Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][C:14](O)=[O:15])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][OH:15])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1nc(-c2ccccc2)no1
Solvent: CO
Solvent: C1CCOC1
Product: OCCCc1nc(-c2ccccc2)no1
Yield: 56.3 %

Procedure:
A solution of 2.5 ml of borane-methyl sulfide complex in 2M solution in tetrahydrofuran, 920 mg of 3-(3-phenyl-1,2,4-oxadiazol 5-yl)-propanoic acid (prepared by SRIRASTAVA et al., J. Heterocycl. Chem., Vol. 21, p. 1193 (1984) and 20 ml of tetrahydrofuran was stirred for one hour at ambient temperature. 10 ml of methanol were added over 5 minutes and evaporation to dryness under reduced pressure was carried out. The residue was chromatographed on silica (eluant: ethyl acetate - hexane (6-4)) to obtain 485 mg of the expected product.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: [N-]=[N+]=NCc1ccc2ncccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc2ncccc2c1
Yield: 25.5 %

Procedure:
6-(azidomethyl)quinoline (320 mg) and triphenylphosphine (880 mg) were dissolved in 7 mL THF. The reaction mixture was treated with 0.5 mL of H2O and refluxed for 7 hours. The reaction mixture was cooled and partitioned between Et2O and 1N HCl. The aqueous portion was then treated with 1N NaOH until basic and extracted into EtOAc. The organic portion was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (70 mg) as a brown oil. MS(CI) m/e 159 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]2[NH:15][N:16]=[C:17]([CH3:18])[C:12]2=[C:11]([CH2:19][N:20]2[C:25]([CH3:27])([CH3:26])[CH2:24][N:23]([C:28](=[O:32])[CH2:29][O:30]C)[C:22]([CH3:34])([CH3:33])[CH2:21]2)[CH:10]=1.FC1C=C(O)C=CC=1C1N=C2NN=C(C)C2=C(CN2CC(C)(C)NCC2(C)C)C=1.C(OCC(Cl)=O)(=O)C>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]2[NH:15][N:16]=[C:17]([CH3:18])[C:12]2=[C:11]([CH2:19][N:20]2[C:25]([CH3:27])([CH3:26])[CH2:24][N:23]([C:28](=[O:32])[CH2:29][OH:30])[C:22]([CH3:34])([CH3:33])[CH2:21]2)[CH:10]=1
Reactant: COCC(=O)N1CC(C)(C)N(Cc2cc(-c3ccc(O)cc3F)nc3[nH]nc(C)c23)CC1(C)C
Agent: CC(=O)OCC(=O)Cl
Agent: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)NCC3(C)C)c12
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)N(C(=O)CO)CC3(C)C)c12

Procedure:
The title compound was prepared in analogy to Example 75 (1-{4-[6-(2-Fluoro-4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2,5,5-tetramethyl-piperazin-1-yl}-2-methoxy-ethanone) using 3-fluoro-4-[3-methyl-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol and acetoxyacetyl chloride.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:37]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[CH:36][C:12]2[NH:13][C:14]([C:16]3[C:20]([NH:21][C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:19][N:18](C4CCCCO4)[N:17]=3)=[N:15][C:11]=2[CH:10]=1>ClCCl>[F:8][C:9]1[C:37]([N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)=[CH:36][C:12]2[NH:13][C:14]([C:16]3[C:20]([NH:21][C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[O:23])=[CH:19][NH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1
Reactant: CN1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4NC(=O)N4CCCCC4)nc3cc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCCCC4)nc3cc2F)CC1
Temperature: 22 °C
Reaction time: 48 h
Yield: 55.3 %

