Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[C:23]([C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([F:37])[CH:36]=1)[C:33](=[O:38])[N:32]([C:39]1[CH:49]=[CH:48][CH:47]=[C:46](B3OC(C)(C)C(C)(C)O3)[C:40]=1[CH2:41][O:42][C:43](=[O:45])[CH3:44])[N:31]=[CH:30]2)([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:23]([C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([F:37])[CH:36]=1)[C:33](=[O:38])[N:32]([C:39]1[CH:49]=[CH:48][CH:47]=[C:46]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:16])=[CH:13][N:14]=4)[CH:3]=3)[C:40]=1[CH2:41][O:42][C:43](=[O:45])[CH3:44])[N:31]=[CH:30]2)([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: O=C(c1ccc(Nc2cc(Br)ccn2)nc1)N1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2ccnc(Nc3ccc(C(=O)N4CCOCC4)cn3)c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C

Procedure:
[6-(4-Bromo-pyridin-2-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone (200 mg, 0.55 mmol), acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzyl ester (410 mg, 0.83 mmol) and K2CO3(152 mg, 1.10 mmol) were dissolved in dioxane/H2O (10:1, 11 ml). Under N2 atmosphere, Pd2(dba)3 (50 mg, 0.055 mmol) and X-phos (105 mg, 0.22 mmol) was added and the mixture was stirred at reflux temperature overnight. After the completion of the reaction, the mixture was cooled to room temperature and filtered. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether:ethyl acetate=2:1). The desired product was obtained as a yellow solid (200 mg, yield 56%). LC-MS: 651[M+1]+, tR=1.397 min.
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:13][O:14][N:15]=[C:16]([C:32]1[O:33][CH2:34][CH2:35][N:36]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]CC1C=CC(Cl)=CC=1>O>[CH3:13][O:14][N:15]=[C:16]([C:32]1[O:33][CH2:34][CH2:35][N:36]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: CON=C(C1=NCCO1)c1ccccc1OCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: O
Product: CON=C(C1=NCCO1)c1ccccc1O
Yield: 56 %

Procedure:
Anisole (152 ml) and aluminium chloride (16.3 g, 122 mmol) were added to 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime (19.08 g, 55.3 mmol), and the mixture was stirred under ice-cooling for 1.5 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime (6.82 g, 56.0%) as an oil.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].C(COC)OC>S([O-])([O-])(=O)=O.[Cu+2].O>[Cl:8][C:6]1[CH:7]=[C:2]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Oc1ccccc1
Reactant: Nc1ncc(Cl)cc1Br
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(Cl)cc1Oc1ccccc1
Yield: 24 %

Procedure:
3-Bromo-5-chloro-2-pyridinamine (520 mg, 2.5 mmol), phenol (2.0 g, 21.3 mmol), potassium hydroxide (flakes, 85%, 600 mg, 9.1 mmol) and anhydrous copper (II) sulphate (100 mg, 0.6 mmol) and dimethoxyethane (250 μl) were heated together at 140° C. for 2 h, allowed to cool and the mixture poured into water (50 ml). EtOAc extracts (5×15 ml) were filtered through celite and extracted into 2N HCl (4×10 ml). The combined aqueous extracts were basified with NaOH and re-extracted into EtOAc (3×20 ml), dried over MgSO4, and concentrated to a brown oil (230 mg). Purification by column chromatography on silica gel eluting with hexane—EtOAc (80:20) gave the title compound as a white solid (136 mg, 0.6 mmol). An analytical sample was prepared by crystallisation from hexane:
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](=[O:5])[CH3:15]
Reactant: CON(C)C(=O)c1cc(F)ccc1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2-Bromo-5-fluoro-N-methoxy-N-methylbenzamide (4.0 g, 0.015 mol) was dissolved in THF (30 mL) and the solution was cooled to 0° C. under N2blanket. Methyl magnesium bromide (15.26 mL, 0.046 mol) was added dropwise over 30 min. The solution was warmed to room temperature and stirred for 1 hour. The solution was cooled to 0° C. and quenched with HCl/EtOH (9 mL, 4 M solution). The reaction mixture was transferred to a separatory funnel, diluted with H2O (30 mL), and extracted with Ethyl Acetate (2×40 mL). The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. The solution was concentrated to afford 1-(2-bromo-5-fluorophenyl)ethanone as a yellow oil in 93% yield . This material was used in the subsequent step without further purification. 1H NMR (CDCl3, 500 MHz) δ2.61 (s, 3H), 7.00-7.04 (m, 1H) 7.15-7.18 (m, 1H), 7.53-7.59 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>>[F:26][C:27]([F:38])([F:39])[C:28]1[CH:29]=[CH:30][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:32][CH:33]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(C(F)(F)F)cc4)c3)c2c1
Yield: 11.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 4-(trifluoromethyl)phenylacetic acid (0.15 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 28 mg (11% yield) of the title compound. 1H NMR (DMSOd6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.22 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.8–7.68 (m, 3H), 7.6 (m, 3H), 7.5 (t, 1H), 7.35 (s, 1H), 7.17 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 439 [M+H]+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9]C)=[O:8])(=[O:4])=[O:3].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>C1COCC1>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH:22][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([OH:9])=[O:8])(=[O:4])=[O:3]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Reaction time: 18 h
Yield: 15.8 %

