Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH3:28])[CH:22]=1.Cl>O1CCCC1.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:22][C:23]=1[CH3:28]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(-c2oncc2CCl)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2oncc2CCC(=O)O)ccc1Cl
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
To a solution of diethyl malonate (5.82 g) in tetrahydrofuran (40 ml) was gradually added sodium hydride (60%, oil, 1.32 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-chloro-3-methylphenyl)isoxazole (4.00 g) in tetrahydrofuran (40 ml) was added dropwise at 0° C. and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate to give a colorless prism (2.56 g, yield 58%) of 3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propionic acid. melting point: 158–159° C.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)[C:6]1C=CC=C[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:34]1(C)C=CC=C[CH:35]=1.[CH2:41]([C@@:44]1([CH3:70])[CH2:49][C@H:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)[C@@H:47]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:46]([C@@H:64]([CH2:67][CH3:68])[CH:65]=[O:66])[C:45]1=[O:69])[CH:42]=[CH2:43]>C1COCC1>[CH2:41]([C@@:44]1([CH3:70])[CH2:49][C@H:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)[C@@H:47]([C:57]2[CH:58]=[CH:59][C:60]([Cl:63])=[CH:61][CH:62]=2)[N:46]([C@@H:64]([CH2:34][CH3:35])/[CH:67]=[CH:68]/[O:3][CH3:2])[C:45]1=[O:69])[CH:42]=[CH2:43].[CH:6]([O:64][CH:65]=[CH2:66])=[CH2:7]
Reactant: Cc1ccccc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](/C=C/OC)CC)C1=O
Product: C=COC=C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride was dried at 80° C. under vacuum for 3 h. To a solution of the dried (methoxymethyl)triphenylphosphonium chloride (1.96 g, 5.71 mmol) in THF (10 mL) was added 0.5 M KHMDS in toluene (10.2 mL, 5.08 mmol) at −78° C. The color of the solution turned blood red in color. After stirring at 0° C. for 30 min., a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 91, Step C; 564 mg, 1.27 mmol) in THF (10.1 mL) was added at 0° C. dropwise. After being stirred at rt for overnight, the reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography on silica gel (SiO2, 40 g, 15% and 20% EtOAc/Hexanes) provided the vinyl ether (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S,E)-1-methoxypent-1-en-3-yl)-3-methylpiperidin-2-one. To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S,E)-1-methoxypent-1-en-3-yl)-3-methylpiperidin-2-one prepared above in acetonitrile (7.8 mL) was added 3 N hydrochloric acid (4.4 mL, 13 mmol) and the resulting solution was stirred at rt for 1.5 h. Then, the reaction was extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a pale yellow film.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1.C([O-])(=O)C.[K+].[N+](C1C=CC=CC=1)([O-])=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:25][CH2:24][CH2:23][C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7](=[O:17])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Reactant: Nc1ccc(CCO)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Nc3ccc(CCO)cc3)cccc21

Procedure:
HEPAAQ was prepared by a procedure described in Lord, M. W.; Peters, A. T.; J. Chem. Soc., Perkins Trans., 1,(20)2305-8, incorporated herein by reference, with a slight modification. In a 250 mL single-necked round-bottom flask equipped with a reflux condenser was placed 1-chloroanthraquinone (10.5 g), 4-aminophenethyl alcohol (11.2 g), potassium acetate (7.87 g), copper acetate (0.46 g), and nitrobenzene (75 mL). The flask was flushed with nitrogen and then heated to reflux for about 2 hours. The mixture was filtered. The solvent was removed from the filtrate, and the resultant solid was washed with methanol. The product was purified by dissolving the dried filtrate in dichloromethane and chromatographing on a silica column using a 10/90 (v/v) acetone/dichloromethane mixture as the eluent. The solvent was removed from the chromatographed material and dried in vacuo.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[NH3:7]>O>[OH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5].[NH4+:7]
Reactant: N
Agent: O=C(O)CCO
Solvent: O
Product: O=C([O-])CCO
Product: [NH4+]

