Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][CH:16]=1)[C:7]=2[CH3:29])=O.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN1CCCC1=O.C(O)(=O)C>[OH:37][C@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]1[NH:30][CH2:1][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:28])[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:19][CH:20]=1)[C:7]=2[CH3:29]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Cc1c(NC(=O)c2ccc(OCC3CCCO3)cc2)ccc2cc(C=O)cnc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Cc1c(NC(=O)c2ccc(OCC3CCCO3)cc2)ccc2cc(CN[C@H]3CCCC[C@@H]3O)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
N-(3-Formyl-8-methylquinolin-7-yl)-4-(tetrahydrofuran-2-ylmethoxy)benzamide (1.0 g) obtained in Reference Example 2% and trans-2-aminocyclohexanol (546 mg) were suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (2.35 g) was added and the mixture was stirred at room temperature for 3 hr. 1N Aqueous sodium hydroxide solution was added to quench the reaction and basify the mixture. The mixture was partitioned and extracted with ethyl acetate, the organic layer was added to a solution of citric acid (4.0 g) in water (40 mL)-dimethyl sulfoxide (20 mL), and the mixture was washed with ethyl acetate. 1N Aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (395 mg, yield 32%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:5][CH:4]=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CC1=CC=C(c2ccccc2)C(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(CC(=O)O)=CC=C1c1ccccc1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of 2,2-dimethyl-(4-biphenyl)acetic acid, methyl ester (4.18 g, 16.5 mmol) and sodium hydroxide (3.29 g) in ethanol (57 mL) and water (25 mL) was heated under reflux for 18 hours. The mixture was cooled to rt and acidified to pH 2 with 6N HCl. The precipitate was collected by filtration and recrystallized from ether to give 2,2-dimethyl-(4-biphenyl)acetic acid (1.37 g 5.7 mmol, 35%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=1.C(N(CC)CC)C.[CH2:18]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH3:34])[C:23]=1[C:24](Cl)=[O:25])[CH2:19][CH3:20]>O1CCCC1>[CH3:8][C:7]([C:4]1[CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]2[C:27]([O:31][CH2:32][CH2:33][CH3:34])=[CH:28][CH:29]=[CH:30][C:22]=2[O:21][CH2:18][CH2:19][CH3:20])[O:6][N:5]=1)([CH3:10])[CH3:9]
Reactant: CCCOc1cccc(OCCC)c1C(=O)Cl
Reactant: CC(C)(C)c1cc(N)on1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1cccc(OCCC)c1C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 25 °C
Yield: 10.9 %

Procedure:
To a stirred solution of 2.8 g of 5-amino-3-(1,1-dimethylethyl)isoxazole in 40 ml of tetrahydrofuran containing 4.5 ml of triethylamine was added dropwise over ten minutes a solution of 4.88 g of 2,6-di-n-propoxybenzoyl chloride in 10 ml of tetrahydrofuran. Following the addition, the reaction mixture was heated at reflux for seventy-two hours. The reaction mixture was then cooled to room temperature and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in a mixture of dichloromethane and water, and the organic layer was separated, washed with fresh water, dried, and the solvent was removed by evaporation to provide an oil. The oil was crystallized from Skelly B and diethyl ether to provide 750 mg of N-[3-(1,1-dimethylethyl)-5-isoxazolyl]-2,6-di-n-propoxybenzamide. M.P. 85°-87° C. Yield 10%.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH:11]([C:13]1[N:14]=[N:15][C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:17]([CH3:19])[N:18]=1)[NH2:12]>CO.[OH-].[NH4+]>[CH:1]([NH:12][NH:11][C:13]1[N:14]=[N:15][C:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:17]([CH3:19])[N:18]=1)=[O:3]
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(NNC=O)nnc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Formic acid (5 ml) was added dropwise to acetic anhydride (10 ml) with stirring under ice cooling, and stirred at 50° C. for 15 minutes. To the solution was added 3-hydrazino-5-methyl-6 -phenyl-1,2,4-triazine (5g) with stirring under ice cooling, and the stirring was continued for 50 minutes under ice cooling. The reaction mixture was poured into ice water, and the resultant precipitates were collected by filtration and washed with water. The above obtained solid was dissolved in methanol (100 ml), the solution was treated with 28% ammonium hydroxide (14 drops) and evaporated to give white powder of 3-(2-formylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (4.505 g).