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (500 mg, 1.79 mmol) and 2-dimethylaminoethylamine (316 mg, 3.58 mmol) in THF (35 ml) was stirred in an ice bath for 1 hour then at 20°-25° for 18 hours. After removing THF under reduced pressure, the residue was partitioned between saturated Na2CO3 solution and EtOAc. The organic extract was washed (saturated NaCl solution), dried (Na2SO4), filtered and concentrated under reduced pressure. Chromatography over silica gel (elution with 5% MeOH-95% CHCl3) gave an oil which when triturated with EtOAc afforded 2-[N-(2-dimethylaminoethyl)aminosulfonyl]-6-nitrobenzoic acid (90 mg, 16%), m.p. 193° decomposed with effervescence.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O.CCO.C1(C)C=CC=CC=1.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.CCCCCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH3:11])=[C:3]([F:10])[CH:4]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1ccc(Br)c(F)c1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccc(-c2ccccc2C)c(F)c1

Procedure:
A mixture of 4-bromo-3-fluoroanisole, 2-methylphenyl boronic acid, tetrakis(triphenylphosphine)palladium (5% mol) and sodium carbonate (0.23 g, 2.1 mmol) in 20 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 5 h. TLC (EtOAc:hexane/2:98) showed that the reaction was over. The solvents was removed. Water (10 ml) was added. The organic was extracted with methylene chloride (3×50 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after purification with preparative TLC using 2% EtOAc in hexane as the eluant.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]=[C:7]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=1)[C:6]2=[O:24])[CH3:2].IC.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:27])[O:9][CH:8]=[C:7]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=1)[C:6]2=[O:24])[CH3:2]
Reactant: CCc1cc2c(=O)c(-c3ccc4ccccc4c3)coc2cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCc1cc2c(=O)c(-c3ccc4ccccc4c3)coc2cc1OC
Yield: 95.8 %

Procedure:
6-Ethyl-7-hydroxy-3-naphthalen-2-yl-chromen-4-one (d, 0.36 g) was dissolved in dry dimethyl formamide (DMF) (5 mL) and treated with iodomethane (MeI) (0.5 mL) and potassium carbonate (1 g) at room temperature for 2 h. The mixture was diluted with water (50 mL) and the precipitate was collected by filtration, washed with water and dried under vacuum to give 6-ethyl-7-methoxy-3-naphthalen-2-yl-chromen-4-one (e, 0.36 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[O:22])[C:5]2=[O:24].[OH:25]OS([O-])=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:23])[CH2:19][CH2:20][C:21]([OH:25])=[O:22])[C:5]2=[O:24]
Reactant: O=S([O-])OO
Reactant: O=CCCC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A mixture of 4-(6-chloro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-yl)-4-oxobutanal (0.2 g, 0.6 mmol) in 3 mL DMF was stirred at room temperature and treated with oxone (0.3 mL, 0.6 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with 10 mL H2O and adjusted to pH=5 with concentrated HCl. The solid was collected by filtration and washed with 10 mL H2O. The crude product was dissolved in 50 mL EtOAc and washed with 20 mL H2O and then with 20 mL brine. The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo to give 0.20 g white solid. MS m/e: 365 (M+H)+. Calculated for C18H17ClO6: 364.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([O:11]CC)=[O:10].Cl.[N:16]1[CH:21]=[CH:20][C:19]([C:22](=[NH:24])[NH2:23])=[N:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].N1CCC[C@H]1C(O)=O>CN(C)C=O.[Cu]I>[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:24]=[C:8]([C:9]([OH:11])=[O:10])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:23]=2)=[N:18][CH:17]=1
Reactant: N=C(N)c1ccncn1
Reactant: CCOC(=O)C(=O)c1ccccc1Br
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: O=C(O)c1nc(-c2ccncn2)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 2-(2-bromophenyl)-2-oxoacetate (9 g, 35.01 mmol, 1.00 equiv) in N,N-dimethylformamide (60 mL). This was followed by the addition of pyrimidine-4-carboximidamide hydrochloride (5.53 g, 45.03 mmol, 1.29 equiv) and Cs2CO3 (11.38 g, 34.93 mmol, 1.00 equiv). The mixture was stirred for 20 min. To this was added L-proline (850 mg, 7.39 mmol, 0.21 equiv) and CuI (670 mg, 3.53 mmol, 0.10 equiv). The resulting solution was stirred for 2.5 h at 95° C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of water. The solids were filtered out. The filtrate was washed with 2×50 mL of ethyl acetate. The pH value of the aqueous layer was adjusted to 5 with hydrogen chloride (2 mol/L). The resulting mixture was concentrated under vacuum. The crude product was purified by Flash. This resulted in 0.5 g (6%) of 2-(pyrimidin-4-yl)quinazoline-4-carboxylic acid as dark brown oil. MS (ESI) m/z 253 ([M+H]+).
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([O:11][C:12]2[CH:27]=[C:26]3[C:15]([CH2:16][C:17]4[CH:21]=[CH:20][N:19]([CH2:22][CH:23](O)[CH3:24])[C:18]=43)=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[N-:35]=[N+:36]=[N-:37].[Na+]>ClCCl.CN(C)C=O.O>[N:35]([CH:23]([CH3:24])[CH2:22][N:19]1[CH:20]=[CH:21][C:17]2[CH2:16][C:15]3[C:26]([C:18]1=2)=[CH:27][C:12]([O:11][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH:13][CH:14]=3)=[N+:36]=[N-:37]
Reactant: CC(O)Cn1ccc2c1-c1cc(OC3CCCC3)ccc1C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(Cn1ccc2c1-c1cc(OC3CCCC3)ccc1C2)N=[N+]=[N-]
Yield: 81.4 %

