2,4-oxadiazol-3-yl]methyl}-2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 291) (0.378 g, 0.662 mmol), 1,1-bisdiphenylphosphinoferrocene (0.073 g, 0.132 mmol), E3N (1.0 mL, 13.6 mmol), Pd(OAc)2 (0.032 g, 0.132 mmol), anhydrous MeOH (2.0 mL) and anhydrous DMF (20 mL). The mixture was then stirred at 70° C. under a carbon monoxide atmosphere for a period of 4 h and then allowed to cooled to rt. The reaction was partitioned between NaHCO3 and EtOAc, dried (MgSO4) and concentrated to dryness. The mixture was purified on a biotage prepak column (0-10% EtOAc-hexanes gradient) to give 0.214 g (64% yield) of pure product: MS (ES) m/z 502 (M+).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].C[Si](C)(C)N[Si](C)(C)C.[I:22]I.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[I:22][CH:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][C:2]1=[O:12]
Reactant: O=C1CCCc2ccccc2N1
Reactant: II
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1Nc2ccccc2CCC1I
Temperature: 30 °C
Yield: 57.5 %

Procedure:
A suspension of 1.8 Kg (11.17 mol) of 2,3,4,5-terahydro-1H-1-benzazepin-2-one in a mixture of 22.33 L of methylene chloride and 11.78 L (55.83 mol) of hexamethyldisilazane was heated at reflux for 10 minutes then cooled to 30° C. and treated with 8.503 Kg (33.5 mol) of iodine in one portion. The mixture was heated at reflux for 2.5 hours then cooled to room temperature. Aqueous sodium sulfite containing 4.926 Kg of sodium sulfite in 44 L of water was cooled to 0° C. and into it was poured the reaction mixture in several portions with vigorous stirring while maintaining the temperature below 10° C. The reaction vessel was rinsed with 3 L of methylene chloride and the washing transferred to the quenching mixture. Methylene chloride (17 L) was added to the quenching mixture and it was stirred vigorously and the layers allowed to separate. The aqueous layer was removed and reextracted with 12 L of methylene chloride. The combined organic layers were washed with 11 L of water and concentrated under vacuum to a final volume of approximately 5 L. The residue was treated with 55 L of toluene and concentrated under vacuum to a final volume of 10 L. The resulting slurry was removed by filtration and the filter cake washed with an additional 5 L of toluene and dried under vacuum at ambient temperature for 24 hours to give 1.842 Kg (6.42 mol, 57%) of product.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC(O)C.C(C1C=CC=CC=1)(=O)C>[CH:1]([OH:8])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(=O)c1ccccc1
Product: OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
1.8 g of benzophenone (10 mmol) and 45 ml of 2-propanol are introduced into a 100 ml flask under argon atmosphere. The system is heated under reflux. 2.5 ml of a 0.1 M solution of NaOH in 2-propanol and 2 ml of a 2-propanol solution containing the catalyst (10) (1.8 mg, 0.0025 mmol) are added. The molar ratios of benzophenone/catalyst/NaOH are equal to 4000/1/100. 1H NMR analysis of the mixture shows that the reaction is complete after 30 minutes. By evaporating the solvent, a colourless residue is obtained which is extracted with 30 ml of diethyl ether. This solution is then passed through a silica filled column to remove the catalyst and sodium hydroxide. The filtrate is dried by adding Na2SO4 and, after filtering and removal of the solvent, the benzhydrol is recovered and then dried under reduced pressure (10−2 mmHg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.[C:27](Cl)(=[O:29])[CH3:28]>CCN(CC)CC>[C:27]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=[O:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2F)C1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NCCO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)-piperidine-1-carboxylate (160 mg, 0.41 mmol) and Et3N (1 mL) at 0° C. was added acetyl chloride (32.3 mg, 0.41 mmol). The mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated in vacuo to give crude (R)-tert-butyl 3-((R)-(2-acetamidoethoxy)-(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (95 mg, 54%), which was used in the next step without further purification. 1H NMR: (400 MHz, CDCl3): 1.20 (m, 1H), 1.40 (s, 9H), 1.70 (m, 2H), 1.98 (s, 3H), 2.60 (m, 2H), 3.48 (m, 4H), 3.90 (m, 1H), 4.42 (m, 1H), 5.82 (m, 1H), 7.10 (m, 1H), 7.20 (m, 1H), 7.34 (m, 1H); MS (E/Z): 429 (M+1). MS (E/Z): 429 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4].[CH2:15](Br)[CH2:16][CH3:17]>>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([CH2:15][CH2:16][CH3:17])[C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4].[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:10]([CH:11]=[C:12]([Br:14])[CH:13]=1)=[N:9][N:8]([CH2:15][CH2:16][CH3:17])[CH:7]=2)=[O:4]
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Reactant: CCCBr
Product: CCCn1cc2c(C(=O)OC)cc(Br)cc2n1
Product: CCCn1ncc2c(C(=O)OC)cc(Br)cc21
Temperature: 40 °C
Yield: 20 %
Yield: 20 %