Reaction SMILES: NC1C(OC2C=CC=CC=2)=NC=C(OC)N=1.N([O-])=O.[Na+].O[C:22]1[C:27]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:26][CH:25]=[C:24]([O:34][CH3:35])[N:23]=1.P(Cl)(Cl)([Cl:38])=O>>[Cl:38][C:22]1[C:27]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:26][CH:25]=[C:24]([O:34][CH3:35])[N:23]=1
Reactant: COc1cnc(N2CCOCC2)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: COc1cnc(Oc2ccccc2)c(N)n1
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cnc(N2CCOCC2)c(Cl)n1

Procedure:
The 2-amino substituent of Step A product when treated with sodium nitrite as described in Step E of Preparation 81 is converted to the 2-hydroxy group. Treatment of the 2-hydroxy-3-morpholino-6-methoxypyrazine with phosphorus oxychloride by Preparation 13, Step B method, gives 2-chloro-3-morpholino-6-methoxypyrazine.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18].[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:16]([NH:19][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1)[C:17]#[CH:18]
Reactant: C#CCN
Reactant: O=C(Nc1nnn[nH]1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCNc1ccc(C(=O)Nc2nnn[nH]2)cc1

Procedure:
A mixture of 20 g (0.097 mol) of 4-fluoro-N-1H-tetrazol-5-ylbenzamide, 12.8 ml (0.193 mol) of propargylamine, 5.6 g of anhydrous potassium fluoride, and 13 g of potassium carbonate, in 320 ml of dimethylsulfoxide is heated at 50°-70° C. for six to twenty hours. The reaction is poured into water and the precipitate is collected, washed with water, and dried in vacuo to give the title compound.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:8][CH2:9][C:10]1[N:11]([CH2:23][CH2:24][C:25]([O:27]CC)=O)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH3:7]>O>[CH2:6]([O:8][CH2:9][C:10]1[N:11]([CH2:23][CH2:24][C:25]([NH2:5])=[O:27])[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH3:7]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Agent: CC(=O)[O-]
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CCC(N)=O
Temperature: 125 °C
Reaction time: 8 h

Procedure:
Ammonium acetate (7 g) and ethyl 3-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (5.0 g, 15 mmol, prepared in Part A of Example 23) were stirred overnight at 125° C. in a sealed vessel. The reaction was allowed to cool to ambient temperature, and water (20 mL) was added. A precipitate formed and was isolated by filtration, washed with saturated aqueous sodium bicarbonate, and dried to provide 2.4 g of 3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propanamide as a tan powder.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]1([CH3:66])[CH:53]=[CH:52][C:51]([C:54]([O:56][C:57]2[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=2[C:59](O)=[O:60])=[O:55])=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:59](=[O:60])[C:58]3[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=3[O:56][C:54]([C:51]3[CH:50]=[CH:49][C:48]([CH3:66])=[CH:53][CH:52]=3)=[O:55])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1ccc(C(=O)Oc2ccccc2C(=O)O)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
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3OC(=O)c3ccc(C)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-[4-toloyloxy]benzoic acid (8.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][NH:13][C:12]1=[S:16].[C:17]([O-])(=[O:19])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C1C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[C:14]([CH:17]=[O:19])[NH:13][C:12]1=[S:16]
Reactant: S=c1[nH]ccn1C1CCc2ccccc2C1
Reactant: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: O=Cc1cn(C2CCc3ccccc3C2)c(=S)[nH]1
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A suspension of 4-(1R,2R,3S,4)-tetrahydroxybut-1-yl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.252 g, 0.72 mmol) and lead tetraacetate (0.851 g, 1.92 mmol) in 15 mL of 33% acetic acid/benzene was stirred until the mixture was homogenous and 30 minutes. The reaction mixture was poured into 125 mL of saturated sodium carbonate solution and the mixture was filtered. The organic layer was separated, dried over magnesium sulfate and concentrated. The residue was dissolved in 40 mL of THF and 2 mL of sulfurous acid (6% SO2). Evaporation of the solvent gave 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde (0.15 g, 0.59 mmol), m.p. 206°-210° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[H-].[Na+].