Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(C=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 100.1 %

Procedure:
To a solution of 2-hydroxy-3-methylbenzaldehyde (3.0 g, 22.07 mmol) in N,N-dimethylformamide (50 mL), potassium carbonate (3.65 g, 26.4 mmol) was added and furthermore benzyl bromide (2.9 mL, 24.2 mmol) was added thereto. The mixture was stirred at room temperature for 26 hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (5.0 g, 100%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.ClCCl>[Cl:15][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2ccccc2c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: ClCc1ccc2ccccc2c1

Procedure:
To 1.26 mol of naphth-2-yl-methanol in 1.5 liters of toluene there are slowly added 3.8 mol of thionyl chloride. The mixture is then heated at reflux for two hours. After cooling, the solvent is evaporated off. The crude product is taken up in toluene twice and evaporated. The oil obtained is taken up in dichloromethane, washed and dried. After filtering and evaporating, the oil obtained is distilled to yield the expected product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-amino-1-N-Boc pyrrolidine (1.0 eq, 2.68 mmol), 4-chlorobenzyl bromide (1.0 eq, 2.68 mmol), and potassium carbonate (1.75 eq) were mixed in ethanol (10 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, filtered and concentrated. The crude product was purified by flash chromatography on silica using ethyl acetate. ESI-MS m/z: 311 (M+1), UV retention time: 1.18 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:6]=[C:5]2I.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH2:38])=[CH:35][CH:34]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:6]=[C:5]2/[CH:38]=[CH:37]/[C:36]1[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=1
Reactant: Fc1cc2c(cc1Br)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(/C=C/c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(F)c(Br)cc23)cc1
Yield: 74.1 %

Procedure:
A solution of 3.0 g of 5-bromo-6-fluoro-3-iodo-1-trityl-1H-indazole, 628 mg of 4-fluorostyrene, 115 mg of palladium acetate, 307 mg of 2-(di-ter-butylphosphino)biphenyl and 3.60 mL of triethylamine in N,N-dimethylformamide was stirred at 70° C. for a day. After diluting with ethyl acetate, washing successively with aqueous ammonium chloride and saturated brine, and drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:100), to afford 2.2 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14](OCC)=[O:15])=[CH:10][C:9]=1[CH3:21])=[O:6])[CH3:3].C(=O)=O.CC(O)C.[CH3:30][NH:31][CH3:32]>C(Cl)(Cl)Cl>[CH3:30][N:31]([CH3:32])[C:14](=[O:15])[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([NH:7][C:5]([O:4][C:2]([CH3:22])([CH3:3])[CH3:1])=[O:6])=[C:9]([CH3:21])[CH:10]=1
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Reactant: CNC
Agent: O=C=O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCC(=O)N(C)C)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 312 h
Yield: 100 %

Procedure:
To a 100 mL pressure vessel with a stirring bar was added ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate (1.00 g, 3.24 mmol). The vessel was cooled in a Dry Ice®/2-propanol bath to -78° C. and dimethylamine was condensed onto the solid to a final volume of ~30 mL. The reaction vessel was sealed, allowed to warm to ambient temperature and stirred for 13 days. The excess dimethylamine was vented and the residue was dissolved in CHCl3 and concentrated, twice to remove the last traces of dimethylamine. The crude product was chromatographed on 75 g of silica gel using 75/25 EtOAC-hexane as eluant to provide 1 g (100% yield) N,N-dimethyl-4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetamide as a white, crystalline solid. 