Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH2:21]1[CH2:25]OC[CH2:22]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]([OH:19])[CH2:25][CH:21]=[CH2:22])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3Cl)nc12
Reactant: C1CCOC1
Product: C=CCC(O)c1cc2cccc(C)c2nc1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Prepared according to procedure K: To a solution of 2-(2-chlorophenyl)-8-methylquinoline-3-carbaldehyde (1.4 g, 5 mmol) in THF (20 mL) at 0° C. under N2 was added dropwise a solution of allylmagenisiumbromide (1M, 1.1 eq, 5.5 mL) in THF and the mixture was stirred at 0° C. for 2 h. The mixture was partitioned between EtOAc (50 mL) and H2O (30 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried (Na2SO4), concentrated and purified by flash chromato-graphy (0% to 25% EtOAc/hexane) to provide 1-(2-(2-chlorophenyl)-8-methyl-quinolin-3-yl)but-3-en-1-ol as a colorless oil. 1H-NMR (CDCl3) δ 8.45 (s, major, 1H), 8.40 (s, minor, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.43-7.60 (m, 6H), 5.56-5.73 (m, 1H), 4.96-5.17 (m, 2H), 4.80-4.84 (m, 1H), 2.80 (s, 3H), 2.34-2.59 (m, 2H). Mass Spectrum (ESI) m/e=324 (M+1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[NH:14][CH:13]=[C:12]2[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22]CCCl.O=P(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:22])=[N:14][CH:13]=[C:12]2[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c[nH]c(=O)c2ccc(SCc3ccccc3)cc12
Reactant: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A vial was charged with 6-(benzylthio)-4-methoxyisoquinolin-1(2H)-one (0.933 g, 3.14 mmol) and DCE (15.69 ml). POCl3 (0.585 ml, 6.27 mmol) was added and the reaction was stirred overnight at 90° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford crude 6-(benzylthio)-1-chloro-4-methoxyisoquinoline (Intermediate VVV) as a brown solid. (ESI) 316.3 (M+H)+.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]1[CH:30]=[CH:29][C:14]2[O:15][CH2:16][CH:17](O)[CH2:18][N:19]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:21]=[C:20]3[C:13]=2[CH:12]=1>C(Cl)Cl.O>[Br:10][C:11]1[CH:30]=[CH:29][C:14]2[O:15][CH2:16][CH:17]([F:7])[CH2:18][N:19]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:21]=[C:20]3[C:13]=2[CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Solvent: ClCCl
Solvent: O
Product: FC1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
DAST (94 mg, 0.583 mmol) was added to a solution of 2-bromo-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7-ol (100 mg, 0.29 mmol) in CH2Cl2 (1 mL) under N2 at −78° C. The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (15 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using p-TLC (petroleum ether:EA=10:1) to provide 2-bromo-7-fluoro-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indole (40 mg, yield: 40.0%). MS (M+H)+: 346/348.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:28]([Sn:32](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)cc3)n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a stirred solution of 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (Example E.69) (0.40 g, 1.0 mmol) in THF (7 mL) was added at 0° C. isopropyl-magnesium chloride lithium chloride (1M in THF, 1.22 mL, 1.22 mmol). The reaction mixture was allowed to stir for 15 min at 0° C., tributyltin chloride (0.43 g, 1.33 mmol) was added, the reaction mixture was stirred at room temperature for 5 h, poured into saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (ethylacetate/heptane) to yield the title compound (0.47 g, 84%) as a light yellow oil. MS (ISP) 561.2 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[N:16][C:17](=[O:21])[O:18][CH2:19][CH3:20].C([Li])(C)(C)C>O1CCCC1>[CH:4]1[C:3]2[CH2:8][CH:9]3[C:10]([NH:16][C:17](=[O:21])[O:18][CH2:19][CH3:20])([C:2]=2[CH:7]=[CH:6][CH:5]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3
Reactant: CCOC(=O)N=C1CCCCCC1Cc1ccccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)NC12CCCCCC1Cc1ccccc12

