Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH:24]=[CH2:25])[CH2:11][CH2:10][CH:9]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C=[O:30])C>O.Cl.Cl[Cu].Cl[Pd]Cl>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[CH:9]1[CH2:8][CH2:7][C:6]([CH2:23][C:24](=[O:30])[CH3:25])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: CN(C)C=O
Reactant: C=CCC1(C(=O)OCC)CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: O
Product: CCOC(=O)C1(CC(C)=O)CCC(N2C(=O)c3ccccc3C2=O)CC1
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of CuCl (147 mg, 1.484 mmol) and PdCl2 (46.1 mg, 0.26 mmol) in DMF (24 ml) and water (4 ml) was stirred under an oxygen (balloon) for 3 hours. A solution of 1-Allyl-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclohexanecarboxylic acid ethyl ester (Intermediate 73, 362 mg, 1.06 mmol) in DMF (16 ml) was added and the mixture was stirred at room temperature for 66 hr under O2. LCMS shows 100% conversion to product and the reaction mixture was diluted with water and 1M HCl, then extracted with ethyl acetate (×3). The organic layers were washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a yellow oil (410 mg, >100%) which was taken to the next step without further purification. LCMS [M+H]=358.3
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=C([S:15]([OH:18])(=[O:17])=[O:16])C=CC=1.NC1C=CC(S(O)(=O)=[O:27])=CC=1.NC1C=CC=CC=1S(O)(=O)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15](=[O:16])(=[O:27])([OH:17])[OH:18]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: Nc1ccccc1S(=O)(=O)O
Solvent: Nc1ccccc1
Product: O=S(=O)(O)O

Procedure:
As a method for the synthesis of a sulfonated polyaniline, there are known, for example, a method for the synthesis of a sulfonated polyaniline by electrochemically polymerizing aniline and m-aminobenzenesulfonic acid (Journal of The Chemical Society of Japan, 1985, 1124 and JA-A-2-166,165), a method for the synthesis of a sulfonated polyaniline by electrochemically polymerizing an o-, m- or p-aminobenzenesulfonic acid alone [Lecture Preprint II in the 64th Autumn Annual Convention of The Chemical Society of Japan, 706 (1992)], a method for the synthesis of a sulfonated polyaniline by chemically polymerizing aniline and an o- or m-aminobenzenesulfonic acid (JP-A-1-301,714), a method for the chemical oxidation polymerization of an aminobenzenesulfonic acid compound or monomers comprising an aminobenzenesulfonic acid compound and an aniline compound (JP-A-6-56,987), a method for the sulfonation with conc. sulfuric acid of an emeraldine type polymer (polyaniline) obtained by chemical or electrochemical polymerization (JP-A-58-210,902), a method for the sulfonation with sulfuric anhydride/triethyl phosphate complex (JP-A-61-197,633), a method for the sulfonation with fuming sulfuric acid [J. Am. Chem. Soc., (1991) 113, 2665-2671, J. Am. Chem. Soc., (1990) 112, 2800 and WO91-06887], a method for the synthesis of a sulfonated polyaniline of the N-substitution type by chemically polymerizing diphenylamine-4-sulfonic acid (sodium salt) [Polymer, (1993) 34, 158-162] and the like.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.CN1CCOCC1>CN(C=O)C>[CH3:12][C:11]1([CH3:13])[C:8]([CH3:9])([CH3:10])[O:7][B:6]([C:4]2[CH:3]=[N:2][N:1]([CH2:21][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)[CH:5]=2)[O:14]1
Reactant: ClCc1cccnc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)OB(c2cnn(Cc3cccnc3)c2)OC1(C)C
Temperature: 100 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 3-picolyl chloride (prepared from the hydrochloride salt using a pre-swelled suspension of morpholinomethyl polystyrene in DMF) according to Method AC (heating to 100° C. under microwave irradiation for 2 h) and was isolated as a brown oil (71%). LCMS (ES+) 286 (M+H)+, RT 1.98 minutes (Method 1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH:16]=[O:17])[CH2:11][CH2:10][CH2:9][CH2:8]1.Cl>C1COCC1>[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH2:16][OH:17])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1OC1CCCC1
Yield: 81 %

Procedure:
1M lithium aluminum hydride in THF (1.5 mL) was added into a stirred solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (1.1 g; 5 mmol) in THF solution in an ice bath. After the reaction was completed (as evidenced by TLC), the mixture was acidified with 2M HCl and extracted with ether. The organic phase was washed with water and dried over MgSO4. Filtration, followed by evaporation gave (3-cyclopentyloxy-4-methoxyphenyl)methanol as an oil ( 0.9 g; 81% yield; purity 98.1% by HPLC area). 1H-NMR: 6.92 (s, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 4.80 (m, 1H), 4.61 (s, 2H), 3.84 (s, 3H), 2.13–1.78 (m, 6H), and 1.61 (s, 2H). 13C-NMR: 149.4, 147.6, 133.6, 119.3, 114.0, 111.7, 80.3, 60.5, 56.0, 32.7, and 24.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CNCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A solution of 254A (243 mg, 0.60 mmol) in CH2Cl2 (3 mL) at 0° C. was treated with trifluoroacetic acid (0.3 mL). The reaction was stirred at room temperature for one hour, then concentrated to an oil. The crude amine was dissolved in EtOAc (10 mL), washed with saturated aqueous NaHCO3 and dried (Na2SO4), filtered and concentrated in vacuo. The product was purified by flash chromatography (10% MeOH/CH2Cl2) on silica gel to afford 95 mg (yield: 52%) of Compound 254B.
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]3[CH2:22][CH2:23][C:24]4[NH:25][C:26](=[O:29])[CH:27]=[CH:28][C:19]([C:20]=43)=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:32])=O>>[Cl:32][CH:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]3[CH2:22][CH2:23][C:24]4[NH:25][C:26](=[O:29])[CH:27]=[CH:28][C:19]([C:20]=43)=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=CC2=CN=C(c3ccc(C(O)Cc4ccccc4)cc3)N3CCC(=C23)N1
Reactant: O=S(Cl)Cl
Product: O=C1C=CC2=CN=C(c3ccc(C(Cl)Cc4ccccc4)cc3)N3CCC(=C23)N1

Procedure:
This compound was prepared from intermediate 247a and thionyl chloride according to the procedure used in Example 171. Received 3.53 g (75%).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=12.S1C2=NC=CC=C2C(CN)=C1>>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([CH2:10][NH2:11])[CH:7]=[CH:6][C:5]=12
Reactant: N#Cc1ccc2ncnn2c1
Agent: NCc1csc2ncccc12
Product: NCc1ccc2ncnn2c1

Procedure:
Intermediate L was prepared from [1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile (L-2) following similar procedures for synthesizing intermediate J from J-4, as described above.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[I:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:20][C:16]1[CH:15]=[C:14]([I:13])[CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc(I)c1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cccc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-bromomethylnaphthalene, 3-iodophenol, potassium carbonate and dimethylformamide was stirred at ambient temperature to provide 3-(naphth-2-ylmethoxy)phenyl iodide.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([F:34])[CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:30]1([CH2:29][O:28][C:20]2[CH:21]=[CH:22][C:23]([CH:25]([F:27])[F:26])=[CH:24][C:19]=2[C:18]2[C:13]3[NH:12][C:11]([CH3:33])=[C:10]([C:8]([NH:7][C@@H:5]4[CH2:6][C@@H:2]([NH:1][C:35](=[O:38])[CH2:36][CH3:37])[CH2:3][C@H:4]4[F:34])=[O:9])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:31][CH2:32]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1F
Product: CCC(=O)N[C@H]1C[C@@H](F)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f71) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[NH2:22][C@H:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[N+:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:19]=[C:20]([NH:22][C@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[O:8][CH2:9][C:10]=2[CH:15]=1)([O-:18])=[O:17]
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Product: O=[N+]([O-])c1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Yield: 80.2 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (3.894 g, 12.0 mmol; HPLC: 4.446 min) and (R)-1-aminotetralin (CAS 21966-60-9) (1.767 g, 12.0 mmol; HPLC: 0.390 min) according to the procedure described for Example 1. Obtained the title compound as a yellow foam (3.11 g, 80%, HPLC 2.211 min), MS (ISP) m/e=324.2 [(M+H)+].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:36])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH:34]=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:36])[CH2:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[CH:34]=[CH:33][N:32]=[N:31]4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-methoxy-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M38) (394 mg, 0.758 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (169 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].S(=O)(=O)(O)O.C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1C(=O)O
Yield: 37.5 %

Procedure:
A mixture of methyl 2-methoxy-4-trifluoromethanesulfonyloxybenzoate (3.49 g), sulfuric acid (90%, 0.1 mL), acetic acid (10 mL) and water (2 mL) was heated under reflux for 16 hrs. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization (solvent: ethyl acetate/n-hexane) to afford the title compound (1.25 g).
