Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCOCC
Product: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A solution of 5-Bromo-2-chlorobenzotrifluoride (5 g, 19.2 mmol) in dry diethyl ether (40 ml) was added dropwise at room temperature to a mixture of Mg (470 mg) in dry diethyl ether (20 ml) under a stream of Argon (g). The reaction gave rise to a solution of Grignard's reagent. A solution of 1-benzyl-4-piperidone (1.3 g, 6.88 mmol) in dry diethyl ether (30 ml) was added dropwise via syringe at room temperature. The combined mixture was stirred for 1 hour, and finally quenched with saturated ammonium chloride solution (40 ml). The mixture was extracted several times with EtOAc and the combined organic phases were dried (MgSO4), filtered and evaporated to dryness. The oily residue was chromathographed on a silica column using EtOAc:toluene (1:1 (v/v)) as eluent affording the title compound (1.6 g, 64%). MS m/z (relative intensity, 70 eV) 369 (M+, 23), 278 (15), 91 (bp), 65 (16), 56 (21).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:39][C:38]([CH3:41])([CH3:40])[CH2:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)CNS(=O)(=O)c1cccc(N)c1
Product: CC(C)(C)CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2,2-dimethyl-propyl)-benzenesulfonamide (example B.4) according to general procedure II. Light yellow solid. MS (ISP) 580.3 [(M−H−]; mp 208° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.[CH:26](=O)[CH2:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:48]C(Cl)C>C(Cl)Cl>[ClH:48].[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:17])[F:18])=[CH:11][CH:10]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH2:26][CH2:27][CH3:28])[CH:20]=2)[N:3]=1
Reactant: CCC=O
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(N)c2)N=C1N
Reactant: CC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCNc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Product: Cl
Yield: 73 %

Procedure:
A mixture 2-amino-5-(3-amino-phenyl)-5-(4-difluoromethoxy-phenyl)-3-methyl-3,5-dihydro-imidazol-4-one (150 mg, 0.43 mmol), propionaldehyde (25 mg, 0.43 mmol), sodium triacetoxyborohydride (184 mg, 0.87 mmol), and acetic acid (0.87 mmol) in dichloroethane (4.3 mL) was stirred at room temperature overnight. The reaction was diluted with methylene chloride and washed with sodium carbonate. The organic layer was concentrated and purified by reverse-phase HPLC followed by treatment with hydrochloric acid to provide the title compound (122 mg, 73%), characterized by NMR and mass spectral analyses. MS (ES+) m/e 389 (M+H)+.
Reaction SMILES: [CH3:1][Mg]I.[C:4]([CH:6]([OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)#[CH:5].S(=O)(=O)(O)O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC.O1CCCC1>[C:4]([CH:6]([OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH2:1])[CH:8]=1)#[CH:5]
Reactant: C[Mg]I
Reactant: C#CC(O)c1cccc(C(=O)c2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(O)c1cccc(C(=C)c2ccccc2)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To methyl magnesium iodide (1.4 g) in ether (25 cm3) was added a solution of α-ethynyl-3-benzoylbenzyl alcohol (0.5 g) in ether (10 cm3) with stirring during 10 minutes at 20° C., then the mixture refluxed for 5 minutes and poured onto a mixture of 40% sulphuric acid (40 cm3), sodium thiosulphate (3 g) and tetrahydrofuran (20 cm3). After 16 hours at 20° C., this mixture was extracted with ether (3×150 cm3), washed with sodium thiosulphate solution (2M), saturated sodium chloride, dried and finally evaporated to give the title product, yield 0.48 g (96%) nD20 1.5942.
Reaction SMILES: N1[CH:6]=[CH:5][C:4]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])=[N:3]C=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[B-](F)(F)F.[K+].CCO.[CH2:38]([N:40](CC)CC)C>C(Cl)Cl>[N:40]1[CH:38]=[CH:6][CH:5]=[C:4]([NH:7][C:8]([N:10]2[CH2:11][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:24]4[C:23]([F:22])=[CH:28][CH:27]=[CH:26][C:25]=4[F:29])=[CH:17][N:16]=3)[CH2:13]2)=[O:9])[N:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(Nc1ccncn1)N1CC(Oc2ccc(I)cn2)C1
Reactant: Fc1cccc(F)c1[B-](F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(-c3c(F)cccc3F)cn2)C1
Temperature: 80 °C
Yield: 16.6 %