Procedure:
To a solution of the N-ethoxycarbonylimine (3.38 g, 0.1 mole) from Example 167 nin dry tetrahydrofuran (100 ml) cooled to -78° C. is treated with t-butyllithium in a similar manner to that described in Example 83 to afford after workup the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][C:19]2[N:20]=[C:21]([OH:30])[C:22]3[N:27]=[C:26]([S:28][CH3:29])[O:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1.[CH2:33](O)[CH2:34][CH3:35].C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][C:19]2[N:20]=[C:21]([O:30][CH2:33][CH2:34][CH3:35])[C:22]3[N:27]=[C:26]([S:28][CH3:29])[O:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1
Reactant: CSc1nc2c(O)nc(Cc3ccc(Cl)cc3)nc2o1
Reactant: CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(SC)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 8.7 mmol of polystyrene-bound triphenylphosphine (Argonaut) and 1.5 g of diethyl azodicarboxylate (DEAD) in 55 ml of tetrahydrofuran was stirred for 15 min at 0° C. Then 2.2 g of 5-(4-chloro-benzyl)-2-methylsulfanyl-oxazolo[5,4-d]pyrimidin-7-ol, 0.65 ml of propan-1-ol and 1 ml of triethylamine were added. The reaction mixture was stirred at room temperature for 3 h. The polymer was filtered off and washed thoroughly with tetrahydrofuran. The solvent was removed in vacuo and the title compound isolated by silica gel chromatography (method SC1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[SH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.COC1C=C(C=CC=1OC)C(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Sc1ccncc1
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)c1cccc(CCl)c1
Agent: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)c1cccc(CSc2ccncc2)c1
Reaction time: 12 h
Yield: 67 %

Procedure:
Subsequently, methyl 5-bromo-2-[3-(chloromethyl)benzoyl]aminobenzoate (1.5 g) was dissolved in anhydrous methylene chloride. Triethylamine (2.0 ml) and 4-mercaptopyridine (compound B′) (880 mg) were added to the solution at room temperature, and the mixture was stirred at that temperature for 12 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over sodium sulfate, and was then concentrated. Diethyl ether was added to the residue for crystallization. The crystals were filtered through Kiriyama Rohto (21 mmφ) and were washed with diethyl ether to give methyl 5-bromo-2-(3-[(4-pyridylsulfanyl)methyl]benzoylamino)benzoate (1.20 g, yield 67%) as a useful intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH2:24]([O:26][C:27](=[O:32])[CH2:28][C:29](Cl)=[O:30])[CH3:25].CC[O-].[Na+]>C1C=CC=CC=1.O>[CH2:24]([O:26][C:27]([C:28]1[C:29](=[O:30])[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:5]2[C:6]([C:7]=1[OH:8])=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:32])[CH3:25]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COc1ccc(CNc2ccc(Cl)cc2C(=O)N(C)OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 80 °C
Yield: 42749.8 %

Procedure:
A solution of 9 (0.13 g, 0.38 mmol) in 3 mL of anhydrous benzene was treated with ethyl-3-chloro-3-oxopropionate (54 μL, 63.0 mg, 0.421 mmol). The reaction mixture was heated to 80° C. for 1 h. The reaction was allowed to cool to room temperature and was concentrated in vacuo. The resulting oil was dissolved in 3 mL of ethanol, treated with NaOEt (40.0 mg, 0.59 mmol). The suspension was heated to 80° C. for 10 min, allowed to cool to room temperature, and diluted with H2O. The resulting precipitate was filtered to give 10 (63.0 g, 43%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]=[CH:7][CH2:8][CH2:9][CH3:10])[CH3:3].[H][H]>C(O)C.[Pd]>[CH3:3][C:2]([CH2:4][C@H:5]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH2:1]
Reactant: [H][H]
Reactant: CCCC=C[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C=C(C)C[C@@H](CCCCC)NC(=O)OC(C)(C)C
Yield: 89 %