Procedure:
The title compounds were prepared in the same manner as described for example 42 (step a) from 6-bromo-1H-indazole-4-carboxylic acid methyl ester (3.0 g, 11.66 mmol) and 1-propyl bromide (1.59 g, 12.94 mmol) wherein the contents were heated at 40° C. for 30 min. The obtained crude products were purified by silica gel chromatography (eluent: 10% ethyl acetate in petroleum ether) to afford the title compounds 6-bromo-1-propyl-1H-indazole-4-carboxylic acid methyl ester (700 mg, 20%) and undesired isomer 6-bromo-2-propyl-2H-indazole-4-carboxylic acid methyl ester (700 mg, 20%) as white solids. 1H NMR (400 MHz, DMSO-d6): (N1-propyl isomer): δ 0.83-0.80 δ (t, J=7.6, 3H), 1.84-1.81 (t, J=14.4 Hz, 2H), 3.95-3.94 (d, J=5.2 Hz 3H), 4.45-4.43 (t, 2H), 7.84 (d, J=1.2 Hz, 1H), 8.43 (d, J=14 Hz, 2H). LCMS (ES+): m/z=297.06.
Reaction SMILES: [NH:1]([C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1)[C:2]#[N:3].Cl.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>ClCCl>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)=[NH:3])=[CH:18][CH:17]=1
Reactant: N#CNc1cccc(C(F)(F)F)c1
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: N=C(NCc1ccc(Cl)cc1)Nc1cccc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 40 h

Procedure:
A mixture of 3-cyanamidobenzotrifluoride (1.20 g, 6.45 mmol) and 4-chlorobenzylamine hydrochloride (1.26 g, 7.09 mmol) was stirred at 150° C. for 40 h. Dichloromethane (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate (100 ml). The organic phase was purified by chromatography using silica gel and a mixture of methanol (10%) and dichloromethane as eluent. The product was isolated as the free base. Yield 1.05 g, 50%. M.p. 103-105° C.
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(NC[C@H]3CC[C@H](C(O)=O)CC3)=O)C3C=CC([F:76])=CC=3N=2)=CC=1.[CH3:77][O:78][C:79](=[O:90])[CH2:80][CH2:81]C1C=CC(N)=C(F)C=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>>[CH3:77][O:78][C:79](=[O:90])[CH2:80][CH2:81][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:7]([F:76])[CH:6]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)ccc21
Reactant: COC(=O)CCc1ccc(N)c(F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was synthesized in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 22, intermediate c), 3-(4-amino-3-fluoro-phenyl)-propionic acid methyl ester, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N-ethyldiisopropylamine.
Reaction SMILES: [NH:1]=[C:2]1[C:15](NC(NC(OC)=O)=S)=[C:14](CC2C=CC=CC=2)[C:13](Cl)=[C:4]([C:5](C2C=CC=CC=2)=O)[CH:3]1Cl.[OH-].[Na+].CI.N=[C:38]1[C:51]([NH:52][C:53](=[N:56][C:57]([O:59][CH3:60])=[O:58])[S:54][CH3:55])=[CH:50][CH:49]=[C:40]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:42])[CH:39]1CC1C=CC=CC=1>CN(C)C=O.O>[NH:1]=[C:2]1[CH:15]=[CH:14][CH:13]=[C:4]([CH2:5][C:43]2([C:41](=[O:42])[C:40]3[CH:49]=[CH:50][C:51]([NH:52][C:53](=[N:56][C:57]([O:59][CH3:60])=[O:58])[S:54][CH3:55])=[CH:38][CH:39]=3)[CH:44]=[CH:45][CH:46]=[CH:47][CH2:48]2)[CH2:3]1
Reactant: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2)C1=N)SC
Reactant: COC(=O)NC(=S)NC1=C(Cc2ccccc2)C(Cl)=C(C(=O)c2ccccc2)C(Cl)C1=N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)N=C(Nc1ccc(C(=O)C2(CC3=CC=CC(=N)C3)C=CC=CC2)cc1)SC
Reaction time: 2 h

