Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]1=2)(=[O:3])[CH3:2].[ClH:43]>O1CCOCC1.CCOCC>[ClH:43].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]=2[CH3:38])[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccccc2N(C(C)=O)[C@H]1C
Reaction time: 2 h
Yield: 84 %

Procedure:
A rt suspension of tert-butyl(S)-1-((2S,3S)-1-acetyl-2-methyl-5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (73.1 mg, 128 μmol) in 4 M HCl in dioxane (638 μl) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((2S,3S)-1-acetyl-2-methyl-5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (54.3 mg, 84%) as a white solid. MS m/z 473 (MH)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:25])[CH3:24])[CH2:12][C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:29]([O:28][C:26](=[O:27])[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[N:13]1[CH2:14][CH2:15][C:16]2[NH:8][CH:9]=[CH:10][C:11]=2[CH2:12]1)[CH3:30]
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2c(ccn2C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
5-[1-(2-Chlorophenyl)-7-ethoxycarbonyl-7-methyloctyl]-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.12 g, 0.23 mmol) was dissolved in dichloromethane (5 mL) with stirring under an argon atmosphere. TFA (0.48 mL, 4.75 mmol) was added to the solution. After 1 hour, TLC showed the starting material was gone. The mixture was poured into ice cold water (50 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/heptane=1/9 to 1/3) to afford 8-(2-chlorophenyl)-2,2 dimethyl-8-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-octanoic acid ethyl ester (Compound Ir, 65 mg, 65.9% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.80 (s, 1H), 7.54 (d, 1H, J=7.5 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.26-7.16 (m, 2H), 6.60 (s, 1H), 5.94 (s, 1H), 4.17 (m, 1H), 4.08 (q, 2H, J=7.2 Hz), 3.75 (d, 1H, J=13.2 Hz), 3.35 (d, 1H, J=13.2 Hz), 2.83-2.57 (m, 4H), 2.01-1.56 (m, 4H), 1.45-1.40 (m, 2H), 1.21 (t, 3H, J=7.2 Hz), 1.24-1.11 (m, 4H), 1.11 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 178.14, 140.07, 134.95, 129.43, 129.25, 127.82, 126.79, 125.12, 116.43, 115.93, 105.80, 63.89, 60.37, 48.79, 48.32, 42.37, 40.94, 33.34, 30.64, 25.55, 25.41, 25.08, 24.07, 14.56. HRMS (HR, DART-TOF): Calculated for C25H35ClN2O2 (M+H)+: 431.2460, found 431.2476.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][CH2:6][N:7]([CH3:14])[CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13])=[O:2].[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=1)[CH2:23][Cl:24])([O-:17])=[O:16]>O>[Cl-:24].[CH3:14][N+:7]([CH2:23][C:22]1[CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=[CH:20][C:21]=1[O:26][CH3:27])([CH2:6][CH2:5][CH2:4][NH:3][CH:1]=[O:2])[CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13]
Reactant: COc1ccc([N+](=O)[O-])cc1CCl
Reactant: CN(CCCNC=O)CCCNC=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1C[N+](C)(CCCNC=O)CCCNC=O
Product: [Cl-]

Procedure:
Proceeding in a manner similar to that described above in B-8a, 142 parts of N,N-bis(3-formamidopropyl)methylamine and 141 parts of 5-nitro-2-methoxybenzylchloride were interacted in 115 parts of water to obtain N-methyl-N-(5-nitro-2-methoxybenzyl)-N,N-bis(3-formamidopropyl)ammonium chloride. The product was not isolated but was used directly in solution for reduction of the nitro group.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9]>>[Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[S:8]([OH:11])(=[O:10])=[O:9]
Reactant: O=S(=O)(O)O
Reactant: Cn1cncc1Cl
Product: Cn1cnc(S(=O)(=O)O)c1Cl