Procedure:
0.6 mL of trifluoroacetic acid is added to a solution of 260 mg of piperidine-1-carboxylic acid [3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide in solution in 1.5 mL of dichloromethane. The reaction medium is stirred at 22° C. for 48 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. After evaporation, the reaction crude is purified by flash chromatography in an Intelliflash apparatus on an Analogix RS-12 cartridge. The elution is carried out in pure dichloromethane for 20 min and then in dichloromethane containing 10% of ammoniacal methanol. 120 mg of N-{3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are obtained in the form of a beige solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.45 to 1.70 (m, 6H); 2.90 (s, 3H); 3.07 (m, 2H); 3.29 (m, 2H); 3.45 (m, 4H); 3.55 (m, 4H); 7.31 (d, J=8.0 Hz, 1H); 7.57 (d, J=11.5 Hz, 1H); 8.02 (s, 1H). EI mass spectrum: m/z=426, M+., m/z=341 (M−C5H11N)+; m/z=114 CF3CO2H+. relative to TFA; m/z=84 C5H10N+; m/z=69 CF3+ relative to TFA; m/z=45 CO2H+ relative to TFA base peak, m/z=43 C2H5N+.; m/z=41 C3H5+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>C1COCC1.C(O)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1ccc(Nc2ccnc(Cl)n2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a stirred solution of N-(4-aminophenyl)acetamide (5 g, 0.033 mol) and NaHCO3 (5.6 g, 0.067 mol) in THF (20 mL) and ethanol (80 mL) was added 2,4-dichloropyrimidine (5.95 g, 0.04 mol) at room temperature. The reaction was gradually heated to 85° C. After the reaction was stirred for four hours at 85° C. under N2, the suspension was filtered and washed thoroughly with ethanol. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with EtOAc to remove excess 2,4-dichloropyrimidine to yield 8.35 g (95.5% yield) of N-{4-[(2-chloropyrimidin-4-yl)amino]phenyl}acetamide as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[C:29](=[O:30])[N:28]([CH3:31])[C:21]4[N:22]=[C:23](SC)[N:24]=[CH:25][C:20]=4[CH:19]=3)[CH:15]=[CH:14][C:13]=2[F:32])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37][NH2:38].C1COCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[C:29](=[O:30])[N:28]([CH3:31])[C:21]4[N:22]=[C:23]([NH:38][CH3:37])[N:24]=[CH:25][C:20]=4[CH:19]=3)[CH:15]=[CH:14][C:13]=2[F:32])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c(=O)n(C)c2n1
Yield: 67 %

Procedure:
Using a procedure analogous to Example A1, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (55 mg, 0.100 mmol) and 2.00N methylamine in THF (4.00 mL, 8.0 mmol) were combined to provide 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (36 mg, 67% yield). 1H NMR (300 MHz, DMSO-d6): δ 2.90 (s, 3 H), 3.53-3.61 (m, 3 H), 7.26-7.31 (m, 2 H), 7.58-7.59 (m, 2 H), 7.60-7.75 (br. m, 1 H), 7.88 (s, 1 H), 8.10 (s, 1 H), 8.33-8.35 (m, 1 H), 8.64-8.77 (m, 2 H), 9.49 (s, 1H); MS (ESI) m/z: 521.0 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:27](OCC)=[O:28].[O-]CC.[Na+].Cl>C(O)C>[OH:28][CH:27]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: O=C1Cc2ccc(C(=O)c3cccc(NC(=O)c4cccs4)c3)cc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Temperature: 78 °C
Yield: 71 %

Procedure:
Thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.27 g, 3.504 mmol) and ethyl formate (0.85 mL, 10.52 mmol) were dissolved in anhydrous ethanol (10 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (3.90 mL, 10.45 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.971 g, 2.487 mmol, 71%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](Cl)=[O:14].C(=O)=O.[CH3:19][C:20](C)=O.C(OCC)C>ClCCl.CCCCCC>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH2:12][C:13](=[O:14])[CH2:20][CH2:19]2
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: CC(C)=O
Agent: O=C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCc2cccc(Cl)c2C1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
To a slurry of 46.5 gm (0.348 mole) AlCl3 in 400 mL dichloromethane at -78° C. was added a solution of 32.76 gm (0.174 mole) of the previously prepared o-chlorophenylacetyl chloride in 100 mL dichloromethane dropwise over 1 hour. The dry ice/acetone bath then was replaced with an ice/water bath and ethylene was bubbled into the reaction mixture during which time the temperature rose to 15° C. The ethylene addition was discontinued at the end of the exotherm and the reaction mixture was stirred at about 5° C. for 4 hours. Ice was then added to the reaction mixture to destroy aluminum complexes. Upon termination of the exotherm, the reaction mixture was diluted with 500 mL of water and stirred vigorously until all solids had dissolved. The phases were separated and the organic phase was washed with 3×400 mL 1N hydrochloric acid and 2×400 mL saturated aqueous sodium bicarbonate. The remaining organic phase was then dried over sodium sulfate and concentrated in vacuo to give a pale orange residue. The residue was dissolved in 1:1 hexane:diethyl ether and was poured over a flash silica column which was then eluted with 1:1 hexane:diethyl ether to give a light yellow residue which was crystallized from 4:1 hexane:diethyl ether to give 10.55 gm of the title compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([CH2:24][OH:25])[CH:20]=[C:19]2[CH3:26])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.CCCCCC.O>[CH:11]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([CH:24]=[O:25])[CH:20]=[C:19]2[CH3:26])([CH3:13])[CH3:12]
Reactant: Cc1cc(CO)nc2c(C(C)C)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C=O)nc2c(C(C)C)cccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
Methyl 8-isopropyl-4-methyl-2-quinolinecarboxylate was dissolved in 10 ml of tetrahydrofuran, followed by the dropwise addition of a 1M hexane solution of diisobutyl aluminum hydride at 0° C. under a nitrogen gas atmosphere. After stirring for 2 hours, saturated aqueous ammonium chloride was added to terminate the reaction. Water was added to the reaction mixture and the precipitate so formed was filtered. The filtrate was concentrated under reduced pressure, whereby 107 mg of 8-isopropyl-4-methylquinoline-2-methanol were obtained in the form of a colorless oil. Under a nitrogen gas stream, a solution of 210 μl of dimethyl sulfoxide in 0.5 ml of dichloromethane was added dropwise to a solution of 172 μl of oxalyl chloride in 1 ml of dichloromethane at −60° C. under a nitrogen gas stream, followed by stirring for 5 minutes. To the reaction mixture, a solution of 107 mg of 8-isopropyl-4-methyl-2-quinolinemethanol in 2 ml of dichloromethane was added dropwise, followed by stirring for 15 minutes, dropwise addition of 1 ml of triethylamine and stirring for 5 minutes. The reaction mixture was raised to room temperature and stirred for one hour. Water was added to the reaction mixture and the resulting solution was extracted with dichloromethane. The organic layer was successively washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 3% ethyl acetate/n-hexane), whereby 87 mg of the title compound were obtained in the form of a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7]N=[CH:5][CH:4]=1)=[CH2:2].[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[CH2:18])=[CH2:10].[C:19](OOC(=O)C1C=CC=CC=1)(=[O:26])C1C=CC=CC=1>>[CH2:2]=[CH:1][C:3]1[CH:8]=[CH:7][C:19]([OH:26])=[CH:5][CH:4]=1.[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[CH2:18])=[CH2:10]
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: C=Cc1ccncc1
Agent: C=Cc1ccccc1C=C
Product: C=Cc1ccc(O)cc1

