Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N+:7]([O-])[C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[O:4][N:3]=1.O=P(Cl)(Cl)[Cl:15].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:15][C:10]1[CH:9]=[C:8]([CH3:11])[N:7]=[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1noc2ccc(C)[n+]([O-])c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c2onc(C)c2n1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
3,5-dimethylisoxazolo[4,5-b]pyridine 4-oxide (0.650 g, 3.96 mmol) in chloroform (5 mL), was added POCl3 (1.45 mL, 15.8 mmol) and the mixture was heated at 80° C. for 2 hours. The solution was cooled and poured onto ice water. The solution was neutralized with saturated NaHCO3 and the solution was then extracted with EtOAc, dried, and concentrated. The solid was triturated with ether and filtered twice to obtain two crops of the title compound (0.417 g, 57.7% yield).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:1]([CH2:2][CH2:3][NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: C=CC#N
Reactant: NCCCCCCCCCCCCCCCCCCc1ccccc1
Solvent: O
Product: N#CCCNCCCCCCCCCCCCCCCCCCc1ccccc1

Procedure:
N-(Beta-cyanoethyl)phenyloctadecylamine was prepared as follows: Acrylonitrile (61.0 grams, 1.15 moles) was added slowly over 2 hours, with stirring, to a mixture of phenyloctadecylamine, prepared as described in Example II, (363.8 grams, 1.05 moles) and 17.0 grams water at 60°-70°C. The resulting mixture was then stirred at 70°-80° for 4 additional hours. The water was separated and the product dried under reduced pressure at 60°-70°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[N:6]=[CH:5]2.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]([CH3:30])[CH:28]=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH:27]([CH3:30])[CH:28]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[N:6]=[CH:5]2)[OH:29]
Reactant: CC(C=O)c1ccc(Cl)cc1Cl
Reactant: COc1cccc(-n2ncc3cc(Br)ccc32)c1
Product: COc1cccc(-n2ncc3cc(C(O)C(C)c4ccc(Cl)cc4Cl)ccc32)c1

Procedure:
In analogy to Example 186, 5-bromo-1-(3-methoxy-phenyl)-1H-indazole was reacted with 2-(2,4-dichloro-phenyl)-propionaldehyde to give 2-(2,4-dichloro-phenyl)-1-[1-(3-methoxy-phenyl)-1H-indazol-5-yl]-propan-1-ol which was oxidized to 2-(2,4-dichloro-phenyl)-1-[1-(3-methoxy-phenyl)-1H-indazol-5-yl]-propan-1-one and converted further to the title compound. Colorless solid. MS (m/e)=495.2 [M+H+].
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14](O)=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1.[NH4+:24].[OH-]>>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH2:24])=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(N)=O
Yield: 96 %

Procedure:
The product was prepared in 96% yield by reaction of the mixed anhydride from BOC-β-Nal-OH (682 mg, 2.17 mmol) with conc. NH4OH according to the procedure of Rzeszotarska, B., Makowski, M., and Kubica, Z. Org. Prep. Proc. Int.1984, 16:136-139. 1H-NMR (CDCl3): δ1.40 (s, 9H), 3.24 (m, 2H), 4.47 (m, 1H), 5.10 (br s, 1H), 5.37 (br s, 1H), 5.75 (br s, 1H), 7.49 (dd, J=2 Hz and 9 Hz, 1H), 7.47 (m, 2H), 7.69 (s, 1H), 7.80 (m, 3H). MS (DCl): m/e 315 (M+H)+, 259, 215.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[O:9][C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: S=C=Nc1ccc(Br)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
2-Amino-4-methylphenol (1.15 g, 9.34 mmol) was added to a solution of 4-bromophenyl isothiocyanate (2.00 g, 9.34 mmol) in tetrahydrofuran (35 mL) and the reaction was stirred at room temperature for 16 h. Anhydrous copper (II) sulfate (14.06 g, 88.10 mmol), silica gel (14.06 g), and triethylamine (1.3 mL, 9.34 mmol) were added, and the mixture was stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure and then added to a silica pad and purified using 1:5 ethyl acetate:heptane (2 L) followed by diethyl ether as the eluent to afford N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine as a light brown solid (2.30 g, 81%);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([CH2:18][CH3:19])[CH2:14][C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu](I)I>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:12][C@H:13]([CH2:18][CH3:19])[CH2:14][C:15]([OH:17])=[O:16])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC[C@@H](N)CC(=O)O
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@H](CC(=O)O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 60 h

