Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:38](I)[CH3:39]>CN(C)C=O>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:38][CH3:39]
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C)C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
5-Methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1 g) is dissolved in dimethylformamide (10 ml) and thereto are added potassium carbonate (0.5 g) and ethyl iodide (0.45 g). The mixture is stirred at room temperature overnight. After completion of the reaction, the reaction solution is poured into ice-water and the precipitated crystal is collected by filtration, and purified by silica gel column chromatography (eluent; dichloromethane:methanol=90:1), and recrystallized from diisopropyl alcohol/petroleum ether to give 5-(N-methyl-N-ethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (50 mg) as white powder, m.p. 192-193° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([CH:23]=[C:24]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[CH:25]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:21][OH:22])([CH3:4])([CH3:3])[CH3:2].I(C1C=CC=CC=1C(O)=O)(=O)=O>CC(N(C)C)=O>[C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([CH:23]=[C:24]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[CH:25]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=1[CH:21]=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CO)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CC(=O)N(C)C
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2C=O)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of the product from Example 127 (0.60 g, 1.20 mmol) in anhydrous DMA (15 ml) was added 2-iodoxybenzoic acid (336 mg, 1.20 mmol). The mixture was stirred at room temperature for 1 h, and then partitioned between EtOAc (20 ml) and H2O (2×20 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 2% MeOH in CH2Cl2 as the eluent to give the title compound as a colorless solid (395 mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.43 (d, J=2.21 Hz, 1H) 10.45 (s, 1H) 10.15 (s, 1H) 8.06 (d, J=16.18 Hz, 1H) 7.97 (d, J=8.82 Hz, 1H) 7.73-7.78 (m, 2H) 7.69 (d, J=2.57 Hz, 1H) 7.51 (dd, J=8.64, 2.39 Hz, 1H) 7.30 (d, J=16.18 Hz, 1H) 7.26 (d, J=2.57 Hz, 1H) 5.66 (dd, J=7.72, 2.21 Hz, 1H) 3.81 (s, 3H) 3.07 (s, 3H) 1.39 (s, 9H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[Br:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:17][C:18]1[CH:19]=[C:20]([O:24][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)[CH:21]=[N:22][CH:23]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cn2nc(Oc3cncc(Br)c3)ccc2n1)C1CC1
Temperature: 140 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.7 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) were added 5-bromopyridine-3-ol (1.7 g, 10 mmol) and potassium carbonate (1.7 g, 13 mmol), and the mixture was stirred at 140° C. for 8 hr. After cooling the mixture to room temperature, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and precipitated from ethyl acetate/diisopropyl ether to give the title compound (1.6 g, 85%) as a yellow powder.
Reaction SMILES: [Cl:1][CH:2]([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[F:20])[S:3]([C:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[O:8][N:7]=1)(=[O:5])=[O:4].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]([C:13]1[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=1[F:19])([F:31])[S:3]([C:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[O:8][N:7]=1)(=[O:4])=[O:5]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC1(C)CC(S(=O)(=O)C(Cl)c2c(F)cccc2F)=NO1
Solvent: C1CCOC1
Product: CC1(C)CC(S(=O)(=O)C(F)(Cl)c2c(F)cccc2F)=NO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
Phosphazene base 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-tBu) (2M in THF) (0.38 ml, 0.77 mmol) was added dropwise to a solution of 3-[chloro-(2,6-difluoro-phenyl)-methanesulfonyl]-5,5-dimethyl-4,5-dihydroisoxazole (0.2 g, 0.64 mmol) in THF (2 ml), and the solution was stirred for 10 minutes at room temperature. N-Fluorobenzenesulfonimide (NFSI) (0.15 g, 0.77 mmol) was added and the mixture was stirred for 1 hour. The reaction was quenched by addition of aqueous hydrochloric acid (2M). The mixture was diluted with ethyl acetate and the two phases were separated. The organic phase was washed several times with brine, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 1.21 of Table 27) as a white solid (44 mg, 98% yield).
Reaction SMILES: C[Si](C[Mg]Cl)(C)C.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]1[S:18][C:19]2[C:24]([N:25]=1)=[CH:23][CH:22]=[C:21]([C:26]1([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27]1)[N:20]=2)[CH:12]=O.[CH3:35]C(C)([O-])C.[K+].Cl>C1COCC1>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH2:35])[CH:14]=[CH:15][C:16]=1[C:17]1[S:18][C:19]2[C:24]([N:25]=1)=[CH:23][CH:22]=[C:21]([C:26]1([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]1)[N:20]=2
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: C[Si](C)(C)C[Mg]Cl
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trimethylsilylmethylmagnesium chloride, 1.1 M solution in THF (15 mL) was added dropwise to a solution at 0° C. of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (4.00 g, 11 mmol) in THF (80 mL) and the reaction mixture was stirred for 30 min at 0° C. The reaction mixture was quenched with 1 N aq. HCl and extracted with EtOAc twice, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in THF (100 mL), and cooled to 0° C. in ice bath. The slurry of potassium t-butoxide (2.4 g, 21 mmol) in THF (12 mL) was added slowly. At the end of the addition the reaction mixture was allowed to stir for 30 min at 0° C. At this time 1 N HCl was added and the mixture was extracted with EtOAc and the organic layer was dried over MgSO4. The residue was concentrated in vacuo and purified by silica gel chromatography to afford 2-(2-fluoro-4-vinylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine. MS (ESI) m/z: calculated: 372.1; Observed: 373.0 (M++1).
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[O:10][N:9]=1)=O)(C)(C)C.O(Cl)Cl.[P+3]>>[CH3:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:11]1[O:10][N:9]=[C:8]([C:6]#[N:5])[CH:12]=1
Reactant: CC(C)(C)Cc1cc(C(=O)NC(C)(C)C)no1
Agent: ClOCl
Agent: [P+3]
Product: CC(C)(C)Cc1cc(C#N)no1
Temperature: 25 °C