Procedure:
A solution of (S)-2 -methyl-4 -(tert butoxycarbonylamino)-5 -nonene (2.0 g) in absolute ethanol (75 mL) was hydrogenated over a 5% palladium on carbon catalyst (1.0 g) at 20°-25° and an initial pressure of 34 psi in a Paar apparatus. After one equivalent of hydrogen had been taken up (1 hour), the mixture was filtered and then concentrated under reduced pressure to give 1.78 g of product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[CH3:26])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][C:7]1=[O:22].C([BH-](C(CC)C)C(CC)C)(CC)C.[K+]>O1CCCC1>[OH:22][C@H:7]1[C@@H:6]([O:5][C:4]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:2]([CH3:1])[CH:3]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:8]1
Reactant: Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2=O)cc1C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.0 g (0.028 mol) of the 4-(3,4-dimethylphenoxy)-1-carbobenzyloxy-3-piperidone described in Example 44 are dissolved in 60 ml of dry tetrahydrofurane and the solution is treated dropwise, at room temperature in a nitrogen atmosphere, with 112 ml of a 0.5 M solution of potassium tri-sec.-butylborohydride (K selectride) (0.056 l mol) in tetrahydrofurane. After the addition has ended, the reaction mixture is stirred for a further 3 hours at room temperature and then concentrated to about 1/3 of the original volume under a water pump vacuum. The solution is cooled to 0° in an ice-water bath, treated dropwise with 130 ml of water and extracted by shaking with twice 150 ml of methylene chloride. The combined organic phases are washed with 0.1 N hydrochloric acid, then with 0.1 N sodium hydroxide solution and finally with water, dried over sodium sulphate and evaporated to dryness under a water pump vacuum. The oily crude product is dissolved in toluene and the solution is filtered through a layer of silica gel. cis-3-hydroxy-4-(3,4-dimethylphenoxy)-1-carbobenzyloxy-piperidine is obtained in the form of a pale yellow oil by elution with a toluene/ethyl acetate mixture (5:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+].[I-:15].C(N)CCN.C(O)CCCC>N.[Cu]I.O>[I:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: N
Agent: NCCCN
Solvent: CCCCCO
Solvent: O
Product: Ic1ccc(-c2ccccc2)cc1
Temperature: 130 °C
Reaction time: 22 h
Yield: 96 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), 4-bromobiphenyl (234 mg, 1.00 mmol), NaI (300 mg, 2.00 mmol), evacuated and backfilled with argon. 1,3-Propanediamine (8.4 μL, 0.10 mmol, 10 mol %) and n-pentanol (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 22 h. The resulting suspension was allowed to reach room temperature, diluted with 30% aq ammonia (2 mL), poured into water (20 mL), and extracted with dichloromethane (3×15 mL). The combined organic phases were dried (MgS04), concentrated, and the residue was purified by flash chromatography on silica gel (hexane) to provide 269 mg (96% yield) of 4-iodobiphenyl as a white solid. Mp: 113-114° C. (lit. 112.5-113.5° C. See lbuki, E.; Ozasa, S.; Murai, K. Bull. Chem. Soc. Jpn. 1975, 48, 1868). The 1H and 13C spectra matched those reported in Dektar, J. L.; Hacker, N. P. J. Org. Chem. 1990, 55, 639.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH2:14])[CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:14][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)c1cccc([C@H](N)C(C)C)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](c3cccc(C(C)C)c3)C(C)C)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(3-isopropylphenyl)-2-methylpropan-1-amine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 573 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=1B(O)O>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=1[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: FC(F)(F)c1cc(Br)c2cn[nH]c2c1
Reactant: COC(=O)c1ccc(OC)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(OC)c(-c2cc(C(F)(F)F)cc3[nH]ncc23)c1
Temperature: 140 °C
Yield: 71 %

Procedure:
A vial was charged with a mixture of 4-bromo-6-(trifluoromethyl)-1H-indazole (0.631 g, 2.381 mmol), (2-methoxy-5-(methoxycarbonyl)phenyl)boronic acid (0.5 g, 2.381 mmol) and PdCl2(dppf) (0.087 g, 0.119 mmol) in dioxane (10 mL) and aqueous saturated NaHCO3 (3 mL). The resulting light brown suspension was heated at 140° C. for 45 minutes in a microwave reactor. The reaction mixture was subsequently concentrated and the crude residue was diluted with DCM and washed with water, concentrated, and then purified by CombiFlash® chromatography, eluting with a gradient of 0-40% MeOH in DCM over a period of 200 minutes. The product-containing fractions were combined and concentrated to give the title compound as a light brown solid (0.592 g, 71.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.85 (s, 3H), 3.84 (s, 3H), 7.21-7.46 (m, 2H), 7.89-7.99 (m, 3H), 8.10 (dd, J=8.59, 2.27 Hz, 1H), 13.62 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C17H13F3N2O3, 351.1. found 351.16.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([OH:20])[CH:22]=3)[N:7]=2)[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1cc(Nc2nc(Cl)ncc2F)cc(OC)c1
Product: COc1cc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc(OC)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with 3-hydroxyaniline gave N4-(3,5-dimethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.98 min.; purity: 90%; MS (m/e): 357 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[N:5][N:4]=[N:3]1.[NH2:15][O:16][CH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C.ClCCl>[CH3:1][N:2]1[C:6]([C:7](=[N:15][O:16][CH2:17][C:18]2[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:4]=[N:3]1
Reactant: NOCc1cccc(N)n1
Reactant: Cn1nnnc1C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 160 °C

