Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:30][CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCC1CCCl
Reactant: COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(O)cc1
Agent: Cl
Product: COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCN2C)cc1
Yield: 44.5 %

Procedure:
The title compound was prepared as described in Example 3.D, using 2-(4-fluorophenyl)-1-(4-hydroxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (0.13 g, 0.36 mmol) and 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (0.079 g, 0.429 mmol) to provide the title compound (0.076 g, 45% yield): ES-MS (m/z) 475 [M+H]+.
Reaction SMILES: C([N:3](CC)CC)C.[C:8]1(C)[C:9]([C:14](Cl)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.C(OCC)(=O)C>C(Cl)Cl>[C:14]([NH2:3])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Yield: 337.5 %

Procedure:
To a solution of 391 mg (1 mmol) of 2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine in 3 mL of anhydrous methylene chloride, was added 0.42 mL (3 mmol) of triethylamine, then at room temperature, 0.12 mL (0.9 mmol) of orthotoluoyl chloride was added. After 15 hours at room temp ethyl acetate was added, washed with 5%. citric acid, saturated sodium bicarbonate, brine, dried, filtered and concentrated to afford 420 mg of crude material. This was chromatographed on 40 g of silica gel using 50% ethyl acetate/hexane to afford 368 mg of pure benzamide, N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl, m/e=516 (M+Li).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:6](F)[CH:5]=1.C(NC([O:23][CH2:24][CH3:25])=O)C>O1CCOCC1.O>[Br:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:6]([O:23][CH2:24][CH3:25])[CH:5]=1
Reactant: Fc1cc(Br)ccc1CN1CCCCC1
Reactant: CCNC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(Br)ccc1CN1CCCCC1
Temperature: 140 °C
Yield: 73.4 %

Procedure:
Sodium hydride (306 mg, 60%, 7.6 mmol) was added in portions to a solution of 1-(4-bromo-2-fluorobenzyl)-piperidine (520 mg, 1.9 mmol) and ethyl urethane (0.91 mL, 7.6 mmol) in dioxane (10 mL) under an atmosphere of nitrogen. The reaction mixture was then sonicated for 30 minutes until gas evolution ceased then heated at 140° C. overnight in a sealed tube. The reaction mixture was diluted with water and extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a colourless oil that was then purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (416 mg, 74%). 1H NMR (CDCl3, 400 MHz): 7.23 (d, J=8.1 Hz, 1H), 7.03 (dd, J=8.1, 1.9 Hz, 1H), 6.95 (d, J=1.9 Hz, 1H), 3.99 (q, J=7.0 Hz, 2H), 3.47 (s, 2H), 2.46-2.35 (m, 4H), 1.61-1.53 (m, 4H), 1.45-1.36 (m, 5H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)/[C:9](=[N:13]/[OH:14])/[CH2:8][CH2:7][CH2:6]2)=[CH2:2].C([N-]C(C)C)(C)C.[Li+].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28](OC)=O.S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[F:23][C:24]([F:35])([F:36])[C:25]1[CH:26]=[C:27]([C:28]2[O:14][N:13]=[C:9]3[C:10]4[C:5]([CH2:6][CH2:7][C:8]=23)=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:12][CH:11]=4)[CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1cccc(C(F)(F)F)c1
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.151 g, 0.808 mmol) was added 5 mL of toluene and the contents were concentrated under reduced pressure. The resulting solid was kept under high vacuum for 10 min. The white solid was cooled to 0° C. and lithium diisopropylamide (2.0 M, 0.8 mL, 1.61 mmol) was added drop wise over a period of 3 min. The reaction mixture was stirred at 0° C. for 20 min., then methyl 3-(trifluoromethyl)benzoate (0.087 mL, 0.539 mmol) was added dropwise over a period of 1 min. at 0° C. After 10 min. at 0° C., concentrated sulfuric acid (0.2 mL) was added dropwise at 0° C. and the reaction was stirred for 20 minutes. Water (2 mL) was added and the homogenous solution was heated at 60° C. for ˜2 hr. The reaction mixture was stirred overnight at room temperature. The contents were concentrated under reduced pressure. Next, 5 mL of dioxane was added and the contents were heated at 100° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield 3-(3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.15 g, 0.439 mmol, 82% yield) as a pale yellow solid. LC/MS M+1=342.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:3]=[C:4]([CH3:14])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=4[C:12]=3[CH3:13])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: Cc1cc(Br)c(C)c2c1OC(C)(C)C2
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(c3cc(C)c4c(c3C)CC(C)(C)O4)CC2)cc1
Yield: 73.7 %