Procedure:
3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyrimidin-4-ylamide (50 mg, 0.126 mmol), potassium 2,6-difluorophenyltrifluoroborate (29 mg, 0.132 mmol), triethylamine (0.05 ml, 0.38 mmol) 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (5 mg, 5 mole %) and EtOH (108 mg, 0.786 mmol) were combined and heated at 80° C. for 16 h. The reaction had not gone to completion so further potassium 2,6-difluorophenyltrifluoroborate (29 mg, 0.132 mmol), 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (5 mg, 5 mole %) and triethylamine (0.05 ml, 0.38 mmol) were added and the mixture heated for a further 5 h. The reaction mixture was allowed to cool before being passed through a pad of celite and washed through with EtOAc and MeOH. These organics were evaporated in vacuo, to afford a crude oil, which was purified by flash chromatography, eluting with a gradient of 0 to 4% MeOH in CH2Cl2 to a afford still impure product as a brown oil. This was purified by HPLC (pH 4, HCO2NH4/HCO2H/H2O/MeCN) to afford the desired product as a white solid (8 mg, 17%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]([CH3:25])([CH3:24])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]2[CH2:23][O:22]2)=[CH:12][CH:11]=1)=[O:9].[CH3:26][O:27][CH2:28][CH2:29][O:30][CH3:31]>CC(O)C>[OH:6][C:7]([CH3:25])([CH3:24])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:22])[CH2:23][N:1]([CH2:18][CH:17]([OH:16])[CH2:26][O:27][CH2:28][CH2:29][O:30][C:31]2[CH:12]=[CH:11][C:10]([C:8](=[O:9])[C:7]([OH:6])([CH3:24])[CH3:25])=[CH:15][CH:14]=2)[CH2:2][CH2:3][CH2:4][OH:5])=[CH:12][CH:11]=1)=[O:9]
Reactant: NCCCO
Reactant: CC(C)(O)C(=O)c1ccc(OCCOCC2CO2)cc1
Reactant: COCCOC
Solvent: CC(C)O
Product: CC(C)(O)C(=O)c1ccc(OCCOCC(O)CN(CCCO)CC(O)COCCOc2ccc(C(=O)C(C)(C)O)cc2)cc1

Procedure:
To a mixture of 2.22 g (29.6 mmol) of 3-amino-1-propanol in 20 ml of 1,2-dimethoxyethane and 40 ml of 2-propanol is added a solution of 11.57 g (41.3 mmol) of the compound of Example 1A in 20 ml of 1,2-dimethoxyethane. The mixture is heated at reflux overnight. Solvent is evaporated to afford a mixture of the title compounds.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17](F)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Solvent: CCO
Product: COc1ccc(CNc2cc3c(Nc4cccc(Br)c4)ncnc3cn2)cc1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
A mixture of 4-[(3-bromophenyl)amino]-6-fluoropyrido[3,4-d]pyrimidine (0.48 g) and 4-methoxybenzylamine (10.3 g) in ethanol (50 mL) was heated to 100° C. for 5 days. The resulting product was chromatographed on silica gel, eluting with CH2Cl2:EtOAc (3:1), to give 4-[(3-bromophenyl)amino]-6-[(4-methoxyphenyl)methylamino]pyrido[3,4-d]pyrimidine (0.18 g,) mp (aqueous methanol), 178-179.5° C. A 0.10 g portion of this was dissolved in 5 mL trifluoroacetic acid and heated under reflux for 1 hour, and the mixture was evaporated to dryness. The residue was partitioned between EtOAc and aqueous ammonia, and the crude product was chromatographed on alumina, eluting with CH2Cl2:MeOH (97:3) to give 6-amino-4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidine (0.040 g,), mp (CH2Cl2) 241.5-242° C.
Reaction SMILES: [C:1]1([CH:7]([CH:9]([C:15]([O-:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CC(C)=O.O>[CH2:13]([O:12][C:10]([CH:9]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:8])[C:15]([OH:17])=[O:16])=[O:11])[CH3:14]
Reactant: CCOC(=O)C(C(=O)[O-])C(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C(=O)O)C(C)c1ccccc1
Yield: 65 %