Procedure:
A mixture of 5-(2,2-dimethyl-propyl)-isoxazole-3-carboxylic acid tert-butylamide (58.0 g, 0.243 mol) and phosphorus (III) oxychloride (156 ml, 1.70 mol) is heated under nitrogen atmosphere at reflux temperature for 2 h. The reaction mixture is cooled to rt and concentrated to remove excess phosphorus (III) oxychloride. The residue is diluted with DCM (2000 ml) and washed with saturated aq sodium bicarbonate (500 ml×2). The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by chromatography on silica (DCM/hexanes 1/1) to yield the target compound as yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=4)[C:12]=3[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=2[CH3:35])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44]>C1COCC1.C(=O)(O)[O-].[Na+]>[C:43]([NH:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=4)[C:12]=3[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=2[CH3:35])[CH:5]=[CH:4][CH:3]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N)n1)OCC2c1ccc(C(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a solution of N-(7-(6-aminopyridin-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (94.3 mg, 0.2 mmol) and triethylamine (0.042 mL, 0.3 mmol) in THF (1 mL) was added acetyl chloride (0.015 mL, 0.22 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 51 mg (yield: 50%) of the title compound. Melting point: 205-208° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=O)[O:24]C4C=CC=CC=4)[CH:17]=3)=[C:13]([F:34])[CH:12]=2)=[O:9])[C:4](=[O:35])[N:3]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[CH3:42][NH:43][CH2:44][CH3:45]>CN1C(=O)CCC1>[CH2:44]([N:43]([CH3:42])[C:23](=[O:24])[NH:22][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:32]=[CH:33][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:35])[N:3]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:12][C:13]=2[F:34])[CH:21]=[CH:20][N:19]=1)[CH3:45]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CCNC
Solvent: CN1CCCC1=O
Product: CCN(C)C(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2F)ccn1
Temperature: 40 °C
Yield: 58.9 %

