Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[CH3:20][S-:21].[Na+]>CO>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[O:10][C:11]3[C:3]([CH2:2][S:21][CH3:20])=[CH:4][C:5]([OH:19])=[CH:6][C:7]=3[CH:8]=2)=[CH:13][CH:14]=1
Reactant: C[S-]
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Agent: [Na+]
Solvent: CO
Product: CSCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of benzyl bromide 4 (0.052 g, 0.161 mmole) in 5 mL methanol was added sodium thiomethoxide (0.013 g, 0.177 mmole). After stirring at R.T. for 1 hour, the solvent was evaporated and the residue was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 4:1) to afford 0.025 g (54%) of thioether 10 as a white solid: Mp=188–190° C.; 1H NMR (DMSO-d6) δ 9.82 (s, 1 H), 9.14 (s, 1 H), 7.69 (d, 2 H, J=8.5 Hz), 7.01 (s, 1 H), 6.86 (d, 2 H, J=8.5 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.63 (d, 1 H, J=2.1 Hz), 3.91 (s, 2 H), 2.05 (s, 3 H); MS 285 (M−H)−
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[C:16]([NH:25][C:26]3[N:31]=[C:30]([C:32]4[N:33]([CH3:40])[CH:34]=[C:35]([C:37](=[O:39])[NH2:38])[CH:36]=4)[CH:29]=[CH:28][N:27]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1.Cl>[CH3:40][N:33]1[C:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([NH:25][C:16]3[CH:15]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:19]=[CH:18][C:17]=3[O:20][C:21]([F:24])([F:23])[F:22])[N:31]=2)=[CH:36][C:35]([C:37]([NH2:38])=[O:39])=[CH:34]1
Reactant: Cn1cc(C(N)=O)cc1-c1ccnc(Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2OC(F)(F)F)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(C(N)=O)cc1-c1ccnc(Nc2cc(N3CCNCC3)ccc2OC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.3 %

Procedure:
To a solution of 4-{3-[4-(4-carbamoyl-1-methyl-1H-pyrrol-2-yl)-pyrimidin-2-ylamino]-4-trifluoromethoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (176 mg, 0.314 mmol) in dioxane (3 mL), HCl in dioxane solution (4N, 4 mL) were added. The reaction was stirred at room temperature for 6 hours and the precipitate collected by filtration. The precipitate was dissolved in HCl water solution (0.1N, 30 mL) and washed with dichlorometane (50 mL). The aqueous layers were collected and the title compound precipitated by addition of sodium bicarbonate. The aqueous phase was eliminated by filtration, the solid washed with water (10 mL) and dried under vacuo at 30° C. to yield 96 mg (66%) of the title compound as an hazelnut powder.
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[C:14]([C:15]2[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20](C=O)=[CH:19][CH:18]=3)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.C1C[O:36][CH2:35][CH2:34]1>>[Cl:4][C:5]1[C:14]([C:15]2[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH2:34][CH2:35][OH:36])=[CH:19][CH:18]=3)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(C=O)ccc21
Reactant: C1CCOC1
Agent: C[Mg]Br
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CCO)ccc21
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesium bromide in THF (3 M, 0.85 mL, 2.56 mmol, 1.3 equiv) was added to a solution of 2-(2-chloro-3-quinolinyl)-5-formyl-1H-indole-1-carboxylate (8-1, 800 mg, 2.0 mmol, 1 equiv) in THF (25 mL) at 0° C., and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between pH 7 phosphate buffer solution and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane, grading to 70% EtOAc in hexane) to provide tert-butyl 2-(2-chloro-3-quinolinyl)-5-(1-hydroxyethyl)-1H-indole-1-carboxylate (8-2) as a white foam. 1H NMR (500 MHz, CDCl3) δ8.29 (d, 1H, J=8.8 Hz), 8.18 (s, 1H), 8.08 (d, 1H, J=8.5 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.78 (br t, 1H, J=7.1 Hz), 7.64 (s, 1H), 7.61 (br t, 1H, J=7.1 Hz), 7.42 (dd, 1H, J=8.6, 1.5 Hz), 6.66 (s, 1H), 5.05 (m, 1H), 1.58 (d, 3H, J=6.6 Hz), 1.27 (s, 9H).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][S:18][CH3:19])=[CH:11][N:10]=2)=CC=1>FC(F)(F)C(O)=O>[CH3:19][S:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[N:14][C:9]([NH2:8])=[N:10][CH:11]=1
Reactant: COc1ccc(CNc2ncc(OCCSC)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CSCCOc1cnc(N)nc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 32.5 %