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=O)[CH2:5][C@H:6]3[C@:26]([CH3:27])([C@@H:2]12)[C:25]1[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@@H:10]([CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:9]=1[O:8][C:7]3=[O:29].O.NN.C(O)(=O)C.O>C(O)C>[OH:1][C@@H:2]1[C@@:26]2([CH3:27])[C@@H:6]([C:7](=[O:29])[O:8][C:9]3[C@H:10]4[C@:22]([CH3:28])([CH2:23][CH2:24][C:25]=32)[C@@H:13]([C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:11]4)[CH2:5][CH:4]=[CH:3]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@]1(C)[C@H](CC(=O)[C@@H]2O[C@@H]21)C(=O)O3
Agent: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@]1(C)[C@H](CC=C[C@@H]1O)C(=O)O3
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Compound 6 (9.0 mg, 0.022 mmol) obtained in Example 5 was dissolved in ethanol (0.5 mL), and hydrazine monohydrate (10 μL) and acetic acid (10 μL) were added thereto at room temperature, followed by stirring for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative thin layer chromatography to obtain the title compound (6.2 mg, 71%).
Reaction SMILES: O[CH2:2][C:3]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]4)=[CH:12][CH:11]=2)=[C:6]([CH:30]([CH3:32])[CH3:31])[O:5][N:4]=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[NH:41][C:42](=[O:47])[C:43]([F:46])([F:45])[F:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[N:41]([CH2:2][C:3]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]4)=[CH:12][CH:11]=2)=[C:6]([CH:30]([CH3:32])[CH3:31])[O:5][N:4]=1)[C:42](=[O:47])[C:43]([F:45])([F:46])[F:44]
Reactant: O=C(Nc1c(Cl)cccc1Cl)C(F)(F)F
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CO)noc4C(C)C)cc3)ccc2n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CN(C(=O)C(F)(F)F)c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.6 %

Procedure:
To a solution of methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (25 mg, 0.058 mmol), N-(2,6-dichlorophenyl)-2,2,2-trifluoroacetamide (15 mg, 0.058 mmol) and triphenylphosphine (30 mg, 0.12 mmol) in dichloromethane was added di-tert-butyl azodicarboxylate (27 mg, 0.12 mmol). The solution was stirred at ambient temperature for approximately 1.5 hours and then was adsorbed onto silica gel and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes gradient elution). The resulting mixture was further purified by chromatography (silica gel, 2% methanol in dichloromethane) to afford methyl 6-[4-({[3-{[(2,6-dichlorophenyl)(trifluoroacetyl)amino]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (10 mg, 26%). 1H-NMR (400 MHz, CDCl3) δ 8.36-8.33 (m, 2H), 8.22 (d, J=9 Hz, 1H), 8.06-8.01 (m, 2H), 7.71 (d, J=9 Hz, 2H), 7.42-7.29 (m, 3H), 7.11 (d, J=9 Hz, 2H), 5.05 (s, 2H), 5.04 (s, 2H), 4.05 (s, 3H), 3.27 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). LRMS (APCI) m/z 672 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[C:22]#[N:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C(Cl)Cl.C1C(=O)N([Br:34])C(=O)C1>CCOCC>[Br:34][C:19]1[S:18][C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:21]([C:22]#[N:23])[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3sccc3C#N)c(C)nc12
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C#N)c(C)nc12