Procedure:
To a solution of 1-bromo-4-trifluoromethylbenzene (2530 g, 11.24 mole) and (R)-3-aminovaleric acid (659 g, 5.63 mole) in N,N-dimethylformamide (12 liter), were added copper iodide (210 g, 1.10 mole) and potassium carbonate (2330 g, 16.86 mole), and the mixture was sealed under nitrogen atmosphere and stirred at 100° C.-120° C. for about 60 hours. When the reaction was completed, the reaction mixture was concentrated in vacuo at 60° C.-70° C. of the bath temperature, the residue was dissolved in water (6.0 liter) and the solution was adjusted to pH about 5.0 with addition of hydrochloric acid. Ethyl acetate (6.0 liter) was added and the mixture was stirred, filtered and washed with ethyl acetate (2.4 liter). The filtrate was separated and the aqueous layer was extracted with ethyl acetate (3.6 liter). The organic layer was combined and extracted with 25% ammonia water (3.0 liter) and water (3 liter). The aqueous layer was acidified to pH about 5.0 with addition of hydrochloric acid, and extracted with ethyl acetate (6.0 liter). The organic layer was dried over magnesium sulfate (600 g), filtered and washed with ethyl acetate (2.4 liter). The filtrate was concentrated in vacuo at 45° C.-55° C. of the bath temperature, and the titled compound was obtained as an oily residue, which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[CH2:18]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1)[CH3:19]>>[CH2:18]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:31][CH2:30]2)=[CH:26][CH:25]=1)[CH3:19]
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: CCOCCOc1ccc(OC2CCNCC2)cc1
Product: CCOCCOc1ccc(OC2CCN(CC(=O)N[C@@H]3COc4nc([N+](=O)[O-])cn4C3)CC2)cc1
Yield: 30.6 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(2-ethoxyethoxy)phenoxy)piperidine (265 mg, 1.0 mmol) as crude materials, 75 mg title compound was generated and yield was 63%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[N:14]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: ClCC1CC1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(Cl)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(Cl)c2)nn(CC2CC2)c1=O
Yield: 72.7 %

Procedure:
Using 6-(3-chloro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedure of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 72.7%.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([CH3:18])[CH:5]=2)[CH2:3][CH2:2]1.C([Li])(CC)C.CON(C)[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:13]([O:12][C:11](=[O:17])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[CH2:18][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Cc1cc(C2CC2)ccc1NC(=O)OC(C)(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1CC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl (4-cyclopropyl-2-methylphenyl)carbamate (666 mg) in tetrahydrofuran (13.5 mL) was added dropwise sec-butyllithium (1.08 mol/L hexane-cyclohexane solution, 5.5 mL) at −45° C., and the mixture was stirred for 30 minutes. Next, a solution of N-methoxy-N-methylbenzamide (489 mg) in tetrahydrofuran (1.4 mL) was added dropwise thereto, and the mixture was stirred at −45° C. for 35 minutes and then stirred at room temperature for 2 more hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution/water (2/1, 30 mL), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (563 mg). 1H-NMR (CDCl3) δ ppm: 0.55-0.70 (2H, m), 0.80-1.00 (2H, m), 1.49 (9H, s), 1.75-1.90 (1H, m), 4.25 (2H, s), 6.85-7.00 (2H, m), 7.20-7.75 (5H, m), 8.00-8.15 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([S:20][CH3:21])[N:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[Cl:12][C:13]1[CH:18]=[C:17]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:16]=[C:15]([S:20][CH3:21])[N:14]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(B(O)O)cn1
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: COCCOC
Solvent: O
Product: COc1ccc(-c2cc(Cl)nc(SC)n2)cn1
Reaction time: 3 h