Procedure:
N-(4-Methoxybenzyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (172.4 mg) was dissolved in trifluoroacetic acid (3 mL) at room temperature, and the solution was stirred at 60° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative silica gel thin layer chromatography (chloroform:methanol=15:1) to obtain 5-[2-(methylthio)ethoxy]pyrimidin-2-amine (34 mg, 18% in 2 steps) as colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C#Cc2ccc(-c3ccccc3F)nc2)cs1
Temperature: 150 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (0.43 mmol, 100 mg), 2-fluorophenylboronic acid (0.47 mmol, 66 mg), dichlorobis(triphenylphosphine)palladium(II) (0.03 mmol, 18 mg), and potassium carbonate (1.72 mmol, 238 mg) were added to deoxygenated DME:water (1:1, 3 mL) at room temperature. The reaction was heated for 5 min at 150° C. via microwave irradiation, then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 10 to 40% EtOAc gradient in hexanes, to afford the title compound as a tan solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 9.13 (s, 1H), 8.69 (d, 1H), 8.30 (d, 1H), 7.98 (s, 1H), 7.84 (dd, 1H), 7.70 (m, 1H), 7.42-7.53 (m, 2H), 2.83 (s, 3H). MS (ESI) 295.13 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:11]2[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Ni]>[O:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:28]=[CH:29][C:24]([N:11]3[C@@H:12]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[CH2:13][CH2:14][C@@H:10]3[C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)=[CH:25][CH:26]=2)[CH2:31][CH2:32]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc([C@H]2CC[C@H](c3ccc([N+](=O)[O-])cc3)N2c2ccc(N3CCOCC3)cc2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc([C@H]2CC[C@H](c3ccc(N)cc3)N2c2ccc(N3CCOCC3)cc2)cc1
Yield: 44 %

Procedure:
The product from Example 98A in tetrahydrofuran (20 mL) was added to Ra-Ni (water wet, A-7000, 0.8 g, 12.63 mmol) in a 50 mL pressure bottle and stirred for 2 hours at ambient temperature under 30 psi of hydrogen. The mixture was filtered through a nylon membrane and concentrated to afford the title compound (0.31 g, 44%). MS (DCI) m/z 415 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][Si](C(C)(C)C)(C)C)[C:25](Br)=[CH:24][C:23]=2[CH2:37][CH3:38])[C:12]=1[CH2:39][CH2:40][CH3:41].[O:43]1[CH:47]=[CH:46][CH:45]=[C:44]1B(O)O.C(=O)([O-])[O-].[Na+:55].[Na+]>O1CCCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Na+:55].[CH2:37]([C:23]1[CH:24]=[C:25]([C:44]2[O:43][CH:47]=[CH:46][CH:45]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38]
Reactant: OB(O)c1ccco1
Reactant: CCCc1c(OCCCOc2cc(O[Si](C)(C)C(C)(C)C)c(Br)cc2CC)cccc1Oc1ccccc1C(=O)OC
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: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccco3)cc2CC)cccc1Oc1ccccc1C(=O)[O-]
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 2-(3-{3-[4-bromo-5-(tert-butyldimethylsilanyloxy)-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (1.05 g, 1.60 mmol), furan-2-boronic acid (0.358 g, 3.20 mmol), tetrakis(triphenylphosphine)palladium(0) (0.185 g, 0.160 mmol), and 2 M aqueous sodium carbonate solution (8 mL) in tetrahydrofuran (20 mL) was heated at reflux for 18 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 0.8 g (94%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 7.90 (d, J=9 Hz, 1H), 7.48 (s, 1H), 7.38 (t, J=8 Hz, 1H), 7.21 (s 1H), 7.13 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 6.81 (d, J=9 Hz, 1H), 6.69 (d, J=9 Hz, 1H), 6.52 (m, 3H), 6.44 (d, J=9 Hz, 1H), 4.20 (m, 4H), 3.83 (s, 3H), 2.67 (t, J=8 Hz, 2H), 2.59 (q, J=7 Hz, 2H), 2.32 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=8 Hz, 2H), 1.18 (t, J=7 Hz, 3H), 0.91 (t, J=7 Hz, 3H); MS ES− m/z=589 (p+AcO−). Anal. Calcd for C32H34O7: C, 72.43; H, 6.46. Found: C, 72.21; H, 6.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(O)(CC)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: C1COCCN1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Solvent: CO
Solvent: CCC(C)O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 105 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
In a 500 mL volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 95.0 g (0.354 mol) of 6-methoxy-7-(3-chloropropoxy)-quinazolin-4-one, 154.2 g (1.77 mol) of morpholine, and 380 mL of sec-butyl alcohol. The resulting mixture was heated to 105° C. under stirring for 18 hours. After the reaction was complete, 380 mL of methanol was added to the reaction mixture. The resulting mixture was stirred at 70° C. for 30 minutes, and cooled to room temperature. The mixture was then stirred for 30 minutes at room temperature. The precipitated crystalline product was filtered, placed in 190 mL of methanol and stirred for washing, again filtered, and dried at 60° C. under reduced pressure to give 104 g (isolated yield: 92%, purity: 98.81% in terms of area percentage determined by high performance liquid chromatography) of 6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-one as a white crystalline product.
Reaction SMILES: O.[OH-].[Na+].[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>CO>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]([C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)C(=Cc1cccnc1)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.2 %