Procedure:
By using 5-bromo-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran (510 mg, 2.00 mmol) synthesized in Reference example 103 and 1-(4-methoxyphenyl)piperazine (769 mg, 4.00 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 540 mg (yield 74%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[K+].[CH2:41]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[CH3:41][O:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CC(C)C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@H](CC(C)C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
In a 10 mL round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (73 mg, 0.135 mmol) was dissolved in THF (1.4 ml) to give a colorless solution. The reaction was cooled in an ice bath and crushed KOH (76 mg, 1.35 mmol), 18-crown-6 (36 mg, 0.135 mmol), and iodomethane (9 μl, 0.135 mmol) were added successively. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-70% EtOAc) to afford 38 mg (50%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methyl-butyl)-amide as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ: 9.18 (s, 1H), 8.64 (s, 1H), 8.52 (dd, J=9.1, 5.3 Hz, 1H), 8.15 (d, J=9.4 Hz, 1H), 7.72 (dd, J=9.6, 2.1 Hz, 1H), 7.13 (td, J=9.1, 1.9 Hz, 1H), 5.73 (s, 2H), 4.41 (td, J=9.0, 5.1 Hz, 1H), 4.17 (s, 3H), 3.60 (t, J=7.9 Hz, 2H), 3.44-3.55 (m, 2H), 3.27 (s, 3H), 1.48-1.72 (m, 3H), 0.91 (d, J=6.0 Hz, 3H), 0.86 (d, J=6.0 Hz, 3H), 0.85 (t, J=7.6 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][CH:13]([F:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1>C(Cl)Cl>[F:12][CH:13]([F:22])[C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[O:21])=[CH:18][CH:19]=1
Reactant: OCc1ccc(C(F)F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(C(F)F)cc1
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
Solid pyridinium chlorochromate (8.22 g, 38.1 mmol) was added slowly to a mixture of Example 38B (4.02 g, 25.4 mmol) and celite filter aid (8.5 g) in CH2Cl2 (125 mL) at ambient temperature. The reaction was allowed to proceed for 30 min, and then filtered. The filtrate was concentrated in vacuo to give a black oil. Flash chromatography (Analogix® Intelliflash 280™; 15% EtOAc/hexanes eluant; SF40-115 g column) yielded 3.68 g (93%) of the title compound as a colorless oil. 1HNMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.08-8.02 (m, 2H), 7.84-7.76 (m, 2H), 7.18 (t, J=55.5, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[C:10]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[F:27])=[C:11]([Cl:18])[C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1)=O)=[O:4]>O=P(Cl)(Cl)Cl>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:10]2[C:9]([C:7]3[O:4][C:3]([CH2:2][Cl:1])=[N:5][N:6]=3)=[CH:14][N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11]=2[Cl:18])=[C:21]([F:27])[CH:22]=1
Reactant: O=C(CCl)NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1cc(Br)ccc1Nc1c(-c2nnc(CCl)o2)cn2ccnc2c1Cl
Temperature: 100 °C

Procedure:
7-(4-Bromo-2-fluorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid N′-(2-chloro-acetyl)-hydrazide (63 mg, 0.13 mmol) was suspended in POCl3 (1 mL). The reaction mixture was heated to 100° C. for 8 hours, during which time it became a bright red solution. The reaction mixture was cooled to room temperature and the solvent evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4 and concentrated. The crude product (38 mg, 62%) was used without further purification in next step. MS ESI (+) m/z 456, 458 (M+, Cl, Br pattern) detected.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15]C(OC(C)(C)C)=O)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1cccc(N)c1
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 93.3 %

Procedure:
To a solution of 2-(3-tert-Butoxycarbonylamino-phenoxy)-2-methyl-propionic acid ethyl ester (0.8 g, 2.4 mmol) in DCM (10 ml) at 0° C. was added TFA (10 ml) and stirred at 0° C. for 100 min. The solvent was removed under reduced pressure; residue was dissolved in DCM and treated with 2.5M solution of NaOH. The organic layer was separated and dried over Na2SO4, concentrated to yield 2-(3-amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.5 g, mmol, 98%). 1H NMR (400 MHz, CDCl3): 1.25 (t, J=7.2 Hz, 3H), 1.56 (s, 6H), 3.62 (brs, 2H), 4.23 (q, J=7.2 Hz, 2H), 6.21-6.22 (m, 2H), 6.32 (d, J=7.2 Hz, 1H), 6.99 (t, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:11]1[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(C)c(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C)c(Oc2ccc(N)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 2-{[2-methyl-5-(methyloxy)phenyl]oxy}-5-nitropyridine (Intermediate 53, 1.5 g) in ethanol (100 mL) was added Pd/C (5%, 200 mg) and the mixture was stirred at room temperature under H2 atmosphere overnight. The mixture was filtered through a pad of celite and the filtrate was evaporated to afford a yellow oil, which was purified by column chromatography on silica gel (mobile phase: EtOAc/PE=1/5−1/2). This afforded the title compound (850 mg).
Reaction SMILES: [ClH:1].[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[ClH:1].[C:15]([N:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4]1)(=[O:17])[CH3:16]
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)N=c1ccn(-c2ccccc2)nc1
Yield: 74 %