Procedure:
A 120×120 mm asbestos paper of the 0.025" L/FX36" type manufactured by John Mansville Co. was soaked with a mixture having the following molar composition: 66% of styrene (ST), 34% of divinylbenzene (DVB) and 1% (molar with respect to the total moles of monomers) of dibenzoylperoxide. The paper was then placed in a Teflon-lined press and held at 80° C. for 1 hour at a pressure of 0.5 kg/cm2 to produce a fluid-impervious sheet with a ST/DVB polymer load of 65% by weight. One side thereof was then coated with a mixture of the following composition by moles: 85% of 4-vinylpyridine (4VP), 15% of divinylbenzene (DVB) and 1% (molar ratio with respect to the total moles of monomers) of dibenzoylperoxide and was then held for 2.5 hours at 80° C. in a reactor to effect copolymerization to obtain a 0.03 mm-thick 4-VP/DVB polymer layer. A double-layer membrane was thus obtained which, after swelling for 10 hours in sym-dichloroethane at 70° C., was then sulfonated at -30° C. with liquid SO3 dissolved in liquid SO2 while raising the temperature to -10° C. over 20 minutes to obtain a sulfonated membrane exhibiting a different polarity on each side. Samples were taken from both sides of the membrane and the elemental analysis thereof gave the following results:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[O:11]([CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26](OCC)=[O:27])[CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[O:11]([CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH:26]=[O:27])[CH2:21]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1CCCN(CCOc2ccccc2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=CC1CCCN(CCOc2ccccc2)C1

Procedure:
Di-isobutylaluminium hydride (13.2 ml of 1.5M solution in toluene) was added to a mixture of ethyl N-(2-phenoxyethyl)piperidine-3-carboxylate (5.0 g) in dry THF (50 ml) at 0° C. under nitrogen with stirring. The mixture was quenched with water (5 ml) and then treated with saturated Rochelles salt solution. The mixture was stirred at room temperature for 30 minutes and then filtered. The filtrate was separated and the organic layer was washed, dried and evaporated to give N-(2-phenoxyethyl)piperidine-3-carbaldehyde as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=2)=[N:3]1.Cl.[N:21]([O-])=O.[Na+]>O>[CH3:1][N:2]1[C:6]([C:7]([F:9])([F:10])[F:8])=[CH:5][C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[N:18]=[N:21][NH:19][C:14]=3[CH:13]=2)=[N:3]1
Reactant: O=N[O-]
Reactant: Cn1nc(Oc2ccc(N)c(N)c2)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1nc(Oc2ccc3nn[nH]c3c2)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
The o-phenylenediamine obtained in step B (1.0 g,3.7 mmol) in water (20 cm3) was treated with concentrated hydrochloric acid (1.7 cm3) at room temperature. After stirring for 15 minutes more water (10 cm3) was added and the mixture cooled in an ice/salt bath to ~0° C. A solution of sodium nitrite (0.544 g, 7.9 mmol) in water (5.5 cm3) was added dropwise, with stirring, maintaining the temperature at ≤0° C. When the addition was complete the reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for a further 2 hours. The mixture was extracted several times with ethyl acetate and the combined extracts washed with water, dried (MgSO4) and evaporated leaving 6-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)benzotriazole as a buff solid m.p. 129°-131° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH:9]1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:29]([C@@H:9]2[CH2:10][C@H:11]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=3)[CH2:12][N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:31])[CH2:42][CH2:41]1)(=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Reactant: O=C(c1ccccc1)N1CCNCC1
Product: O=C(c1ccccc1)N1CCN(C(=O)[C@@H]2C[C@H](NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CN2Cc2ccccc2)CC1
Yield: 12.1 %