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile (0.83 g, 2.56 mmol) and CH2Cl2 (10 mL) is added NBS (0.48 g, 2.69 mmol). The solution is stirred for 1 hour, diluted with Et2O (100 mL), washed with water (3×100 mL), brine (100 mL), dried (MgSO4) filtered and concentrated to furnish the title compound (1.03 g, 2.55 mmol, >99%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.56 (s, 3H), 2.60 (s, 3H), 3.24-3.32 (m, 1H), 6.76 (s, 1H), 7.30 (s, 1H). LC/MS (m/z): calcd. for C18H19BrN4S (M+H)+: 404.4; found: 404.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C(C)(C)C)[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.Cl>ClC1C=CC=CC=1Cl.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:15]=[C:9]([C:9]([CH3:15])([CH3:10])[CH3:8])[C:8]2[O:12][C:11](=[O:13])[C:10](=[C:10]3[C:7]4[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:15]=[C:9]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:8]=4[O:12][C:11]3=[O:13])[C:7]=2[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2=C1C(=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Reaction time: 0.5 h

Procedure:
10 g of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (prepared as described in Ex. 1a of U.S. Pat. No. 5,614,572) are placed in 25 ml of 1,2-dichlorobenzene, and 0.5 g of 4-dimethylaminopyridine and 3 ml of thionyl chloride are added thereto. The solution is then slowly heated to 373 K at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. It is then stirred at that temperature for a further ½ hour. The temperature is then increased to reflux temperature. After 75 min, the 1,2-dichlorobenzene is distilled off, under reduced pressure at the end. The isoxindigo is crystallised out by adding 30 ml of acetonitrile to the residue, is filtered off, washed with acetonitrile and dried, yielding 6.8 g (73% of the theoretical yield) of 5,7,5′,7′-tetra-tert-butyl-[3,3]bibenzofuranylidene-2,2′-dione of formula (LIa).
Reaction SMILES: [OH-].[Na+].[C:3]([S:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])(=O)[CH3:4].[CH3:16]/[C:17](/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:18]\CCI.O>C(O)C>[CH3:18]/[C:17](/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:16]\[CH2:4][CH2:3][S:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCI
Reactant: CCOP(=O)(CSC(C)=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CSCC/C=C(\C)CC/C=C(\C)CCC=C(C)C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
Solid sodium hydroxide (0.14 g, 3.5 mmol) was added to a stirred solution of diethyl acetylthiomethylphosphonate (0.59 g, 2.5 mmol) in ethanol (10 mL). The resulting mixture was stirred at room temperature under nitrogen until all the sodium hydroxide dissolved, then added a solution of (E,E)-4,8,12-trimethyl-3,7,11-tridecatrienyl iodide (0.84 g, 2.4 mmol) in ethanol (2 mL). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was poured into cold water and extracted with ether. The ethereal extract was washed with water, dried, filtered and evaporated to give a residue, which was purified by flash chromatography on a silica gel column. Elution of the column with methylene:acetate (10:1, v:v) afforded the title compound (0.91 g, 2.26 mmol, 94%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:33][CH3:34])=[CH:5][C:6]2[N:12]([CH2:13][CH3:14])[C:11](=[O:15])[CH:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[N:9]=[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7]=2[CH:32]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[C:4]([O:33][CH3:34])=[CH:5][C:6]2[N:12]([CH2:13][CH3:14])[C:11](=[O:15])[CH:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:23])[N:9]=[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7]=2[CH:32]=1