Procedure:
A mixture of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)pyridin-2-yl)carbamate (100 mg, 0.18 mmol), NMP (5 mL) and N-methylethanamine (12 mg, 0.2 mmol) was heated at 40° C. for 2 hours. The solvent was evaporated under reduced pressure at 40° C., and then diluted with water (10 mL). The precipitate was collected by filtration, and then purified by a silica gel column chromatography (DCM/MeOH (v/v)=60/1) to give the title compound as a white solid (55 mg, 62%).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].Br[CH2:10][C:11]([O:13]CC)=[O:12]>>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:10][C:11]([OH:13])=[O:12])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1cc[nH]n1
Product: CC(C)c1ccn(CC(=O)O)n1

Procedure:
Prepared according to the analogous method described for Preparation 75, using 3-isopropyl-1H-pyrazole and ethyl bromoacetate isolating the higher running peak as the desired isomer, followed by the hydrolysis method of Preparation 74.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=S)[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].[CH3:37][NH2:38]>C1COCC1.Cl[Hg]Cl>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=[N:38][CH3:37])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3]
Reactant: CN
Reactant: CC(C)Cn1c(=O)n(C)c(=S)c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)nc21
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: CN=c1c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)nc2n(CC(C)C)c(=O)n1C
Temperature: 110 °C

Procedure:
7-Isobutyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-4-thioxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one (15 mg, 0.030 mmol) and HgCl2 (16.4 mg, 0.060 mmol) are suspended in THF, and then 2.0 M methylamine solution in THF (240 μL, 0.12 mmol) is added. The reaction mixture is heated in a Biotage microwave at 110° C. for 5 hours. After routine workup, the mixture is purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 494.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[F:20][C:21]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][C:22]=1[CH2:23]O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:23][C:22]1[CH:25]=[C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][C:21]=1[F:20])=[O:15]
Reactant: OCc1cc(Oc2ccccc2)ccc1F
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1cc(Oc2ccccc2)ccc1F

Procedure:
The acid chloride of 2(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with 2-fluoro-5-phenoxybenzyl alcohol using the procedure of Example 1 to give 2-fluoro-5-phenoxybenzyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH2:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)=[O:34])=[CH:3][C:4](=[O:14])[O:5]2)=[CH:10][CH:9]=1)#[N:13]
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(CC(=O)Nc3cccc(Cl)c3)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (673 mg, 3. 6 mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (5.4 mL). After 30 minutes 3-chloro-1-isocyanato-benzene (222.3 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-100% ethyl acetate in hexanes to yield 2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(3-chloro-phenyl)-acetamide as a yellow solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: FC(F)(F)c1cccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)c1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401(c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 3-(trifluoromethyl)phenylboronic acid (Aldrich Chemical Company) (47 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 373 (M+1). Mp: 138.9-140.5° C.
Reaction SMILES: C(O)C=C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](O)=[O:13])=[CH:10][CH:11]=1>CC(C)=O>[C:6]1([CH3:5])[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: C=CCO
Solvent: CC(C)=O
Product: Cc1ccc(C=O)cc1

Procedure:
Epoxidation of allyl alcohol is carried out with 200 g of the per-p-toluic acid product solution containing 31.6% by weight of per-p-toluic acid, obtained by autooxidizing p-tolualdehyde with air in the absence of catalyst in acetone as a solvent. That is to say, the per-p-toluic acid product solution contains 63.2 g (0.415 moles) of per-p-toluic acid, 13.2 g (0.097 moles) of p-toluic acid and the solvent acetone. 24.4 g (0.420 mole) of allyl alcohol, which is equimolar to the per-p-toluic acid, is fed to an autoclave containing the per-p-toluic acid product solution, the autoclave being provided with a rotating stirrer and a reflux cooler, and subjected to reaction at a temperature of 50° to 52°C at a stirring speed of 500 rpm for 2 hours.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11](O)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:15].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:15][CH:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:12]
Reactant: CC(O)c1ccc2ncccc2c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(Br)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
To a solution of 1-quinolin-6-yl-ethanol (0.4 g, 2.3 mmol) in dry CH2Cl2 (20 mL) was added PBr3 (0.22 mL, 2.3 mmol). The reaction mixture was allowed to stir at room temperature for 12 h, and then was treated slowly with a saturated solution of NaHCO3 (100 mL) until basic. The CH2Cl2 layer was removed, product was extracted from the aqueous layer with ethyl acetate (100 mL), and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford 0.4 g (72%) of a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 8.89-8.96 (m, 1H), 8.11-8.20 (m, 2H), 7.82-7.89 (m, 2H), 7.41-7.49 (m, 1H), 5.39 (dt, 1H), 2.15 (d, 3H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.C([C:10]1[CH:15]=[CH:14][C:13]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=1)=O.N1CCCCC1>N1C=CC=CC=1>[CH3:20][S:17]([O:16][C:13]1[CH:12]=[CH:11][C:10](/[CH:3]=[CH:2]/[C:1]([OH:7])=[O:6])=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: O=C(O)CC(=O)O
Reactant: CS(=O)(=O)Oc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Temperature: 90 °C
Yield: 57.4 %