Procedure:
As described for Example 56d, 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid (65 mg, 0.146 mmol) was converted, using phenyl-piperazin-yl-methanone instead of 1-(3-trifluoromethyl-phenyl)-piperazine, to the title compound (10.9 mg, 12.1%) as light yellow oil. MS m/e=619.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9].C([Li])CCC.[Cl:15][Si:16](Cl)([CH3:18])[CH3:17]>O1CCCC1.CCCCCC>[CH3:1][C:2]1[C:3]([CH3:9])=[C:4]([CH3:8])[C:5]([Si:16]([CH3:18])([CH3:17])[Cl:15])([CH3:7])[CH:6]=1
Reactant: CC1=C(C)C(C)=C(C)C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1=CC(C)([Si](C)(C)Cl)C(C)=C1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Into a two-necked round-bottomed flask, the atmosphere in which was replaced with nitrogen, were charged 15 g of tetrahydrofuran, 12 g of n-hexane and 1.10 g of tetramethylcyclopentadiene. The mixture was cooled to 0° C. with stirring and 4.90 ml of n-butyl lithium (1.6M solution in n-hexane) (7.84 mmol as n-butyl lithium) was gradually added dropwise thereto over 20 minutes. The obtained reaction mixture in the form of a white slurry was stirred for at 0° C. for 3 hours, and a pre-cooled tetrahydrofuran (10 g) solution containing 1.01 g (7.84 mmol) of dichlorodimethylsilane was added in several divided portions. The mixture was then gradually heated to room temperature.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([O-:12])(=[O:11])=[S:10].[K+]>C(O)C.CCCCCC>[CH2:1]([O:12][S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[S:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Reactant: ClCc1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=S)OCc2ccccc2)cc1
Yield: 77.6 %

Procedure:
The title compound was prepared as described in General Method 2 using 0.05 mol of benzyl chloride, 0.05 moles of potassium thiotosylate in 150 mL of ethanol. The residue was dissolved in hexane and seeded with a crystal of the product to afford 10.8 g (77%) of benzyl-p-toluenethiosulfonate (m.p. 52°-56.5° C.). 1H NMR (CDCl3) δ 2.45 (s, 3 H), 4.26 (s, 2 H), 7.18-7.30 (m, 7 H), 7.74 (d, 2 H).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][CH2:5][C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH3:3]>O1CCOCC1.ClCCl>[CH2:2]([O:4][CH2:5][C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22]([NH2:1])=[O:23])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH3:3]
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCC(=O)Cl
Reactant: N
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOCc1nc2cnc3cccnc3c2n1CCCC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ammonia in dioxane (33 mL of 0.5 M) was added to a solution of 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanoyl chloride (4.64 mmol, prepared as described in Parts A and B of Example 38) in dichloromethane (20 mL), and the reaction was stirred overnight at ambient temperature. An analysis by HPLC indicated the reaction was incomplete; ammonia gas was bubbled through the solution for 10 minutes. The reaction was then stirred for one hour and concentrated under reduced pressure. The residue was triturated with water and isolated by filtration to provide 1.02 g of 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanamide. The filtrate was extracted with dichloromethane (3×20 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an additional 0.39 g of product. The combined solids were mixed with material from another run.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 98.4 %

Procedure:
To a 3-necked RBF (round bottomed flask) is added dichloromethane (2.4 L), (S)-4-benzyl-2-oxazolidinone (200 g, 1.13 moles) and N,N-Dimethyl-4-pyridinamine, (13.6 g; 111.32 mmoles). The flask is cooled in an ice water bath and triethylamine (472 mL; 3.39 moles) is added dropwise at 0° C. To the resulting solution is then added dropwise butanoyl chloride (152.2 mL; 1.46 moles) over 3 h, while keeping the temperature below 5° C. The reaction is then filtered and the filtrate is washed with 1M HCl (aq.) (500 ml×1) and saturated NaHCO3 (500 ml×1). The organic phase is dried over Na2SO4, filtered, and concentrated to afford the title compound (275 g, MS:[M+H]+=248.1 m/z).