Procedure:
A 2 wt % 3-hydroxypropionic acid-containing culture fluid (30 g) from which microorganisms are removed, tridecylamine (180 g), and dodecanol (20 g) were added into a 500-mL three neck flask. The flask was submerged in an oil bath and connected to a vacuum pump. The flask was heated while the solution therein was stirred. When the solution temperature reached 85° C., the vacuum pump was turned on. During the reaction, ammonium 3-hydroxypropionate was decomposed to discharge ammonia and water. These are removed by a cold trap under reduced pressure. At the same time, 3-hydroxypropionic acid produced by decomposition of ammonium 3-hydroxypropionate was extracted into an organic phase formed of tridecylamine and dodecanol. To the organic phase formed of tridecylamine and dodecanol which contains 3-hydroxypropionic acid, a ⅕ volume of water was added and mixed. The mixture was heated to 140° C. to give an aqueous solution containing 3-hydroxypropionic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CCOCC>[CH3:21][S:22]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:24])=[O:23]
Reactant: OCCCCCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6-phenyl-1-hexanol (3.2g; 18 mmol) dissolved in CH2Cl2 (60 ml) is added Et3N (3.7 ml) and the solution is cooled to 0° C. Methanesulfonyl chloride (1.5 ml; 20 mmol) is added dropwise and then the reaction mixture is allowed to stir for 30 minutes at 0° C. This is then diluted with Et2O and washed with 2N HCl, NaHCO3 solution 2× and brine, dried (MgSO4) and concentrated to dryness to obtain 6-phenylhex-1-yl methylsulfonate as an oil which is used directly in Step E.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[C:18]([C:19](O)=[O:20])=[CH:17][C:16]([O:22][CH3:23])=[CH:15][C:13]=3[CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:25][NH:26][O:27][CH3:28].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:28][O:27][N:26]([CH3:25])[C:19]([C:18]1[C:12]2[O:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[CH:14][C:13]=2[CH:15]=[C:16]([O:22][CH3:23])[CH:17]=1)=[O:20]
Reactant: CNOC
Reactant: COc1cc(C(=O)O)c2oc(-c3ccc(OC)c(F)c3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)OC)c2oc(-c3ccc(OC)c(F)c3)cc2c1
Yield: 63.5 %

Procedure:
A solution of 44 (0.400 g, 1.27 mmole), N,O dimethylhydroxylamine hydrochloride (0.247 g, 2.53 mmole), DMAP (0.309 g, 2.53 mmole), and EDCI (0.364 g, 1.90 mmole), in 40 mL dimethylformamide was stirred at rt for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 7:3) to afford 0.290 g (63%) of amide 45 as a tan solid: Mp=100-102° C.; 1H NMR (DMSO-d6) δ 7.74 (dd, 1H, J=2.0 Hz), 7.66 (d, 1 H, J=8.6 Hz), 7.37 (s, 1 H), 7.31 (t, 1 H, J=8.7 Hz), 7.24 (d, 1 H, J=2.6 Hz), 6.93 (d, 1 H, J=2.6 Hz), 3.90 (s, 3 H), 3.82 (s, 3 H), 3.59 (br s, 3 H), 3.30 (s, 3H); MS 360 (M+H)+
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:15]([O:16][CH3:17])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>CS(C)=O>[Br:3][C:4]1[C:15]([O:16][CH3:17])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[N:10]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1cc2c(cc1Br)CCNC(=O)C2
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1Br)CCN(CCCCl)C(=O)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.24 gm of a 55% sodium hydride dispersion in oil were added to a mixture of 1.35 gm (5 mol) of 7-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one in 15 ml of dimethylsulfoxide at room temperature. After stirring the mixture at room temperature for 30 minutes and at a temperature between 35° and 40° C. for 10 minutes, the obtained solution was added to 0.79 gm (5.5 mol) of 1-bromo-3-chloro-propane in 5 ml of dimethylsulfoxide. After stirring the mixture at room temperature for 2 hours, it was poured into ice water, and the aqueous mixture was extracted four times with methylene chloride. The methylene chloride extracts were washed with water, dried and evaporated in vacuo. The residue was purified by chromatography on silica gel, using ethyl acetate as the eluant.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C(N(C(C)C)C(C)C)C.[F:31][C:32]([F:50])([F:49])[C:33]1[CH:34]=[C:35]([C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1>O1CCCC1>[F:31][C:32]([F:50])([F:49])[C:33]1[CH:34]=[C:35]([C:43]([CH3:48])([CH3:47])[C:44]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][C:6]([N:16]3[CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: CNc1cnc(N2CCSCC2)cc1-c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(N2CCSCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of 2.32 g (7.7 mmol) methyl-(6-thiomorpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine and 1.50 g (11.6 mmol) N-ethyldiisopropylamine in 20 ml tetrahydrofuran was cooled in an ice bath and 2.72 g (8.5 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added dropwise. The reaction mixture was stirred at room temperature overnight and evaporated in vacuo. The residue was suspended in 200 ml 1 N sodium carbonate solution and extracted three times with 200-ml portions of ethyl acetate. The combined organic layers were dried (sodium sulfate) and evaporated. The residue was crystallized from ethanol to give 3.60 g (80%) of the title compound as white crystals.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]CCC(OC)=O)(=[S:3])C.Cl.[C:19]([O:22][CH2:23]C)(=[O:21])[CH3:20].C(CC(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>CO.ClCCl>[SH:3][CH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:20][C:19]([O:22][CH3:23])=[O:21]
Reactant: CCOC(C)=O
Reactant: COC(=O)CCCCCCCCCCC(C)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Solvent: CO
Product: COC(=O)CCCCCCCCCCS
Reaction time: 48 h
Yield: 68 %