Procedure:
15.0 g (72.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 100 ml of acetic anhydride were heated at 100° C. for 2 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was washed with acetone and recrystallized from ethanol. 13.3 g (74% of theory) of 4-acetylimino-1,4-dihydro-1-phenylpyridazine hydrochloride were isolated as colorless crystals of melting point 257°-260° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[CH:11]([CH2:12][NH:13]3)[CH2:10]2)[N:3]=1.[C:16]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](N1C2C(CCNC2)C1)=[O:23].ClC1N=C(C)C=C(C)N=1.ClC1C=NC2C(=CC=CC=2)N=1>>[C:16]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([N:13]1[CH2:12][CH:11]2[CH:14]1[CH2:15][N:9]([C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)[CH2:10]2)=[O:23]
Reactant: Cc1cc(C)nc(N2CC3CNC3C2)n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Agent: Cc1cc(C)nc(Cl)n1
Agent: Clc1cnc2ccccc2n1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)C3C2)n1

Procedure:
The title compound was prepared from Intermediate 9 in a manner analogous to Example 1, substituting biphenyl-2-yl-(3,6-diaza-bicyclo[3.2.0]hept-6-yl)-methanone for biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone and 2-chloro-4,6-dimethyl-pyrimidine for 2-chloro quinoxaline. MS (ESI) mass calcd. for C24H24N4O, 384.49; m/z found, 385.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: Nc1cc(Cl)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Nc1cc(Cl)ccc1C=O
Reaction time: 1 h

Procedure:
(2-amino-4-chlorophenyl)methanol (10.08 g, 64.0 mmol) was suspended in chloroform (250 mL) and treated with manganese dioxide (15.87 g, 183 mmol). The mixture was stirred vigorously and heated at reflux. The oxidation was followed by TLC and found to be complete after 1 hour. The suspension was filtered through a pad of CELITE™ and evaporated to dryness under reduced pressure. Further drying under high vacuum gave a dark red solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12](=O)[CH3:13].CC(O)=O.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.N1C=CC=CC=1.CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:12][CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC=O
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCNc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 49.8 %

Procedure:
4-chloro-2-nitroaniline (8.6 g; 0.05 mole), acetaldehyde (5.5 ml; 0.05 mole) and HOAc (4.0 ml; 0.1 moles) were dissolved in toluene (100 ml) and stirred for 1 hr. BH3 * pyridine (5.0 ml; 0.01 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc (40% EtOAc/Hexane). Additional TFA, BH3 * pyridine and acetaldehyde were added until the tlc indicated that the 4-chloro-2-nitroaniline was consumed. The reaction mixture was washed 2× with water and placed on a bed of silica and eluted with 20% EtOAc/Hexane. The product was the first major component to elute. The product was crystallized from MeOH which produced 5.0 g (50%) of a yellow crystalline solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(N(CC)CC)C>ClCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: OB(O)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1ccncc1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.6 %