Procedure:
Malonic acid (7.80 g, 74.92 mmol) was added to a solution of the crude methanesulfonic acid 4-formylphenyl ester (10 g, 49.95 mmol), which was synthesized in the preceeding step, and piperidine (0.7 ml, 7.09 mmol) in pyridine (50 ml). The reaction mixture was heated to 90° C. for 2.5 h. It was cooled to room temperature. Concentrated hydrochloric acid/ice (400 ml/100 ml) was added. The precipitation was filtered off and washed with a 10% aqueous solution of acetic acid (200 ml). It was dried in vacuo to give 6.95 g of (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([C:27]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1)=[O:28])[CH2:23][CH2:22]2.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([C:27]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1)=[O:28])[CH2:23][CH2:22]2)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2CCc3cccc(O)c3C2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2CCc3cccc(OS(=O)(=O)C(F)(F)F)c3C2)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
Trifluoromethanesulfonic anhydride (1.76 g, 6.24 mmol) was added to a stirred, 0° C. mixture of 1-tert-butyl 2-methyl (2S,4R)-4-{[(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.81 g, 4.30 mmol) and Et3N (1.31 g, 12.90 mmol) in DCM (20 mL) and stirred for 18 h. The resulting mixture was poured into saturated aqueous NaHCO3 and extracted into dichloromethane. The organic layer was washed with 10% citric acid solution, dried over Na2SO4 and concentrated to red oil. The oil was purified by column chromatography on silica gel (gradient elution, 10 to 70% EtOAc in hexanes) to give a yellow oil, 1-tert-butyl 2-methyl (2S,4R)-4-({[8-{[(trifluoro methyl)sulfonyl]oxy}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}oxy)pyrrolidine-1,2-dicarboxylate (1.65 g, 69.4% yield).
Reaction SMILES: [Li+].[Cl-].C([Sn](CCCC)(CCCC)[CH:8]=[CH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]#[N:21])[CH:14]=[CH:13]2)CCC.[CH3:30][N:31]([CH:33]=O)C>C(OCC)(=O)C.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>[CH:14]([C:30]1[C:11]2[C:10](=[CH:19][CH:18]=[C:17]([CH:8]=[CH:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([C:20]#[N:21])[CH:14]=[CH:13]4)[CH:12]=2)[CH2:9][CH2:33][N:31]=1)([CH3:15])[CH3:13]
Reactant: CN(C)C=O
Reactant: CCCC[Sn](C=Cc1ccc2cc(C#N)ccc2c1)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(C)C1=NCCc2ccc(C=Cc3ccc4cc(C#N)ccc4c3)cc21
Temperature: 80 °C
Reaction time: 1.75 h

Procedure:
A solution of Example 13I (70 mg, 0.23 mmol), dichlorobis(triphenylphosphine)palladium (II) (7.0 mg, 0.01 mmol), and LiCl (31 mg, 0.73 mmol) in DMF (1.7 mL) was treated dropwise with a solution of Example 13E (120 mg, 0.26 mmol) in DMF (0.2 mL). The mixture was heated to 80° C., stirred for 1.75 hours, cooled to room temperature, diluted with ethyl acetate, washed with H2O and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product.