Procedure:
33 g (0.28 mol) of 5-chloro-1-methylimidazole in 200 ml of fuming sulfuric acid are heated at 160°-180° C. for 4 hours. After cooling, the reaction mixture is cautiously added to ice. The product crystallizes out from the cold aqueous solution (about 1.5 l). After recrystallizing twice from water, the title compound is obtained in the form of coarse yellowish crystals of melting point 309°-310° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCC(CC)CBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)Cn1ccc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc2c1=O
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a solution of the product of Example 11 (100 mg) in DMF (3 mL) was added potassium carbonate (217 mg) followed by 3-(bromomethyl)pentane (0.44 mL) and the mixture stirred at 80° C. for 17 hrs. The reaction mixture was filtered and purified by HPLC to give the title compound (55.0 mg) as a solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@H:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:7].C(N(CC)CC)C.O>ClCCl>[C:1]([NH:5][C@H:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH2:16]1)[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C[C@H](N)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
Acetyl chloride (1.71 mL, 24.0 mmol) was added to a solution of crude tert-butyl 4-{2-[(1S)-1-aminoethyl]-4-chlorophenyl}piperidine-1-carboxylate (3-7) (5.42 g of ˜70% pure material, 11.2 mmol) and triethylamine (6.69 mL, 48.0 mmol) in dichloromethane at approximately 0° C. After 2 h, the reaction 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; 35 to 50% ethyl acetate/hexanes as eluent) provided tert-butyl 4-{2-[(1S)-1-(acetylamino)ethyl]-4-chlorophenyl}piperidine-1-carboxylate (3-8) as a pale yellow foam (4.1 g). If desired, traces of the minor R-enantiomer could be removed using preparative chiral high pressure liquid chromatography on CHIRALPAK AD Phase, (7.5% ethano/heptanes as eluent) to give in order of elution: R-enantiomer as a colorless solid followed by the S-enantiomer as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[K].[CH3:25]C(C)([O-])C.CI.[Cl-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH3:25])[C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(Nc1cccc2ccccc12)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CN(C(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.2 g (0.01 mol) of 4-chloro-3-nitro-N-(naphthalen-1-yl)-benzamide and 1.1 g (0.01 mol) of potassium-tert.-butoxide are dissolved in 50 ml dimethylsulphoxide and stirred for 30 minutes at ambient temperature. Then 1 ml methyl iodide is added thereto and the mixture is stirred for a further 3 hours at ambient temperature. The solution is poured onto saturated sodium chloride solution and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12](Cl)=[O:13])([CH3:3])[CH3:2].[N+:15](=[CH2:17])=[N-:16]>C(Cl)Cl.CCOCC>[N+:15](=[CH:17][C:12](=[O:13])[CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[N-:16]
Reactant: C=[N+]=[N-]
Reactant: CC(C)c1ccccc1CCC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1ccccc1CCC(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
A solution of 3-(2-isopropylphenyl)propanoyl chloride (crude, 10.5 mmole) in methylene chloride was slowly added to a solution of diazomethane (generated from 6.95 g of 1-methyl-3-nitro-1-nitrosoguanidine) in ether (50 ml) cooled in an ice bath. The mixture was then warmed up to room temperature and stirred overnight. The mixture was concentrated in vacuo and purified by column chromatography (20% ethyl acetate/hexanes) to give 1-diazo-4-(2-isopropylphenyl)butan-2-one (1.87 g, 82% over 2 steps) as a bright yellow oil. 1H NMR (CDCl3) δ 7.10-7.30 (4H, m, phenyl), 5.21 (1H, broad s, diazo), 3.15 (1H, m, CH of iPr), 3.00 (2H, t, benzylic), 2.57 (2H, m), 1.24 (6H, d, 2 CH3 of iPr). Step 3:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20]>>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH:20][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: CN(C)CCCN
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCCCN(C)C)CCCC2=O
Yield: 82.9 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and N1,N1-dimethylpropane-1,3-diamine 0.21 g (2.1 mmol) was reacted to give 0.23 g (83%) of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[N:26]4[CH:27]=[CH:28][N:29]=[C:25]4[CH:24]=[CH:23][CH:22]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].C1C(=O)N([Cl:39])C(=O)C1.O>C(O)C>[Cl:39][C:27]1[N:26]2[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:13])([F:12])[F:14])=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=4)[O:20][N:19]=3)=[CH:22][CH:23]=[CH:24][C:25]2=[N:29][CH:28]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4nccn34)no2)cc1C(F)(F)F)C(F)(F)F
Solvent: CCO
Solvent: O
Product: CC(Oc1ccc(-c2nc(-c3cccc4ncc(Cl)n34)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Reaction time: 15 h
Yield: 68.3 %

Procedure:
To a solution of 5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (150 mg) in ethanol was added NCS (67 mg) at room temperature, followed by stirring at 80° C. for 15 hours. To the reaction solution was added water, followed by extraction with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. It was purified by silica gel column chromatography (n-hexane:EtOAc=90:10 to 75:25) to obtain 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (110.4 mg) as a white solid. To a solution of 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine (100 mg) in methylene chloride (2 ml) was added dropwise 10 equivalents of 4M HCl/dioxane at room temperature. After stirring at room temperature as it was for 1 hour, it was concentrated under reduced pressure. It was powdered/washed with diisopropyl ether, and then collected by filtration to obtain 3-chloro-5-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}imidazo[1,2-a]pyridine hydrochloride (102.6 mg) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH3:20].[OH2:21]>COCCOCCOC>[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH:20]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O
Reactant: Cc1nc2ccccc2n1C
Reactant: O=C(Cl)c1ccccc1
Solvent: COCCOCCOC
Product: Cn1c(C(C(=O)c2ccccc2)C(=O)c2ccccc2)nc2ccccc21
Temperature: 150 °C
Reaction time: 6 h