Procedure:
100 ml of water, followed by 28 ml of 10% strength aqueous sodium hydroxide solution, were added to a stirred solution of 22.6 g (0.1 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one and 21.4 g (0.2 mol) of 3-pyridinealdehyde in 500 ml of methanol. The solution was subsequently stirred at room temperature for 4 days, the methanol was removed in vacuo and the aqueous residue was taken up in ether. The aqueous phase was separated off, the organic phase was extracted three times with 1 N hydrochloric acid and the hydrochloric acid extracts were neutralized with solid sodium bicarbonate and extracted three times with ethyl acetate. 22.8 g (72% of theory) Of 2-(4-chlorophenoxy)-4,4-dimethyl-1-pyridin-3-yl-1-penten-3-one of melting point 74°-76° C. were obtained from the ethyl acetate phase.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([OH:25])[C@@H:22]([OH:26])[CH:21]1[OH:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:30](OC)([CH3:32])[CH3:31].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@H:23]2[O:25][C:30]([CH3:32])([CH3:31])[O:26][C@H:22]2[CH:21]1[OH:27])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](O)[C@@H](O)C1O)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)O[C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(O)[C@@H]2O1
Temperature: 60 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To a stirred solution of (2R,3S,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydrofuran-2,3,4-triol (compound 25a, 33 g, 85 mmol) in acetone (250 mL) was added 2,2-dimethoxypropane (13.2 g, 127 mmol) and p-toluene sulfonic acid (1 g, 5.8 mmol). After being stirred at 60° C. for 2 hours, the resulting solution was adjusted to pH 7.0 by addition of saturated NaHCO3 solution and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:11 EtOAc in petroleum ether) to afford 20 g of (3aS,5R,6aS)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol (compound 25b).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH2:17]1[O:21][C:20]2[CH:22]=[C:23]([Cl:28])[C:24]([CH:26]=O)=[CH:25][C:19]=2[O:18]1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:26]([C:24]2[CH:25]=[C:19]3[O:18][CH2:17][O:21][C:20]3=[CH:22][C:23]=2[Cl:28])[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1cc2c(cc1Cl)OCO2
Product: CC(C)N1C(=O)NC(c2cc3c(cc2Cl)OCO3)c2cc3c(cc21)OCO3
Yield: 65 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (410 mg) and 6-chloropiperonal (350 mg) by the procedure described in example 10 in 65% yield. 1H NMR (CDCl3): 6.86 (s, 1H), 6.77 (s, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 5.95 (s, 4H), 5.66 (d, J=2.5, 1H), 5.21 (s, 1H), 4.48 (m, 1H), 1.53 (d, J=6.5, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)O1>>[F:11][C:4]1[CH:3]=[C:2]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]#[N:10]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: N#CCc1ccc(Br)cc1F
Product: N#CCc1ccc(-c2ccc(O)cc2)cc1F

Procedure:
According to a method similar to Example (8-1), from (4-bromo-2-fluorophenyl)acetonitrile (3.0 g, 14 mmol) obtained in Example (11-1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.45 g, 14 mmol), (3-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl)acetonitrile was obtained as a colorless solid (2.9 g, yield: 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH2:21][OH:22])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[BH4-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO>[NH2:8][CH2:7][C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][OH:22])[N:15]=[CH:14]2
Reactant: N#Cc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Reaction time: 3 h