Procedure:
The ethyl (1-phenylethyl)malonate is stirred overnight with sodium hydroxide (1.3 eq) in an acetone/water (3:1 by volume) mixture. After concentrating to dryness, the residue is taken up with water (40 mL) and the mixture is then extracted three times with ethyl acetate (25 mL). The organic phase is washed, dried, filtered and concentrated to dryness to yield 3.5 g of 2-ethoxycarbonyl-3-phenylbutanoic acid in a 65% yield in the form of an oil, having the following characteristics: Rf =0.50 [methylene chloride/methanol (9:1 by volume)].
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:18]=[N:17][CH:16]=[CH:15][C:9]=3/[C:10](=[N:13]/[OH:14])/[C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:19]([O:23][C:24](=[O:34])[NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH:32]=O)([CH3:22])([CH3:21])[CH3:20].C([O-])(=O)C.[NH4+:39].C(O)(=O)C>C(OCC)(=O)C.O>[OH:14][N:13]1[C:10]2[C:9]3[CH:15]=[CH:16][N:17]=[CH:18][C:8]=3[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:11]=2[N:39]=[C:32]1[C:31]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[NH:25][C:24](=[O:34])[O:23][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: [NH4+]
Reactant: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C=O
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cnccc1-c1nc2c(n1O)-c1ccncc1Nc1ncccc1-2
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of (6Z)-5H-dipyrido[2,3-b:4′,3′-f]azepine-5,6(11H)-dione 6-oxime (80.0 mg, 0.333 mmol), tert-butyl-(4-formylpyridin-3-yl)carbamate, ammonium acetate (0.513 g, 6.66 mmol), water (0.12 mL) and acetic acid (0.76 mL) was stirred at 80° C. for 3 h. The solution was diluted with ethyl acetate and water, the organic solution was washed with brine, dried over MgSO4 and concentrated. The crude residue was purified by preparative LCMS to yield the desired product (102 mg, 69%). LCMS for C23H22N2O3(M+H)+: m/z=444.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:45][C:46]2[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=2)=[O:43])=[C:18]([F:23])[CH:17]=1
Reactant: CCc1nnc(N)s1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nnc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-ethyl-1,3,4-thiadiazole (43 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 49 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(Cl)Cl>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]>[N+:9]([C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([F:24])([F:23])[F:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:11])=[O:10]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
4-Bromo-2-nitroaniline (10.1 g, 46.7 mmol), 2-trifluoromethylphenylboronic acid (1.3 eq., 11.5 g, 60.7 mmol), and (dppf)PdCl2.DCM (0.05 eq., 1.91 g, 2.34 mmol) were placed in a 500 mL round-bottom flask equipped with a magnetic stir bar. The vial was evacuated and backflushed with Ar, and DME (180 mL) and 2M aq Na2 CO3 (60 mL) were added via syringe. The flask was capped tightly, and the reaction was stirred at 90° C. for 16 h. The reaction was cooled to RT, diluted with EtOAc, and washed sequentially with water and brine. The organic extract was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was dry-loaded onto 25 g of SiO2 and purified by column chromatography using an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 20 min, yielding 12.8 g (97%) of the desired compound. 1H-NMR (400 MHz, CDCl3) δ: 8.11 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.54-7.62 (m, J=7.6 Hz, 1H), 7.44-7.53 (m, J=7.8 Hz, 1H), 7.36 (dd, J=8.6, 1.3 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[C:24]3=[N:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28][N:23]3[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C@@H:19]3[C:24]4=[N:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28][N:23]4[CH2:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=S1(=O)CCN2CCC[C@H](c3ccc(O)cc3)C2=N1
Reactant: CCc1ccc(B(O)O)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1ccc(Oc2ccc([C@H]3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
A mixture of (4-ethylphenyl)boronic acid (1.34 g), (9R)-9-(4-hydroxyphenyl)-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (500 mg), diacetoxycopper (648 mg), triethylamine (1.24 mL), and powdered 4A MS (1.50 g) in DMF (20 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc—IPE to give the title compound (53.0 mg) as a white solid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[NH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[NH:29][CH:28]=[CH:27]2>>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[CH:23][C:22]=2[NH:21][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]4[O:18][C:14]([CH3:13])=[CH:15][CH:16]=4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH:27]=[CH:28]1
Reactant: Nc1cccc2cc[nH]c12
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(Nc4cccc5cc[nH]c45)cccc3n2)o1