Procedure:
Benzoyl chloride (1.68 g) was added to a mixture of 1,2-dimethylbenzimidazole (0.5 g) and TEA (1.21 g) in Diglyme (5 ml) at room temperature. The reaction mixture was stirred at 120° C. for 1 hour and successively at 150° C. for 6 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain crude crystals from the fractions eluted with chloroform. The crystals were recrystallized from ethyl acetate to obtain 2-(1-methyl-1H-benzimidazol-2-yl)-1,3-diphenylpropane-1,3-dione (0.81 g). Hereinafter, the compound of Example 115 was obtained similarly.
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]C)(=[O:5])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C(C1C=NC2C(C=1Cl)=CC=CC=2O)(=O)CCC.[F:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[C:43]([CH3:48])[CH:42]=1>ClCCl.O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:45][C:44]1[CH:46]=[CH:47][C:41]([F:40])=[CH:42][C:43]=1[CH3:48])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1cc(F)ccc1N
Agent: BrB(Br)Br
Agent: CCCC(=O)c1cnc2c(O)cccc2c1Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 3-butyryl-4-chloro-8-methoxyquinoline (131.9 g, 0.5 mol) in dichloromethane (1 liter) was cooled to -78°, then boron tribromide (142 ml, 1.5 mol) added slowly over 10 minutes. The mixture was warmed slowly to 0°, stirred 2 hours, then allowed to warm to room temperature overnight. After recooling in ice the reaction was quenched cautiously with water, then the resulting solid filtered off and dried. This was heavily contaminated with boron-containing impurities, but was used without purification. Crude 3-butyryl-4-chloro-8-hydroxyquinoline (64 g) and 4-fluoro-2-methylaniline (16.7 ml, 0.15 mol) were dissolved in dioxan (300 ml), heated on a steam bath for 2 hours, then left to stand overnight. The dioxan was evaporated, dichloromethane and aqueous sodium bicarbonate added, the mixture stirred until all the solid had dissolved, then the organic layer dried and evaporated. Recrystallisation from methanol gave 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxy-quinoline (37 g), m.p. 121°-122°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[O-:11][C:12]#[N:13].[Na+].C(O)(C(F)(F)F)=O>C1C=CC=CC=1.[OH-].[Na+]>[C:12](=[O:11])([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[NH2:13]
Reactant: N#C[O-]
Reactant: OCCc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of commercially available 2-(2-bromophenyl)ethanol (1 eq.) in Benzene (0.85M) at room temperature was added sodium cyanate (2.1 eq) then TFA (2.2 eq) dropwise. The mixture was stirred at room temperature for 6 h, poured in aqueous NaOH (1N) and extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Recrystallization in Et2O afforded the desired compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[S:26][N:25]=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1C(=O)C2C(=CC=CC=2)C1=O.CC(O)C.O.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[S:26][N:25]=[CH:24][CH:23]=2)=[C:6]([CH:19]=1)[CH2:7][NH2:8]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1OCc1ccns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(Cl)ccc1OCc1ccns1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-[5-chloro-2-(isothiazol-5-ylmethoxy)benzyl]isoindole-1,3-dione (464 mg, 1.20 mmol), 2-propanol (20 mL), water (2.5 mL), and THF (25 mL) was added NaBH4 (295 mg, 7.80 mmol). The reaction was stirred at room temperature for 16 h. The organic solvent was then removed by rotary evaporation and the resulting oil was taken up in CH2Cl2 (50 mL). The organic layer was washed with water (50 mL), saturated aqueous NaCl (50 mL), dried over NaSO4, filtered, and concentrated on a rotary evaporator. This material was taken up in 2-propanol (20 mL), glacial acetic acid (1.2 mL), and water (1.0 mL) and the reaction was heated to 80° C. in a sealed tube for 24 h. The organic solvent was then removed by rotary evaporation and the resulting oil was taken up in CH2Cl2 (50 mL). The organic layer was washed with water (50 mL), saturated aqueous NaCl (50 mL), dried over NaSO4, filtered, and concentrated on a rotary evaporator to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCl)CC)C.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]Cl)[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCCN1CCOCC1
Reactant: Clc1ccc(CN2CCNCC2c2ccccc2)cc1Cl
Agent: CCN(CC)CCCl
Product: Clc1ccc(CN2CCN(CCN3CCOCC3)CC2c2ccccc2)cc1Cl