1H NMR (CDCl3): d 1.50 (s, 9H), 2.22 (s, 3H), 2.96 (s, 3H), 3.07 (s, 3H), 4.63 (s, 2H), 6.09 (br s, 1H), 6.77, (s, 2H), 7.52 (br s, 1H). ##STR51## N,N-Dimethyl 4-amino-3-methylphenoxyacetamide (5-3)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H](C3C=CC=CC=3)C)[CH2:9]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+].O1CCCC1.CO>[Pd].O>[NH:10]1[CH2:11][CH2:12][O:13][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ccc([C@H]2CNCCO2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of (2S)-2-(4-aminophenyl)-4-((1R)-1-phenylethyl)morpholine (17.45 g, 61.8 mmol) and ammonium formate (11.7 g, 185.4 mmol) in mixture of tetrahydrofuran (180 ml), methanol (180 ml) and water (45 ml) was added 10% palladium on carbon (wet, 1.8 g) and the mixture was stirred at 95° C. for 3 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give 4-((2S)-morpholin-2-yl)phenylamine (10.45 g, 95%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]#[N:19])=[CH:4][CH:3]=1.[NH2:20][OH:21].Cl.C([O-])([O-])=O.[K+].[K+].O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18](=[N:20][OH:21])[NH2:19])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(Cc1c(-c2ccc(Cl)cc2)nc2ccccn12)=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetonitrile (0.13 mol, 34.0 g) in absolute EtOH (300 mL) was added NH2OH.HCl (0.32 mol, 22.1 g) and K2CO3 (0.32 mol, 44.1 g), respectively. The mixture was stirred at r.t. overnight, filtrated, and washed with EtOH for 3 times. The EtOH-filtrate was concertrated to small volume, and the precipitation was collected by filtration, to give one partial products. The solid was dispersed into water, sonicated for 10 mins, filtrated, washed with water, and dried in vacuo, to give another partial products. Combined two portions products added up to 25.0 g (65.4%). m/e+=301 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CI>>[CH:8]1[C:9]2[C:4](=[N:1][C:22]3[C:17]([C:16]=2[NH:1][C:4]2[CH:9]=[CH:8][C:7]([N:10]4[CH2:15][CH2:14][N:13]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH2:12][CH2:11]4)=[CH:6][CH:5]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: CI
Product: c1ccc(CN2CCN(c3ccc(Nc4c5ccccc5nc5ccccc45)cc3)CC2)cc1
Yield: 2 %

Procedure:
Following the procedure outlined in Step 1 of Example 1, but substituting 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16) for N-(4-nitrophenyl)piperazine, and benzyl bromide for methyl iodide, afforded the title compound (15%, overall yield 2%)
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:47][CH2:48][CH3:49])[N:18]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[C:19](=[O:31])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:47][CH2:48][CH3:49])[N:18]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:3][C:4](=[O:7])[O:5][N:46]=3)=[CH:37][CH:38]=2)[C:19](=[O:31])[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[CH:25][CH:26]=1)[CH3:14]
Reactant: CCCc1nc(CC)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogen carbonate (1.0 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-{[4-ethyl-5-(4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.50 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.44 g, 79%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(C)=O)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
1-(4-Benzyloxy-3-methoxy-phenyl)-ethanone (24.61 g, 96 mmol) was dissolved in acetic acid (100 ml) and the mixture was cooled to 10° C. Nitric acid fuming (Fluka ID 84392, 100%, 10 ml, 240 mmol) was added dropwise to the cooled solution over 2 hours. The reaction mixture was allowed to come to room temperature and stirred for 16 hours. The reaction mixture was poured into water (400 ml). The precipitate was filtered, washed with water, then taken up in sodium hydrogencarbonate saturated aqueous solution (300 ml) and stirred for 2 hours. The precipitate was filtered, washed with water and dried. The raw product was recrystallized from ethyl alcohol (1000 ml) to give 18.25 g of product [B]. Yield 65%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([N:20]2[CH2:23][C:22]([C@@H:25]([NH:27][C:28](=[O:34])[O:29]C(C)(C)C)[CH3:26])([OH:24])[CH2:21]2)=[O:19])=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.Cl.[CH3:36]O>>[C:28]([OH:29])(=[O:34])[CH3:36].[NH2:27][C@H:25]([C:22]1([OH:24])[CH2:23][N:20]([C:18]([C:11]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:15][C:14](=[O:16])[N:13]([CH3:17])[N:12]=2)=[O:19])[CH2:21]1)[CH3:26]
Reactant: CO
Reactant: C[C@H](NC(=O)OC(C)(C)C)C1(O)CN(C(=O)c2nn(C)c(=O)cc2Nc2ccc(I)cc2F)C1