Reactant: CCN1C(=O)C(Cc2ccccc2[N+](=O)[O-])N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Agent: [Pd]
Solvent: CO
Product: CCN1C(=O)C(Cc2ccccc2N)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Yield: 70 %

Procedure:
Stir a mixture of 80 mg (0.17 mmol) of 7,8-dimethoxy-1-ethyl-3-(2-nitrobenzyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one IIbh, 10 mg of Pd/C 10% by weight in 15 ml of MeOH under 65 psi of H2 at room temperature for 2 hours. Filter the suspension on celite, rinse three times with 10 ml of MeOH. Evaporate to dryness and purify by silica chromatography (AcOEt 1/hexane 4, 1/2). Recrystallize in EtOH. Yield: 70%. M: degradation at 280° C. 1H-NMR (DMSO, 300 MHz): d 0.86–0.90 (m, 3H, CH3), 3.21–3.31 (m, 2H, CHCH2), 3.59 (s, 3H, OCH3), 3.69–3.76(m, 2H, NCH+CHCH2), 3.88 (s, 3H, OCH3), 4.22–4.30 (m, 1H, NCH), 6.46–6.51 (m, 1H Ar), 6.59–6.61 (m, 2H Ar), 6.85–6.88 (m, 1H Ar), 7.01–7.03 (m, 1H Ar), 7.41–7.53 (m, 5H Ar). Mass: (M+H)+=430.22.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[Na+].[Cl-].[C:14]1([CH:20]([OH:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCCl>[C:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])[CH3:21]
Reactant: CC(O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Fe(NO3)3.9H2O (16.1607 g, 40.0 mmol), TEMPO (6.2510 g, 40.0 mmol), NaCl (2.3377 g, 40.0 mmol) and DCE (400 mL) were added to a 2 L-three-necked flask, and were stirred for 10 mins at room temperature under oxygen atmosphere. 1-Phenyl ethanol (488.64 g, 4.0 mol) was then added dropwise to the reaction solution. The reaction was exothermic, and the reaction temperature was kept below 50° C. The reaction was monitored by TLC till it was complete. The reaction solvent DCE was recovered after distillation under atmospheric pressure (350 mL, recovery of 88%) and acetophenone was obtained after further distillation under reduced pressure (b.p. 98˜100° C./20 mmHg, 436.6414 g, 91%).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH2:18][CH3:19])[C:15]([NH2:17])=[O:16].F[B-](F)(F)F>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:4][Si:3]([C:1]#[C:2][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH2:18][CH3:19])[C:15]([NH2:17])=[O:16])([CH3:6])[CH3:5]
Reactant: CCC(C(N)=O)c1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCC(C(N)=O)c1ccccc1C#C[Si](C)(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Ethynyltrimethylsilane (0.11 mL, 0.80 mmol) and dry DMF (9.0 mL) was added to a mixture of 2-(2-iodophenyl)butanamide (I2) (193 mg, 0.668 mmol), PdCl2(PPh3)2 (23 mg, 0.033 mmol), t-Bu3PH.BF4 (10 mg, 0.033 mmol) and CuI (6 mg, 0.033 mmol) under nitrogen. The resulting solution was degassed with a stream of nitrogen for 10 minutes before the addition of Et3N (3.0 mL). The resulting mixture was stirred at 60° C. under nitrogen for 16 hours then adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound I3 as a tan coloured solid (151 mg, 87); 1H NMR (400 MHz, d6-DMSO) δ 7.46-7.39 (m, 2H), 7.34 (td, J=7.7, 1.4 Hz, 1H), 7.26 (br, 1H), 7.21 (td, J=7.5, 1.4 Hz, 1H), 6.97 (br, 1H), 3.80 (dd, J=8.9, 5.7 Hz, 1H), 1.95-1.80 (m, 1H), 1.69-1.55 (m, 1H), 0.85 (t, J=7.3 Hz, 3H), 0.25 (s, 9H). LCMS-A: rt 6.267 min; m/z 260 [M+H]+.