Procedure:
A mixture of 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.1 g, 0.21 mmol), 4-pyridylboronic acid (52 mg, 0.42 mmol), cupric acetate (58 mg, 0.32 mmol) and triethylamine (60 μL, 0.42 mmol) in dichloromethane (2 mL) was stirred for 2 d at room temperature. Chromatography on silica gel (ethyl acetate) yielded the desired product (26 mg, 21%), MS: m/e=549.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17][C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=1>CN(C)C=O.O>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[CH:22]=[C:18]1[CH2:17][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:12])[C:3]([OH:2])=[O:13])=[CH:6][CH:7]=1
Reactant: ClCc1cc2ccccc2o1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCc2cc3ccccc3o2)cc1
Reaction time: 0.17 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.52 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.405 g), stirred for 10 minutes and treated with 2-chloromethylbenzofuran (1.4 g). The mixture was stirred at room temperature under argon for 3 hours, diluted with water, and extracted with ethyl acetate. Evaporation of the organic extracts provided crude methyl ester as a liquid. Treatment of a portion of this ester (1.02 g) with potassium hydroxide (0.18 g) in a methanol-water mixture, followed by acidification of the mixture with hydrochloric acid and filtration provided 4-[[2-benzofuranyl)methoxy]-alpha-oxobenzeneacetic acid as a white solid, mp 120° C.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][CH:11]([CH2:14][OH:15])[O:12][CH3:13].[O:16]1[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:17]1>CCCCCC>[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][CH:11]([O:12][CH3:13])[CH2:14][O:15][CH2:17][CH:18]([OH:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCC1CO1
Reactant: COC(CO)COC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCC(O)COCC(COC1CCCCO1)OC
Temperature: 70 °C
Yield: 54 %

Procedure:
Sodium hydride (50% in oil) (1.74 g, 36.3 mmoles) was washed with n-hexane and dried in a nitrogen gas stream. After addition of 80 ml of dry DMSO, the mixture was heated on a water bath at 70° C. for 30 minutes. When the mixture became homogeneous, 6.9 g (36.3 mmoles) of 2-methylglycerol tetrahydropyranyl ether was added dropwise and, after 15 minutes, 4.62 g (18.2 mmoles) of 1,2-epoxyheptadecane was added dropwise. The mixture was stirred at 70° C. for an hour, poured into 100 ml of broken ice and extracted with 300 ml of n-hexane-ethyl acetate (1:1). The extract was washed with water, dried and concentrated and the residue was purified by silica gel column chromatography to give 4.37 g (53.9%) of the desired compound as a colorless oil.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:12]=[CH:11][C:9](N)=[C:8]([O:13][C:14]([F:17])([F:16])[F:15])[CH:7]=1.[Br-:18]>>[Br:18][C:9]1[CH:11]=[CH:12][C:6]([CH:2]=[O:1])=[CH:7][C:8]=1[O:13][C:14]([F:17])([F:16])[F:15]
Reactant: Nc1ccc(C2OCCO2)cc1OC(F)(F)F
Reactant: [Br-]
Product: O=Cc1ccc(Br)c(OC(F)(F)F)c1

Procedure:
In Scheme 31 are shown 2 methods that may be used for the synthesis of 4-bromo-3-(trifluoromethoxy)benzaldehyde or 4-chloro-3-(trifluoromethoxy)benzaldehyde. Method 1: Commercially available 4-amino-3-(trifluoromethoxy)benzoic acid can be converted into the ester followed by a Sandmeyer reaction, described in Scheme 30, to provide the bromide or chloride. Reduction of the ester provides 4-bromo-3-(trifluoromethoxy)benzyl alcohol. The alcohol can be oxidized to the aldehyde to give the desired substituted benzaldehyde. Method 2: Commercially available 4-bromo-2-(trifluoromethoxy)aniline can be protected on the amino group with a suitable amino protecting groups well known to those skilled in the art of organic chemistry. The bromine can then be converted to the lithio or magnesio derivative and reacted directly with dimethylformamide to provide the 4-aminoprotected-3-(trifluoromethoxy)benzaldehyde derivative. Removal of the N-protecting group followed by protection of the aldehyde provides 4-(1,3-dioxolan-2-yl)-2-(trifluoromethoxy)aniline. Conversion of the amine to a bromide via the Sandmeyer method of Scheme 30 followed by hydrolysis of the dioxolane provides 4-bromo-3-(trifluoromethoxy)benzaldehyde.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=O.[CH:11]([NH2:13])=O>O>[OH:2][C:3]1[C:5]2[S:6][CH:7]=[CH:8][C:9]=2[N:10]=[CH:11][N:13]=1
Reactant: COC(=O)c1sccc1N
Reactant: NC=O
Solvent: O
Product: Oc1ncnc2ccsc12
Temperature: 200 °C
Reaction time: 2 h

Procedure:
3-aminothiophene-2-carboxylic acid methylester (1.6 g, 10 mmol) was added to formamide (3.4 ml), and the mixture was stirred at 200° C. for 2 hours. The reaction mixture was returned to room temperature, and water was added thereto, which was extracted with chloroform. The solid obtained by distilling off the solvent under reduced pressure was washed with ethyl acetate to obtain 4-hydroxythieno[3,2-d]pyrimidine (60 mg, 0.39 mmol).