Procedure:
To a solution of 3-imino(2,6-dichloro)phenylmethyl-4-(3-carbomethoxythioureido)benzophenone (2.43 g.; 0.005 mole) in dimethylformamide (100 ml.) is added water (5.0 ml.) and then sodium hydroxide (50% aqueous; 0.4 g.; 0.005 mole). The solution is stirred for 11/2 hours and then methyl iodide (0.71 g.; 0.005 mole) is added. The solution is stirred for one-half hour. The precipitate which forms is collected by filtration and dried to afford 1.3 g. of 3-iminophenylmethyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone, m.p. 63°-68° C. (dec.).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[CH:14](=[N:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]([O:25][CH3:26])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:39][CH:40](Br)C>O1CCCC1.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O>[Cl:39][CH2:40][C:22]([N:21]=[CH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH2:27][CH2:28][CH2:29][CH2:30][N:31]=[CH:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(CCCCN=Cc1ccccc1)N=Cc1ccccc1
Reactant: CC(Cl)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CCl)(CCCCN=Cc1ccccc1)N=Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of lithium diisopropylamide (10 mmol) prepared in situ from a solution of 1N diisoproppylamine in tetrahydrofuran (THF) and a solution of butyl lithium (2N) in hexane and hexamethylphosphoramide (HMPA) (2.5 ml) in THF cooled to -78° C., magnetically stirred, and kept under nitrogen, is added slowly a solution of methyl 2,6-bis(benzylideneamino)hexanoate (3.365 g, 10 mmol) in dry THF (20 ml). The reaction mixture is stirred at -78° C. for 1/2 hour, and then a solution of chlorobromoethane (1.3 g, about 10 mmol) in dry THF (10 ml) is added rapidly. the temperature is allowed to rise slowly to room temperature, and the stirring is continued overnight. The reaction mixture is quenched with water and extracted with ether. The ether extract is washed with water and concentrated at reduced pressure to give methyl 2-chloromethyl-2,6-bis(benzylideneamino)hexanoate as an oily residue.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH2:16])[CH2:14][NH2:15]>C(O)C>[CH2:13]([NH:16][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][NH:15][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC1CO1
Reactant: NCCN
Solvent: CCO
Product: CCCCCCCCCC(O)CNCCNCC(O)CCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-undecene oxide (40 g.) and ethylenediamine (7.07 g.) and two recrystallizations of the resulting solid (14.9 g.) from ethanol gave N,N'-ethylenebis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = (CH2)2, Z = H) (12.4 g., m.p. 130.2°-137.8° C. ).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:23])[C:7]=2[N:6]=[C:5]1[CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>>[NH2:23][C:8]1[C:7]2[N:6]=[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])[N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)C(C)C
Yield: 25.8 %

Procedure:
1-(2-Aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.01 mL, 7.26 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372–376. The crude product was recrystallized from isopropanol (4 mL/g) and then triturated with acetonitrile (12.5 mL/g), isolated by filtration, and dried overnight in a drying oven to provide 0.61 g of N-{2-[4-amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 228–230° C.