Procedure:
0.75 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.44 g of (RS)-1-(7-cyclopentoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 2.66 ml of triethylamine in 55 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green oil obtained was dissolved in 30 ml of anhydrous dimethylformamide, treated with 0.62 g of sodium azide and the reaction mixture was heated to 60° for 16 hours while stirring. After cooling, the solution was poured into 100 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/hexane 1:4). 1.27 g (82%) of (RS)-1-(2-azido-propyl)-7-cyclopentoxy-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a light yellowish solid which was used directly in the next reaction.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a solution of 6-quinolinecarboxylic acid (500 mg, 2.89 mmol) and 4-benzyloxyphenylamine (681 mg, 2.89 mmol) in dichloromethane (25 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.53 g, 3.47 mmol) and triethylamine (0.96 mL, 6.94 mmol), and the solution was stirred overnight at room temperature. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (194 mg, 19%) was obtained as a white solid.
Reaction SMILES: C(N(CC)CCCN1C2C(=C(Cl)C=CC=2)C(N)=N1)C.Br.Br[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[NH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)[NH:34][N:33]=1.Br.BrCCCN(CC)CC.NC1C2C(=CC=CC=2Cl)NN=1>>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][N:34]2[C:35]3[C:40](=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[C:32]([NH2:31])=[N:33]2)[CH2:26][CH2:27]1
Reactant: Nc1n[nH]c2ccc(Cl)cc12
Reactant: BrCCCN1CCOCC1
Agent: Br
Agent: CCN(CC)CCCBr
Agent: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Product: Nc1nn(CCCN2CCOCC2)c2ccc(Cl)cc12
Yield: 110.7 %

Procedure:
The same procedures for preparing 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole as described in Example 89 were repeated except that 5.03 g of 3-bromopropylmorpholine hydrobromide and 5.66 g of 3-amino-5-chloroindazole were employed instead of the 3-bromopropyldiethylamine hydrobromide and the 3-amino-4-chloroindazole, respectively. As a result, 5.68 g of 1-(3-morpholinopropyl)-3-amino-5-chloroindazole was obtained.
Reaction SMILES: Cl[C:2]1[C:10]([CH3:11])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[N:17][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[C:10]([CH3:11])=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:16]=[N:17][CH:18]=1
Reactant: Cc1c(Cl)nn2ccccc12
Reactant: OB(O)c1cncc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(-c2cncc(F)c2)nn2ccccc12
Temperature: 100 °C