Procedure:
To a solution of (5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzonitrile (1.0 g, 3.36 mmol) and NCl2.6H2O (148 mg, 0.336 mmol) in MeOH (30 mL) was added NaBH4 (636 mg, 16.8 mmol) in portions (2-3), and the reaction was stirred for 3 hours. A solution of saturated Na2CO3 (15 mL) was slowly added and the mixture was stirred for 75 minutes, during which a fine solid formed. The reaction mixture was filtered thru GF/F and the cake was washed with MeOH (20 mL). The filtrate was concentrated to about 15 mL under vacuum, isopropyl acetate (20 mL) was added, and the mixture was concentrated. To the concentrate was added isopropyl acetate (20 mL) and the mixture was stirred for 5 minutes. The phases were separated, and the organic layer was washed with 10% brine (20 mL). Citric acid (0.1 M, 20 mL) was added and the phases were vigorously mixed. The organic layer was removed and the aqueous was washed with isopropyl acetate (20 mL) and EtOAc (20 mL). To the aqueous layer was added isopropyl acetate (20 mL) and 50% NaOH (1 mL) was added. The phases were vigorously mixed and the aqueous was removed. The organic was washed with 10% brine (20 mL), dried over Na2SO4 and concentrated to 850 mg (85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[N:10][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][C:7]2=1)([O-:3])=[O:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:13]1[C:12]2[CH:11]=[N:10][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2
Reactant: ClCc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12
Product: CCOC(=O)c1cc2c3cc([N+](=O)[O-])ccc3n(Cc3cccc(Cl)c3)c2cn1

Procedure:
The title compound was prepared by alkylation of ethyl 6-nitro-9H-β-carboline-3-carboxylate (prepared according to Settimj, et. al., J. Heterocycl. Chem., 25, 1391–1397 (1988)) with 3-chlorobenzyl chloride in a manner similar to step (a) of example 7. LCMS (APCI, M+H+): 410.1/412.1=3/1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.Cl[C:12]1[S:13][C:14]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=2[N:16]=1.C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.O>[Cl:8][C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([Cl:10])[C:5]=1[O:9][C:12]1[S:13][C:14]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Yield: 49.3 %

Procedure:
To the solution of 4-amino-2,6-dichloro phenol (6 g, 26.5 mmol) and 2,6-dichlorobenzothiazole (363) (6 g, 29.4 mmol, 1.1 eq) in DMSO (25 ml), was added K2CO3 (11 g, 80 mmol, 3.0 eq). The mixture was stirred and heated to 160 degree. After 5.5-hr water (20 ml) was added to the reaction mixture, which was neutralized with 2N HCl., and was extracted with AcOEt three times. And the organic layer was washed with Brine and was dried over anhydrous MgSO4, and then concentrated. Crude residue was purified by column chromatography (CHCl3/Acetone=9/1, 180 g of silica gel) to afford 3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (364) as a black solid (4.52 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[CH3:34][O:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:41]2[C:36]([O:35][CH3:34])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: COc1ncccc1B(O)O
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: CC#N
Product: COc1ncccc1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 90 °C
Yield: 72.6 %

Procedure:
Intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.350 g, 0.62 mmol) in a mixture of acetonitrile (12 ml) and water (12 ml) was treated with 2-methoxypyridin-3-ylboronic acid (0.190 g, 1.24 mmol), sodium carbonate (0.20 g, 1.88 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.15 g). The reaction mixture was degassed, flushed with argon and heated at 90° C. for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.245 g (72% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.63 (6H, s, 2×CH3), 3.89 (3H, s, OCH3), 4.04 (4H, m, 2×CH2), 4.37 (2H, broad, NCH2), 5.26 (2H, s, OCH2), 6.93 (1H,dd, J=2.5 Hz and J=9 Hz, aromatic), 7.0 (1H,dd, J=5 Hz and J=7 Hz, aromatic), 7.06 (1H, m, aromatic), 7.3–7.5 (8H, m, aromatics and NH), 8.24 (1H, m, aromatic). HRMS (ESI+) calculated for C30H30FN4O5 [M+H+]: 545.2200. found: 545.2184.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32]([C:34]1[CH:42]=[C:41]2[C:37]([C:38]([CH:43]=O)=[CH:39][NH:40]2)=[CH:36][CH:35]=1)=[O:33]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:43][C:38]3[C:37]4[C:41](=[CH:42][C:34]([C:32]([OH:33])=[O:31])=[CH:35][CH:36]=4)[NH:40][CH:39]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Product: O=C(O)c1ccc2c(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)c[nH]c2c1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3-formyl-1H-indole-6-carboxylic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 564.