Agent: Cl
Product: CC(=O)O
Product: C[C@H](N)C1(O)CN(C(=O)c2nn(C)c(=O)cc2Nc2ccc(I)cc2F)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
1,1-Dimethylethyl {(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate (55 mg, 0.09 mmol), prepared using procedures similar to those described in Example 36, was taken up in methanol (2 mL) and hydrochloric acid (4N in dioxane, 1 mL, 4 mmol) was added and the reaction was stirred at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 6-({3-[(1S)-1-aminoethyl]-3-hydroxyazetidin-1-yl}carbonyl)-5-[(2-fluoro-4-iodophenyl)amino]-2-methylpyridazin-3(2H)-one acetate as yellow solid (40 mg, 87%). 1H NMR (400 MHz, CDCl3): 10.17 (d, 1H), 7.52-7.46 (m, 2H), 7.09 (t, 1H), 6.13-6.12 (m, 1H), 4.51-4.48 (m, 2H), 4.18-4.03 (m, 2H), 3.73 (d, 3H), 3.35-3.28 (m, 1H), 3.22-2.80 (br, 3H), 1.21-1.19 (m, 3H); MS (EI) for C17H19FIN5O3: 488 (MH+).
Reaction SMILES: ClC[C:3]([N:5]([CH2:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]#[N:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:6][CH2:7][NH:8][C:9](=O)OC(C)(C)C)=[O:4].CCO.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1>[O:4]=[C:3]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]([C:27]#[N:28])[CH:24]=[CH:25][C:26]1=2
Reactant: CC(C)(C)OC(=O)NCCN(CC1CCCc2cc(C#N)ccc21)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: N#Cc1ccc2c(c1)CCCC2CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{(chloroacetyl)[(6-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}ethyl)carbamate (140 mg, 0.35 mmol) in HCl/dioxane (20 mL) was stirred at RT for 12 hours and then concentrated to dryness. To the residue was added 2 mL EtOH and K2CO3 (143 mg, 1.04 mmol). The resulting mixture was heated to reflux for 4 hours before cooled to RT and filtered. The filtrate was concentrate and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness to give the title compound. MS m/z: 270 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])=[CH:2][CH3:3].C1(OCC=C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30]>O.CN(C)C=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])=[CH:2][CH3:3]
Reactant: CC=Cc1ccccc1O
Reactant: COC(=O)C(C)Br
Agent: C=CCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=Cc1ccccc1OC(C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 500 mg (3.72 mmol) of 2-propenylphenol (E/Z mixture), prepared by Claisen rearrangement of phenylallylether followed by double bond isomerisation, 1.02 g of potassium carbonate (0.74 mmol) and 745 mg of rac. methyl 2-bromopropionate (4.46 mmol) and 10 ml of dimethylformamide was stirred overnight at RT and then for 4 hours at 80° C. The reaction mixture was then added to 40 ml of water and extracted three times with 30 ml diethyl ether. The organic phase was washed with 5% sodium hydroxide solution, separated off, dried with Na2SO4 and concentrated by evaporation. 685 mg (83.6% of theory) of virtually pure methyl 2-(2-propenyl-phenyloxy)propionate were obtained.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]1[CH:17]([OH:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl.O>CCCCCC.CN(C)C=O>[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[CH:5]1[CH:17]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1C(O)c1ccc(F)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: COCCOCOC(c1ccc(F)cc1)C1C(=O)NCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 0.13 g (0.0054 mole) of NaH (0.22 g of a 61% dispersion in oil, washed with hexane) in 10 ml of dimethylformamide (DMF) was added 1.6 g of 35 in 20 ml of dry DMF, and the mixture stirred at 0° C. for 30 minutes. A solution of 0.67 g (0.0055 mole) of (2-methoxyethoxy)methyl chloride in 5 ml of dry DMF was added and the mixture allowed to warm to room temperature, stirred for 1 hour, and poured into 50 ml of water. The product was extracted into ethyl acetate and the extract washed with brine and dried over MgSO4. After filtration, the solvent was removed at reduced pressure and the residue triturated with hexane and filtered to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:13][CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)N