Procedure:
Compound 104 (15.6 g, 56.9 mmol) in methanol (50 ml) was added to a solution of hydrogen chloride in methanol (HCl was bubbled into 600 ml of MeOH for 10 min). The reaction was monitored by TLC (SiO2, ethyl acetate:isooctane 1:5). After 48 h, an excess of sodium hydrogen carbonate was added and the mixture was diluted with dichloromethane (150 ml), filtered and concentrated. Distillation gave pure 105 (9.0 g, 68%) with b.p. 93°-94° (7×10-2 torr). 1H-NMR (CDCl3, Me4Si) δ 3.68 (s, 3H, MeO), 2.53 (q, 2H, J~7 Hz, H--S--CH2), 2.31 (t, 2H, J=7.5 Hz, CH2CO). 13C-NMR (CDCl3, Me4Si) δ 174.2 (CO), 51.3, 34.0, 33.9, 29.3, 29.2, 29.1, 29.0, 28.9, 28.3, 24.8, 24.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])[O:20][N:19]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)CCCNC(=O)c1cc(-c2ccc(N)cc2)no1
Reactant: O=C=Nc1ccccc1F
Product: COC(=O)CCCNC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Yield: 73 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 1-fluoro-2-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and methyl 4-(3-(4-aminophenyl)isoxazole-5-carboxamido)butanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 73% of the title compound. MS (ES+): m/z 441 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 9.3 (s, 1H), 9.0 (t, 1H), 8.62 (s, 1H), 8.12 (m, 1H), 7.85 (d, 2H), 7.61 (d, 2H), 7.53 (s, 1H), 7.24 (m, 1H), 7.1 (m, 1H), 7.02 (m, 1H), 3.57 (s, 3H), 3.26 (q, 2H), 2.36 (t, 2H), 1.77 (m, 2H).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].C([O:9][C:10]([C:12]1[C:16]([CH2:17][CH2:18][CH2:19]SC)=[C:15]([CH:22]=[O:23])[NH:14][C:13]=1[CH3:24])=[O:11])C.[CH3:25]O>O>[CH:22]([C:15]1[NH:14][C:13]([CH3:24])=[C:12]([C:10]([OH:11])=[O:9])[C:16]=1[CH2:17][CH2:18][CH2:19][S:3]([CH3:25])(=[O:5])=[O:2])=[O:23]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCSC
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: Cc1[nH]c(C=O)c(CCCS(C)(=O)=O)c1C(=O)O
Reaction time: 3 h

Procedure:
Oxone (614 mg, 1 mmol) dissolved in water (2 mL) was added portionwise to a solution of 5-formyl-2-methyl-4-(3-methylsulfanyl-propyl)-1H-pyrrole-3-carboxylic acid ethyl ester (269 mg, 1 mmol) in methanol (4 mL) cooled in an ice bath. The mixture was stirred for 3 hours, keeping the temp between 0° C. and rt. The reaction was diluted with 10 mL of water, the resulted precipitate was collected by vacuum filtration, washed with water and dried to give 95 mg of the desired product. The water filtrate was extracted with ethyl acetate, dried and concentrated to give another 74 mg of the product. Total of 169 mg (56%) of 5-formyl-4-(3-methanesulfonyl-propyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:22][CH:23]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([C:8](N(OC)C)=[O:9])[CH:7]=1.[CH3:24][Mg]Br.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:22][CH:23]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([C:8](=[O:9])[CH3:24])[CH:7]=1
Reactant: CON(C)C(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Reactant: C[Mg]Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
8-Chloro-5-(3-fluorophenyl)-N-methoxy-N-methylimidazo[1,5-a]pyridine-6-carboxamide (0.15 g, 0.45 mmol) was stirred in tetrahydrofuran (0.73 mL) and cooled to 0° C. A solution of 3.0 M methylmagnesium bromide (0.52 mL, 1.57 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The mixture was cooled to 0° C. and a solution of 1.0 M hydrogen chloride in water (1.8 mL) was added. The mixture was poured into saturated sodium bicarbonate and extracted into ethyl acetate 3×. The ethyl acetate extracts were combined and washed with water, dried over sodium sulfate, filtered, concentrated and purified by flash column chromatography with ethyl acetate in hexanes (0-80%) to give the desired compound (0.12 g, 93%). LCMS calculated for C15H11ClFN2O (M+H)+: m/z=289.1. found: 288.9. 1H NMR (300 MHz, DMSO-d6): δ 7.89 (s, 1H), 7.62 (m, 2H), 7.50 (m, 2H), 7.40 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[H-].[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:11])[N:6]([CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2cc(Br)ccc2nn1CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
To a solution of 5-bromo-3-methyl-1H-indazole (2.0 g) in N,N-dimethylformamide (20 ml) were added (2-bromoethoxy)(tert-butyl)dimethylsilane (2.5 g) and 60% sodium hydride (682 mg) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (492 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:26])[O:11][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[CH:13]=2)=[CH:5][C:4]=1[CH3:27].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K].[I-].[Na+].CCCCCC>CN(C)C=O.O>[Cl:25][C:20]1[CH:19]=[C:18]([C:12]2([C:14]([F:15])([F:17])[F:16])[O:11][N:10]([CH3:26])[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:32]4[C:28](=[O:38])[C:29]5[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:31]4=[O:33])=[C:4]([CH3:27])[CH:5]=3)=[CH:13]2)[CH:23]=[C:22]([Cl:24])[CH:21]=1
Reactant: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CN1C(=O)c2ccccc2C1=O
Yield: 98 %