Procedure:
Under protective gas (argon), a reaction tube containing a solution of (1-methyl-1H-tetrazol-5-yl)(phenyl)methanone (188 mg; 1.0 mmol), 6-[(aminooxy)methyl]pyridin-2-amine (139 mg; 1.0 mmol) and p-toluenesulfonic acid monohydrate (190 mg; 1.0 mmol) in 2-propanol (2 mL) is sealed and heated in a microwave oven at 160° C. for 90 min. For workup, the mixture is allowed to cool down, diluted with dichloromethane (10 mL) and washed twice with 3 ml each time of sat. aq. sodium bicarbonate. The aqueous phase is extracted with dichloromethane and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Purification on silica gel affords 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine as a colourless oil [205 mg; 66% of theory; HPLC/MS: m/z=310 (M+H); log P(HCOOH)=1.13].
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C:14]([N:22]([CH3:24])[CH3:23])=[N:13]2)=[CH:8][CH:7]=1)([OH:5])=[O:4].[CH3:25]O>>[ClH:1].[C:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C:14]([N:22]([CH3:24])[CH3:23])=[N:13]2)=[CH:10][CH:11]=1)([O:5][CH3:25])=[O:4]
Reactant: CO
Reactant: CN(C)C1=NC(c2ccc(C(=O)O)cc2)c2ccccc2C1
Agent: Cl
Product: COC(=O)c1ccc(C2N=C(N(C)C)Cc3ccccc32)cc1

Procedure:
The basic aqueous solution from the above experiment was made acidic with 5N hydrochloric acid, and evaporated to dryness to leave a white solid, containing 1-(4-carboxyphenyl)-1,4-dihydro-3-dimethylaminoisoquinoline hydrochloride. The crude acid was suspended in methanol (100 ml) and ethereal hydrogen chloride (2 ml) at room temperature for 16 h. The suspension was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in dilute hydrochloric acid, washed with ethyl acetate, then basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and ethereal HCl was added. The solvent was removed under reduced pressure and the residual solid was recrystallised from dichloroethane/ethyl acetate to give 1-(4-carbomethoxyphenyl)-1,4-dihydro-3-dimethylamino-isoquinoline hydrochloride as a pale yellow powder, m.p. 187°-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:6]([S:9](=[O:14])(=[O:13])[N:10]([CH3:12])[CH3:11])[C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:6]([S:9](=[O:13])(=[O:14])[N:10]([CH3:12])[CH3:11])[C:7]=1[O:8][CH2:34][CH:31]1[CH2:33][CH2:32]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Br)c(O)c(S(=O)(=O)N(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(OCC2CC2)c(S(=O)(=O)N(C)C)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 41.5 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-(N,N-dimethylsulfamoyl)-4-hydroxyphenyl)-4-methylpentanoate (0.75 g, 1.77 mmol) in DMSO (25 mL) were added K2CO3 (367 mg, 2.106 mmol) and cyclopropylmethylbromide (0.2 mL, 2.13 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 80° C. temperature over a period of 14 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and quenched with water and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×75 mL), brine and dried over Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-(N,N-dimethylsulfamoyl)phenyl)-4-methylpentanoate (350 mg) as a liquid.
Reaction SMILES: [Ag:1].[CH2:2]([OH:4])[CH3:3].[CH:5]([OH:8])([CH3:7])[CH3:6].C(O)CCC.C([CH2:17][C:18](=[O:20])[CH3:19])(=O)C>O.CO>[CH:5]([OH:8])([CH3:7])[CH3:6].[CH:18]([O:20][CH2:3][CH2:2][OH:4])([CH3:17])[CH3:19].[Ag:1]
Reactant: CCO
Reactant: CC(=O)CC(C)=O
Agent: [Ag]
Solvent: CO
Solvent: CCCCO
Solvent: CC(C)O
Product: CC(C)OCCO

Procedure:
The same procedures used in Example 1 were repeated except for using, as the medium in which the silver-containing solid content was dispersed, an ethyl alcohol/isopropyl alcohol/butyl alcohol (4:4:1) mixture (Example 2), a 99:1 mixture of an ethyl alcohol/isopropyl alcohol/butyl alcohol (4:4:1) mixture with acetyl acetone (Example 3), an isopropyl alcohol/2-isopropoxy ethanol (80:20) mixture (Example 4) or a water/methyl alcohol (85:15) mixture (Example 5), to thus give each corresponding silver sol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-])=O.[H][H].[S]>C(O)C.[Ni]>[C:11]1([S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:17]([F:20])([F:18])[F:19])[CH:6]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccccc2)cc1C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Agent: [S]
Solvent: CCO
Product: Nc1ccc(Sc2ccccc2)cc1C(F)(F)F

Procedure:
2-Nitro-5-phenylthiobenzotrifluoride (25.6 g, 0.86 mole) in ethanol (500 ml) is reduced over Raney nickel at about 45 psi of hydrogen gas. After hydrogen uptake is complete the mixture is deactivated with elemental sulfur, filtered, and the filtrate evaporated under reduced pressure to afford product as an oil. The infrared spectrum shows an absorption at 2.9μ (strong NH band). The product crystallizes on standing to give a solid, m.p. 63°-66.5° C.