Procedure:
The title compound, MS: m/e=369.1 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 7-aminoindole.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([CH3:38])[CH:29]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[C:30]([CH3:38])[CH:29]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
To a cooled and stirred solution of 3′-[4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.21 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.17 g, 68%). MS (ISP) 484.2 [(M+H)+]; mp 222.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:36]=[C:35]([CH:34]=[CH:33][CH:32]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: Oc1cccc(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3cccc(F)c3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-fluorophenol: ESMS m/e: 492.9 (M+H)+.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[C:19]1([CH2:25][CH2:26][C:27](OCC)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCCC1>[O:28]=[C:27]([CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)CCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CCc1ccccc1)OC
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A solution of dimethyl methylphosphonate (12.4 g., 0.1 mole) in dry tetrahydrofuran (75 ml.) is stirred, maintained under a nitrogen atmosphere, cooled to -50° C., and treated with a 2 N solution of n-butyl lithium in hexane (50 ml., 0.1 mole) added dropwise. Upon completing the addition, the reaction mixture is kept at -50° C. for 1/2 hour to ensure anion formation and then is treated with ethyl 3phenylpropionate (8.9 g., 0.05 mole) added dropwise at -50° C. After stirring for an additional 11/2 hours at -50° to -40° C., the reaction mixture is poured into ice water (250 ml.) providing a turbid solution which is acidified with 2 N hydrochloric acid and extracted with ethyl acetate (4 × 75 ml.). The combined organic extract is dried over sodium sulfate and filtered. Evaporation of the filtrate in vacuo at 40° to 50° C. leaves an oily residue which is distilled to provide the title compound as an oil (11.0 g., 86%), b.p. 148°-150° C./0.1 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][C:8]2=[O:13].I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21])[C:8]2=[O:13]
Reactant: Cc1ccncc1I
Reactant: COc1cccc2c1CCNC2=O
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cccc2c1CCN(c1cnccc1C)C2=O
Yield: 3.7 %

Procedure:
Using analogous reaction conditions as described in Example 1, 5-methoxy-3,4-dihydro-2H-isoquinolin-1-one (I-13d: 0.09 g, 0.5 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.133 g, 0.0006 mol), 1,4-dioxane (30 mL), copper iodide (0.0096 g, 0.05 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.021 g, 0.13 mmol) and potassium phosphate (0.269 g, 0.0012 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM), followed by preparative TLC afforded 5 mg of the product (38.46% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][C:15]([NH:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1c(Br)cc(Br)c2cccnc12
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CNC(=O)Oc1c(Br)cc(Br)c2cccnc12
Temperature: 25 °C

Procedure:
5,7-Dibromo-8-hydroxyquinoline (19.7 g), ethyl isocyanatoacetate (13.0 g) and triethylamine (6.58 g) were mixed in 200 ml of toluene and heated at reflux temperature for about 47 hours. The solution was cooled to room temperature and the desired ethyl N-(((5,7-dibromo-8-quinolinyl)oxy)carbonyl)glycinate was obtained as a white, crystalline solid, m.p. 129.5° C. (decomposition).