Procedure:
A solution 2-chloro-3-methylpyrazolo[1,5-a]pyridine (38-1; 0.15 g, 0.9 mmol), (5-fluoropyridin-3-yl)boronic acid (0.15 g, 1.05 mmol), and potassium phosphate tribasic (0.574 g, 2.7 mmol) in tetrahydrofuran (10 mL) was degassed for 10 min. Then 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.074 g, 0.18 mmol) and palladium acetate (0.02 g, 0.09 mmol) were added and heated in a sealed tube at 100° C. for 18 h. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. Purification of the resulting residue by prep HPLC (Analytical Conditions: Column: XTERRA C18 (250 mm×4.6 mm×5 μm) mobile phase(A):0.01% ammonia in water, mobile phase (B): acetonitrile flow rate: 1.0 mL/min time/% B: 0/20, 8/50, 25/50, 26/20, 30/20) provided 2-(5-fluoropyridin-3-yl)-3-methylpyrazolo[1,5-a]pyridine. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1 H), 8.67-8.65 (d, J=8.0 Hz, 1 H), 8.06-8.03 (d, J=12 Hz, 1 H), 7.73-7.71 (d, J=8.0 Hz, 1 H), 7.23-7.20 (t, J=4.0 Hz, 1 H), 6.92-6.89 (t, J=4.0 Hz, 1 H), 2.45 (s, 3 H). MS (M+1): 228.0.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][NH3+:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CN(C=O)C.O>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[CH:20][CH:21]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)C[NH3+]
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNCc1ccc(C#N)cc1
Reaction time: 12 h
Yield: 69 %

Procedure:
A solution of 2-(tert-butoxy)-2-oxoethanaminium chloride (3.00 g, 17.9 mmol) and potassium carbonate (4.95 g, 35.8 mmol) in DMF (20 mL) was stirred at room temperature for 2 min. To the reaction mixture was added 4-(bromomethyl)benzonitrile (3.19 g, 16.3 mmol) and stirring continued for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (3×20 mL). The combined organic extract was dried over MgSO4 then concentrated. Purification of the crude product by a silica gel column (DCM/MeOH) gave 2.77 g (68%) of tert-butyl 2-((4-cyanobenzyl)amino)acetate INT-31 as a yellow oil. LCMS-ESI (m/z) calculated for C14H18N2O2: 246; found 247 [M+H]+, tR=0.92 min (Method 3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:29][CH:30]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCOC1CCCCO1
Product: COc1cc2c(Oc3ccc(CC(=O)O)cc3)ncnc2cc1OCCOC1CCCCO1
Yield: 74 %

Procedure:
Using an analogous procedure to that described in the portion of Note [1] above that is concerned with the preparation of starting materials, 4-chloro-6-methoxy-7-(2-tetrahydropyran-2-yloxyethoxy) quinazoline was reacted with 2-(4-hydroxyphenyl)acetic acid to give 2-{4-[6-methoxy-7-(2-tetrahydropyran-2-yloxyethoxy)quinazolin-4-yloxy]phenyl}acetic acid in 74% yield; 1H NMR: (DMSOd6) 1.5 (m, 4H), 1.7 (m, 2H), 3.45 (m, 1H), 3.6 (s, 2H), 3.8 (m, 2H), 3.95 (s, 3H), 4.0 (m, 1H), 4.35 (m, 2H), 4.7 (s, 1H), 7.25 (d, 2H), 7.35 (d, 2H), 7.4 (s, 1H), 7.55 (s, 1H), 8.55 (s, 1H); Mass Spectrum: M+H+ 455.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5](O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].CS(Cl)(=O)=O.[CH3:37][CH:38]([SH:40])[CH3:39].CC(C)([O-])C.[K+].O1CCCC1.Cl>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([S:40][CH:38]([CH3:39])[CH3:37])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(C)S
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(CC(SC(C)C)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester (0.69 mmol, 300 mg) dissolved in pyridine (3 mL) was added methanesulfonyl chloride (0.69 mmol, 0.534 mL). The mixture was stirred at room temperature overnight. A portion of the reaction mixture (0.115 mmol) was added to a solution containing 2-propane thiol (0.115 mmol, 0.107 mL) dissolved in anhydrous CH2Cl2 (2 mL). To this stirred solution was added a 1M solution of potassium tert-butoxide in tetrahydrofuran (0.115 mmol, 0.115 mL). The mixture was stirred overnight then poured over 1 M HCl. The mixture was extracted with diethyl ether (3×). The organic layers were combined, washed with 1 M HCl (2×), saturated brine (2×), dried over Na2SO4, and concentrated to a crude film. The film was purified by chromatography on silica gel (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate in hexanes to give 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-isopropylsulfanyl-propionic acid ethyl ester as a clear film containing an approximate 1:1 mixture of methyl and ethyl ester (30.2 mg, 55%).