Solvent: CO
Product: CC(C)Nc1cc(Cl)nc(N)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
In a 25 mL sealable tube under argon were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) and isopropylamine (0.78 mL, 9.15 mmol) in CH3OH (15 mL). The vial was sealed and the resulting mixture was stirred overnight at 50° C. The reaction was cooled to room temperature and stirred over the weekend. The reaction mixture was concentrated, and the resulting orange oil was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (453 mg, 71%) as a yellow foam. LC-MS (ES) m/z=187 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].[C:13]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14](C2C(C(O)=O)=CC=CC=2)=[CH:15][CH:16]=[CH:17][CH:18]=1.CN([C:37]([O:41]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:37]([C:31]2[CH:30]=[CH:29][C:28]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:33][CH:32]=2)=[O:41])[C:5]=1[NH2:11]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccccc1-c1ccccc1-c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccc3)cc2)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,3-diamino-benzoic acid methyl ester (200 mg, 1.2 mmol, and biphenyl benzoic acid (238 mg, 1.2 mmol), HATU (1.14 g, 3 mmol) in dry DMF (5 mL) was added diisopropylethyl amine (0.6 mL, 3.6 mmol). The mixture was stirred at ambient temperature overnight and poured into water (50 mL). The precipitated solid was filtered and dried in a vacuum oven to afford the required compound which was used directly for the next step without any purification (300 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11])[CH:5]=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2>>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[CH:5][C:4]1[CH:3]=[C:2]([CH3:1])[C:9]([O:10][CH3:11])=[C:8]([CH3:12])[CH:7]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COc1c(C)cc(C=O)cc1C
Product: COc1c(C)cc(C=C2C(=O)Nc3ccc(F)cc32)cc1C

Procedure:
3,5-Dimethyl-4-methoxybenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.3 g of 5-fluoro-3-(4-methoxy-3,5-dimethylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][C:42]([CH3:46])([CH3:45])[C:43]#[N:44])=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[C:43]([C:42]([CH3:46])([CH3:45])[CH2:41][O:40][C:39]1[CH:38]=[C:37]([CH3:50])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:48]([CH3:49])[CH:47]=1)#[N:44]
Reactant: Cc1cc(OCC(C)(C)C#N)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)C#N)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 3-(4-bromo-3,5-dimethylphenoxy)-2,2-dimethylpropanenitrile following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.89 min; Mass spectrum (ESI+): m/z=544 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([O:3]C)=[O:2].Cl.[N:13]([O-])=O.[Na+].[OH:17][C:18]1[CH:23]=[C:22]([CH3:24])[O:21][C:20](=[O:25])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([C:5]1[CH:11]=[CH:10][C:8]([N:9]2[C:22]([CH3:24])=[CH:23][C:18](=[O:17])[C:19]([C:20]([OH:21])=[O:25])=[N:13]2)=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1cc(O)cc(=O)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To an ice cooled suspension of 11.33 g (0.075 mol) 4-carbomethoxy aniline in 40 ml of water there is added 30 ml of 12N hydrochloric acid. The suspension is cooled to 0° C. and to it there is added 5.7 g (0.0825 mol) of sodium nitrite in 15 ml of water, dropwise. The solution formed is added to an ice cooled solution of 9.45 g (0.075 mol) 4-hydroxy-6-methyl pyr-2-one and 33 g (0.3075 mol) of sodium carbonate in 190 ml of water (considerable foaming is observed). The suspension is stirred at 5° C. for 1 hr., room temperature for 2 hrs. And refluxed for 1/2 hr. The solution formed is allowed to stand at room temperature for 18 hrs. and is extracted with 3 (200 ml) portions of methylene dichloride. The aqueous solution is acidified with 12N hydrochloric acid at 10° C. and the suspension formed is vacuum filtered. The filter cake is boiled in 300 ml of methanol and vacuum filtered hot. The filter cake is air dried to afford 13.1 g (64% yield) of product, mp 290° C. decomp.