Procedure:
524 mg of 3-(4-Chloromethyl-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole, 216 mg of potassium phthalimide and 10 mg sodium iodide in 7 ml N,N-dimethylformamide were stirred at ambient temperature overnight. The mixture was diluted with water (100 ml) and extracted with 200 ml of ether. The organic phase was washed with water and dried. Evaporation of the solvent afforded a foam. Trituration with hexane gave 2-{4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzyl}-isoindole-1,3-dione as a white solid in 98% yield. 1H-NMR (CDCl3, δ in ppm): 7.88 (m, 2H), 7.75 (m, 2H), 7.22-7.43 (m, 6H), 5.30 (s, 1H), 4.86 (s, 2H), 2.96 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[NH2:16][OH:17]>C(O)C>[OH:17]/[N:16]=[C:12](\[NH2:13])/[C:11]1[CH:10]=[CH:9][C:8]([O:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(Oc2ccncc2)cc1
Reactant: NO
Solvent: CCO
Product: N/C(=N\O)c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
4-(Pyridin-4-yloxy)benzonitrile (293 mg, 1.49 mmol) was dissolved in ethanol (6.0 mL) and hydroxylamine (197 mg, 5.97 mmol) was added. The mixture was refluxed for 3 hours and cooled to room temperature and then concentrated in vacuo to give the product which immediately formed white crystals and was taken to the next step without further purification. A small quantity was purified by column chromatography (Hex/EtOAc 1:8) to give the pure product (323 mg, 94%). 1H NMR (500 MHz, DMSO-d6) δ(ppm): 5.95 (2H, s), 6.24 (2H, d, J=8.0 Hz), 7.56 (2H, d, J=8.8 Hz), 7.84 (2H, d, J=8.6 Hz), 8.02 (2H, d, J=7.8 Hz), 9.81 (1H, s). 13C NMR (125 MHz, DMSO-d6) δ(ppm): 118.0 (CH), 122.1 (CH), 126.7 (CH), 132.6, 139.6 (CH), 142.8, 149.8, 177.4. MS (FAB+): 230 (MH+). HRMS for C12H11N3O2 (MH+): calculated: 230.0930; found 230.0950.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2=[C:6]3[N:17]=[C:16]([C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[NH:15][C:7]3=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH:10]=[CH:9]3)=[C:4]2[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:16]1[NH:15][C:7]2=[C:8]3[C:13](=[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([Cl:28])=[CH:34][CH:33]=5)[CH:27]=[CH:26][C:5]4=[C:6]2[N:17]=1)[C:12](=[O:14])[NH:11][CH:10]=[CH:9]3
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Reactant: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(Br)cc3c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(-c4ccc(Cl)nc4)cc3c12
Temperature: 80 °C

Procedure:
9-Bromo-2-(2-chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one (500 mg, 1.130 mmol) was dissolved in ethanol (15 ml) and toluene (15.00 ml). (Dichlorobis)palladiumtriphenylphosphine (79 mg, 0.113 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (298 mg, 1.242 mmol) and Na2CO3 (2 M, 1.135 mL) were added and argon was bubbled through the solution for several minutes. The solution was heated at 80° C. for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate and water. The organic layer was separated, dried over magnesium sulftate, filtered and concentrated. The crude residue was purified via a chiral AD column which afforded the title compound. 1H NMR (500 MHz, CD3OD, δH) 10.68 (s, 1 H), 8.56 (d, 1 H, J=1.8 Hz), 8.30 (dd, 1 H, J=8.4, 3.0 Hz), 8.04 (dd, 1 H) J=9.0, 1.8 Hz), 7.68-7.64 (m, 1 H), 7.63-7.60 (m, 2 H), 7.54 (d, 1 H, J=8.4 Hz), 7.38 (td, 1 H, J =9, 1.2 Hz): [M+1]+ 475.