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:22]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[C:22]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:44])=[O:45])=[CH:39][CH:38]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: CCCCC(CC)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(CC)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of 2-ethyl-1-hexanol (65 mg, 0.5 mmol) in THF (15 mL) at room temperature was added NaH (60% oil suspension) (20 mg, 0.5 mmol) and after 10 minutes 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (193 mg, 0.5 mmol) was added. The resulting mixture was stirred at room temperature for the next 2 hours. The mixture was quenched with 10% citric acid and extracted with ethyl acetate. The extract was washed with water, brine, dried with MgSO4, and purified by chromatography (silica gel, 2:1 hexanes-ethyl acetate) to provide the desired product (yield: 140 mg, 60%). mp 120-122° C. 1H NMR (300 MHz, DMSO-d6) δ 0.75 (m, 6H), 1.1 (m, 6H), 1.20 (quintet, J=7 Hz, 2H), 1.44 (m, 1H), 3.27 (s, 3H), 4.30 (d, J=6 Hz, 2H), 7.37 (t, J=9 Hz, 2H), 7.65 (m, 2H), 7.89 (d, J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.18 (s, 1H). MS (APCI+) m/z 473 (M+H)+; (APCI−) m/z 507 (M+Cl)−. Anal. calc. for C25H29FN2O4S.0.5H2O: C, 62.35; H, 6.27; N, 5.87. Found: C, 62.22; H, 6.14; N, 6.22.
Reaction SMILES: Cl.[C:2]([N:5]1[C:13]2[C:8](=[C:9]([CH3:19])[C:10]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([CH3:14])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[CH2:20](O)[CH3:21]>>[C:2]([N:5]1[C:13]2[C:8](=[C:9]([CH3:19])[C:10]([CH2:15][C:16]([O:18][CH2:20][CH3:21])=[O:17])=[C:11]([CH3:14])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCc2c1cc(C)c(CC(=O)O)c2C
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1c(C)cc2c(c1C)CCN2C(C)=O
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of hydrogen chloride (665 g) in ethanol (2000 ml) was added (1-acetyl-4,6-dimethylindolin-5-yl)acetic acid obtained in Example 15 (150 g), and the resulting mixture was stirred for 30 minutes at 45–50° C., and then an ethanol fraction containing hydrochloric acid (1000 ml) was evaporated off in vacuo. At about 20° C., water (2000 ml) was added, and crystals precipitated were separated by filtration and dried to afford 1-acetyl-5-ethoxycarbonylmethyl-4,6-dimethylindoline (146 g, yield: 87%), of which the physico-chemical properties were the same as those of the product obtained in Example 2.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]2[CH2:19][N:18]([C:20](=[O:24])[CH:21]([F:23])[F:22])[CH2:17][CH2:16][O:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][CH:21]([F:23])[C:20]([N:18]1[CH2:17][CH2:16][O:15][C@H:14]([CH2:13][NH:12][C:10]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=[C:2]([C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:43][CH:42]=3)[N:11]=2)[CH2:19]1)=[O:24]
Reactant: O=C(C(F)F)N1CCO[C@H](CNc2nc(Cl)cc3nccnc23)C1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2ccc(-c3cc4nccnc4c(NC[C@@H]4CN(C(=O)C(F)F)CCO4)n3)cc2)CC1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-1-(2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholino)-2,2-difluoroethanone (72 mg, 0.2 mmol) in dioxane/H2O (5 mL/0.5 mL) was added Cs2CO3 (98 mg, 0.3 mmol), Pd (PPh3)4 (46.2 mg, 0.04 mmol) and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (72.5 mg, 0.24 mmol). The mixture was stirred at 110° C. for 24 hours under N2. The reaction was filtered, concentrated and purified on column (CH2Cl2:MeOH=20:1) to give yellow solid. MS (m/z): 498 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[NH:39]1[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]1>>[O:45]=[S:42]1(=[O:46])[CH2:43][CH2:44][N:39]([CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:40][CH2:41]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: O=S1(=O)CCNCC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCS(=O)(=O)CC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and thiomorpholine-1,1-dioxide were converted to the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9](/[CH:12]=[N:13]/[OH:14])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[OH:14][N:13]=[C:12]([Cl:19])[C:9]1[C:8]([C:15]([F:17])([F:18])[F:16])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C/c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: ON=C(Cl)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbaldehyde oxime (step C, 0.360 g, 1.41 