Procedure:
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 3b, is alkylated by following the procedure described in Example 3c whereby, in place of diethylamino ethylchloride, the equimolecular amount of morpholino ethylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 230° C./0.04 mm. Hg.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:16]C(OC(Cl)C)=O>ClCCCl>[ClH:16].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1
Reactant: N#CC1CCN(Cc2ccccc2)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: N#CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
11.0 g of 1-benzyl-4-piperidinecarbonitrile was dissolved in 100 ml 1,2-dichloroethane, 7.1 ml 1-chloroethyl chloroformate was added thereto under ice-cooling. The mixture was stirred at room temperature for 15 min, and then heated under reflux for 1 hr and 20 min. After evaporating, 50 ml methanol was added thereto and it was heated under reflux for 1 hr. The reaction solution was evaporated, and the crystalline residue was washed with ethyl acetate and collected by filtration to give 8.0 g of 4-piperidinecarbonitrile hydrochloride as white crystals.
Reaction SMILES: [BH4-].[Na+].C(O)C.[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=1[O:27][CH3:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([CH2:20][CH:21]([N+:24]([O-:26])=[O:25])[CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=1[O:27][CH3:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCC(=Cc1ccc(OC)c(OCc2ccccc2)c1)[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(Cc1ccc(OC)c(OCc2ccccc2)c1)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
Finely powdered sodium borohydride (3.38 g, 89.3 mmol) was covered with THF (40 mL) and ethanol (40 mL) and cooled to 0° C. 257 (13.95 g, 44.5 mmol) was dissolved in THF (120 mL) and added slowly over 2 h via dropping funnel. The reaction mixture was stirred for 4 h at 0° C. and then for 60 h at room temperature. Hydrochloric acid (2M, 45 mL) was added very carefully. The two layers were separated and the organic layer was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2: 100 g, hexane/ethyl acetate 90:10) to give the title compound (8.83 g, 62%) as yellow solid. 1H NMR (270 MHz, CDCl3) δ 0.91 (3H, t, J 7.4, CH2CH3), 1.62-1.79 (1H, m, one of CHCH2CH3), 1.81-2.00 (1H, m, one of CHCH2CH3), 2.88 (1H, dd, J 14.3, 6.0, one of ArCH2CH), 3.12 (1H, dd, J 14.3, 8.3, one of ArCH2CH), 3.84 (3H, s, OCH3), 4.42-4.55 (1H, m, CHNO2), 5.11 (2H, OCH2Ph), 6.65 (1H, d, J 1.9, CH), 6.69 (1H, dd, J 8.2, 1.9, CH), 6.80 (1H, d, J8.0, CH), 7.25-7.45 (5H, m, OCH2C6H5).
Reaction SMILES: [CH2:1]([Al:3](CC)[CH2:4][CH3:5])[CH3:2].[F:8][C:9]([F:13])([F:12])[CH2:10][OH:11]>>[F:8][C:9]([F:13])([F:12])[CH2:10][O-:11].[CH2:1]([Al+:3][CH2:4][CH3:5])[CH3:2]
Reactant: OCC(F)(F)F
Reactant: CC[Al](CC)CC
Product: CC[Al+]CC
Product: [O-]CC(F)(F)F
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 81.36 g (0.71 mole) of triethylaluminum was placed in a flask immersed in a chilled oil bath (-20° C.). In an addition funnel there was placed 77 g (0.77 mole) of 2,2,2-trifluoroethanol. Temperature of the reaction mixture was permitted to rise to 10° C., at which point addition of the trifluoroethanol commenced. The temperature was slowly raised by increasing the speed of addition and at the end of the addition of the alcohol was 40° C. The total time consumed was one hour.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([O:16]CC)=[O:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CCO.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([OH:16])=[O:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1ncn(-c2ccc(F)c(F)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn(-c2ccc(F)c(F)c2)n1
Temperature: 50 °C
Yield: 81.7 %

Procedure:
To a solution of ethyl 1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylate (0.30 g, 1.2 mmol, 1 eq) in 5 mL of EtOH/H2O (1.5:1) was added NaOH (0.095 g, 2.4 mmol, 2 eq). The reaction mixture was heated at 50° C. for 1 h then quenched with 0.20 mL of cone. HCl. The contents were filtered and washed with EtOAc then with MeOH and the MeOH filtrate was dried with Na2SO4 and concentrated in vacuo to afford 1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (0.22 g, 0.98 mmol, 84%).