Procedure:
A mixture of 2-methoxy-5-pyridyl-boronic acid (600 mg, 2.04 mmol, Intermediate (37), prepared according to the procedure described in J. Org. Chem., 67, 7541, 2002), 4,6-dichloro-2-methylsulfanyl-pyrimidine [700 mg, 3.59 mmol, Intermediate (29)], and Cs2CO3 (2.9 g, 8.97 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.18 mmol) at room temperature. After 3 hours at 85° C., the mixture is diluted with water (50 mL), and extracted twice with EtOAc (50 mL). The extracts are dried over magnesium sulfate, filtered, and concentrated to afford 4-chloro-6-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrimidine [1.1 g, Intermediate (38)] as an oil. LCMS: RT=3.72 minutes, MS: 268 (M+H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C@H:3]2[CH:7]=[CH:8][CH2:9][CH2:10][C@@H:2]12.Cl.[NH2:13][CH:14]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]1(=[O:11])[N:13]([CH:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:4](=[O:6])[C@H:3]2[CH:7]=[CH:8][CH2:9][CH2:10][C@@H:2]12
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Reactant: O=C1OC(=O)[C@@H]2CCC=C[C@H]12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)[C@H]2C=CCC[C@H]2C1=O
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A stirred mixture of cis-1,2,5,6-tetrahydrophthalic anhydride (0.76 grams, 5.0 mmol), methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (1.38 grams, 5.0 mmol), and sodium acetate (0.41 grams, 5.0 mmol) in 20 mL of acetic acid under N2 was heated to reflux for 20 hours. The cooled reaction mixture was concentrated in vacuo and the residue diluted with 25 mL of methylene chloride and then 25 mL of saturated sodium bicarbonate was added in portions and the resulting mixture stirred for 30 minutes. The organic phase was separated, dried (sodium sulfate), and concentrated in vacuo to afford the crude product as an oil. The crude product was purified by flash chromatography (silica gel, 1/9 ethyl acetate/hexanes) to afford 0.85 grams (46%) of methyl 3-(cis-1,2,5,6-tetrahydrophthalimido)-3-(3,4-dimethoxyphenyl)-propionate as a solid: mp 100°-101.5° C.; 1H NMR (CDCl3 /TMS) δ 7.00 (m, 2H), 5.83 (m, 2H), 5.77 (dd, J=10.0, 5.9 Hz, 1H, CH), 3.85 (s, 6H, 2 OCH3), 3.62 (dd, J=10.0, 16.4 Hz, 1H), 3.64 (s, 3H, OCH3), 3.10 (dd, J=16.4, 5.9 Hz, 1H), 3.00 (m, 2H), 2.62-2.45 (m, 2H), 2.30-2.22 (m, 2H); 13C NMR (CDCl3 /TMS) δ 180.0, 179.7, 170.3, 148.8, 130.6, 127.6, 127.5, 120.1, 111.0, 110.8, 55.8, 55.8, 51.8, 51.4, 38.8, 35.3, 23.5, 23.4; TLC (1/9 EtOAc/hexanes, UV) Rf =0.34. Anal. Calcd for C20H23NO6. Theory C, 64.33; H, 6.21; N, 3.75. Found C, 64.29; H, 6.19; N, 3.68.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:27][C:22]1[CH:21]=[C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: Nc1ccc(O)c(F)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(O)c(F)c4)c3c2s1
Yield: 58 %