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature was added N-chlorosuccinimide (0.281 g, 2.11 mmol) in one portion. The resulting green, homogeneous reaction mixture was stirred at room temperature for 30 min. An additional 220 mg of NCS was added, and the reaction mixture was stirred for an additional 30 min. The reaction mixture was diluted with ethyl acetate (35 mL), washed with a 10% aqueous solution of lithium chloride (2×), and brine. The combined aqueous layers were extracted with ethyl acetate (35 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a pale green solid which was triturated with ether and filtered. The white solid was rinsed with ether, and the filtrate was concentrated under reduced pressure and dried under reduced pressure overnight to give a quantitative yield of N-hydroxy-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbimidoyl chloride as a green solid. The compound had an HPLC ret. time=2.72 min. (condition A); LC/MS M+1=291.0. 1H NMR (400 MHz, CDCl3) δ ppm 7.51-7.58 (m, 2H), 7.58-7.64 (m, 1H), 7.70 (d, J=7.48 Hz, 2H), 8.04 (s, 1H), and 9.69 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.[OH:31][C:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:37]([C:36]1[C:32]([O:31][CH2:2][C:3]2[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=2)=[N:33][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=1)=[O:38]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.51 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.21 g), potassium carbonate (0.15 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (0.55 g, yield 86%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 157-158° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C([Li])CCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:30]
Reactant: O=Cc1ccccc1
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cn1c(C(O)c2ccccc2)nc2cnc3ccccc3c21
Temperature: -78 °C

Procedure:
1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinoline (4 g; 0.017 mole) was dissolved in 50 mL of tetrahydrofuran then cooled to -78° C. A 7.75 mL portion of n-butyl lithium (2.5M in hexanes) was added dropwise to the cooled solution. At 15 minutes post addition, benzaldehyde (2.7 mL; 0.027 mole) was added and the reaction mixture was allowed to warm slightly. The reaction was quenched with water then diluted with ethyl ether. The ether was separated, dried with magnesium sulfate then concentrated under vacuum. The resulting residue was purified by silica gel chromatography using 5% methanol in methylene chloride as the eluent to give an oily yellow solid. This material was recrystallized from methylene chloride/hexane to provide 1-(2-Methylpropyl)-α-phenyl-1H-imidazo[4,5-c]quinoline-2-methanol as a white crystalline solid, m.p. 160°-166° C. Analysis: Calc'd: C, 76.1; H, 6.4; N, 12.7; Found: C, 75.9; H, 6.3; N, 12.7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]Br.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][S:11]([O-:14])(=[O:13])=[O:12].[Na+:15]
Reactant: BrCCc1ccccc1Br
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCc1ccccc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A solution of 1-bromo-2-(2-bromoethyl)benzene (6.23 g, 23.6 mmol) in ethanol (20.5 mL) was added to a solution of sodium sulfite (3.12 g, 24.7 mmol) in water (25.0 mL). The mixture was heated at 100° C. for 24 hours. The reaction mixture was filtered, and the filtrate was then left to stand at 3° C. overnight. The resulting white crystals were collected by filtration and dried to give sodium 2-(2-bromo-phenyl)ethanesulfonate (4.00 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:7][S:8][C:9]=1S(C)(=O)=O)=[O:4].C[N:19](C=O)C.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:7][S:8][C:9]=1[NH2:19])=[O:4]
Reactant: COC(=O)c1c(S(C)(=O)=O)nsc1S(C)(=O)=O
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(S(C)(=O)=O)nsc1N
Yield: 75 %

Procedure:
In a 3 neck flask fitted with a condenser, compound 16 (1 g, 3.33 mmol) is dissolved in THF (20 mL) and DMF (2 mL) and warmed to 50° C. Ammonia gas is then bubbled into the reaction mixture for 16 hrs. The solvent is then removed in vacuo to provide a crude solid. Water is added to the solid and the mixture is then filtered and washed with water (2×) followed by methylene chloride (5 mL×2) to provide 17 (588 mg, 75%) as a yellow powder. 1H NMR (d6 DMSO): δ 8.11 (2H, br. s), 3.74 (3H, s), 3.30 (3H, s). LRMS (M+): 237.1, (M−): 235.0.