Procedure:
Prepared from VII and 4-amino-2-fluorophenol. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 58%; orange solid; mp>260° C.; IR (KBr) νmax/cm−1 3375, 2228, 1731, 1649, 1619, 1578, 1512, 1470, 1373, 1347, 1292, 1241, 1204, 1150, 1111, 978, 943, 856, 836; 19F NMR (282 MHz, DMSO-d6) δ −136.8; 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, 1H, J=9.0 Hz), 8.15 (s, 1H), 7.69 (d, 1H, J=9.0 Hz), 6.97-6.81 (m, 3H); HRMS calcd for C16H9N5OSF (M+H+): 338.0512, found 338.0516.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[O:12][N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:14]1[C:10]([CH3:9])=[N:11][O:12][C:13]=1[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
N-chlorosuccinimide (0.266 g, 2 mmol) was added, in one lot, to a stirred suspension of N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (0.327g, 1 mmol, Example 14b) in chloroform (10 ml) and stirred at room temperature for 2 h The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (2×50 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography using ethyl acetate as eluent to give N-(4-chloro-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide [210 mg, 58% yield, m.p. 260° C. (de coup)].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:15])[O:14][CH2:13][CH2:12][O:11]1)[CH3:2].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C1COCC1.CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:7][CH2:8][CH2:9][C:10]1([CH3:15])[O:14][CH2:13][CH2:12][O:11]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)CNCCCC1(C)OCCO1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CCCC1(C)OCCO1)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of 2-4 (24 g, 0.104 mol) in 100 mL THF were added a trace of DMAP, 20 drops of triethylamine, and BOC2O (23.8 g, 0.109 mol). After 4 h, evaporative removal of the solvent gave 2-5 as a colorless oil. TLC Rf =0.38 (silica, 30% ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3, mixture of rotamers) δ 4.22 (m, 3H), 3.93 (m, 4H), 3.27 (m, 2H), 1.63 (m, 4H), 1.51 (s, 3H), 1.47 (s, 3H), 1.42 (s, 3H), 1.31 (s, 3H), 1.28 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:33])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[O:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:33])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:26][C:25]=1[O:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(O)cc1OC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(OCC(=O)OC(C)(C)C)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-hydroxy-2-methoxyphenyl)octanamide (prepared as described in Preparation 46) and t-butyl bromoacetate, the title compound was obtained as a foam-like substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O.[Se](=O)=[O:22]>O1CCOCC1>[OH2:2].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:19])[CH:18]=[O:22])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(COc2ccc(C(C)=O)cc2)cc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(COc2ccc(C(=O)C=O)cc2)cc1

Procedure:
A 10.0 g portion of 1-[4-[(4-methoxyphenyl)-methoxy]phenyl]ethanone was dissolved in 50 ml of hot p-dioxane. A 2.0 ml portion of water and 4.4 g of selenium dioxide were added and the mixture was stirred at reflux for 67 hours, then cooled and filtered through diatomaceous earth. The filtrate was poured into 300 ml of water and the solid collected. This solid was extracted with eight 100 ml portions of ethyl acetate. The extracts were combined, washed with water, dried and evaporated. The residue was dissolved in 100 ml of boiling toluene, treated with charcoal and filtered through diatomaceous earth. The filtrate was treated with 200 ml. of hexane, giving the desired product as a pale yellow solid, m.p. 127°-138° C.
Reaction SMILES: [S:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([OH:3])=[O:2].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21]I.[OH-].[Na+]>O.C(O)C>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21][S:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])=[O:2]
Reactant: O=C(O)c1cccc(S(=O)O)c1
Reactant: ICCOC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)CCOC2CCCCO2)c1
Yield: 14.8 %

Procedure:
To a solution of 3-sulfino-benzoic acid (1 g) and 2-iodoethyl tetrahydro-2H-pyran-2-yl ether (1.4 g) in water (20 ml) and ethanol (20 ml) was added NaOH solution to give a pH of 9. The resulting mixture was refluxed for 3 hours before evaporation of the ethanol. The aqueous was acidified to pH3 and the product extracted with EtOAc. The organic layer was separated, dried with MgSO4 and solvent removed by evaporation to give the sub-title compound (0.25 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=2)=[CH:2]1.[CH2:14]([Mg]Br)[CH3:15]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]=[CH:8][C:9]([CH:10]([OH:11])[CH2:14][CH3:15])=[CH:12][CH:13]=2)=[CH:2]1
Reactant: O=Cc1ccc(-c2ccoc2)nc1
Reactant: CC[Mg]Br
Product: CCC(O)c1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 47b (194 mg, 1.12 mmol) and ethylmagnesium bromide (2.24 mL, 2.24 mmol, 1 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Product was used directly in the next step without further characterization. White solid. Yield: 73 mg, 32%. MS (ESI): m/z=204.30 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30](Cl)=O.C(N(CC)CC)C>C(#N)C>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([C:30]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)[CH:33]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Br)ccc2Cl)n1
Temperature: 150 °C
Yield: 26 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 5-bromo-2-chlorobenzoyl chloride (0.134 g, 0.529 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.021 g (26% yield) of pure product: MS (ES) m/z 523 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](O)(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24](=[O:33])/[CH:25]=[CH:26]/[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(O)C=Cc1ccccc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)/C=C/c4ccccc4)nc3cc21

Procedure:
(E)-N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-acrylamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and cinnamoic acid (131 mg, 0.89 mmol). The title compound was obtained as yellow powder (86 mg, 24%).