Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.CN(C)C=O.ClCCl.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>Cl>[NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:21])[CH:27]=2)=[CH:6][N:7]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CNC(=O)c1nc(Br)cnc1N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Temperature: 87.5 °C
Yield: 54.3 %

Procedure:
To a solution of 3-amino-6-bromo-N-methyl-2-pyrazinecarboxamide (1.23 g, 5.30 mmol) in N,N-dimethylformamide (30 mmol) were added [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1, 433 mg, 0.53 mmol), 3-aminophenylboronic acid (1.15 g, 7.41 mmol), and triethylamine (1.07 g, 10.6mmol). The solution was degassed with nitrogen 3-5 min. The reaction was heated at 85-90° C. for 15 h with stirring. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (400 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered, and concentrated to give crude product. To the crude product was added 4.0 N hydrochloric acid (1,4-dioxane solution, 30 mL). The resulting solid was filtered and washed with diethyl ether/methanol (4:1). The solid was dissolved in methanol and neutralized with sufficient AG 1-X8 Resin (hydroxide form) that the pH of the solution became basic. The mixture was filtered, and the filtrate was concentrated on a rotary evaporator at reduced pressure to afford 3-Amino-6-(3-aminophenyl)-N-methylpyrazine-2-carboxamide (0.70 g, 54% yield) as dark green solid. 1H NMR (400 MHz, d6-DMSO): 8.70(br s, 1H), 8.62 (s, 1H), 7.60 (br s, 2H), 7.25 (m, 2H), 7.10 (t,. 1H), 6.15 (d, 1H), 5.06 (s, 2H), 2.8 (br s, 3H); MS (EID for C12H13N5O: 244 ).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCc1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CCCCCCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (608 mg, 4 mM) and n-octylbenzene (1.77 ml, 8 mM) were dissolved in dichloroethane (8 ml), titanium tetrachloride (0.66 ml, 6 mM) was added, and reacted at room temperature for 30 minutes. Using the same procedure as in Example 1, 4'-n-octylbenzoin was obtained as crystal (810.0 mg, 62.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.I[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)=[C:4]([CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Ic1cnccn1
Reactant: CCOC(=O)c1cc(Cl)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)ccc1-c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [4-chloro-2-(ethoxycarbonyl)phenyl]boronic acid (3-1, 0.300 g, 1.313 mmol, 1.0 equiv), 2-iodopyrazine (0.352 g, 1.707 mmol, 1.3 equiv), 4M Cs2CO3 (1.15 mL, 4.60 mmol, 3.5 equiv) and PdCl2(dppf) (0.096 g, 0.131 mmol, 0.1 equiv) in DMF (6.5 mL) was combined and stirred at room temperature overnight. The reaction was partitioned between EtOAc and saturated aqueous NaHCO3, washed with water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc/hexanes) to provide 3-2 as a solid. ESI+ MS [M+H]+ C18H17N3O2: 263.01 found, 263.70 required.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[Br:17])[CH2:5][CH2:4]1)=O>Cl>[Br:17][C:10]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=1[N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: COc1ccc(N2CCN(C=O)CC2)c(Br)c1
Agent: Cl
Product: COc1ccc(N2CCNCC2)c(Br)c1

Procedure:
A mixture of 1-formyl-4-(2-bromo-4-methoxyphenyl)piperazine (VII, 3.92 g, 3.1 mmol) and hydrochloric acid (4N, 70 ml) is heated at 100° for 50 min. The mixture is then concentrated under reduced pressure to remove most of the aqueous hydrochloric acid. Saturated sodium bicarbonate is then cautiously added and the aqueous phase is extracted with dichloromethane. The combined organic phase is backwashed with saline, dried over magnesium sulfate, and concentrated to give 1-(2-bromo-4-methoxyphenyl)piperazine (VIII), NMR (CDCl3) 2.55, 2.95, 3.08, 3.77, 6.83, 7.01, 7.14 δ.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:18]([O:20][CH:21]([O:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24]Cl)[CH3:19].O>CN(C)C=O>[CH2:18]([O:20][CH:21]([O:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24][N:8]1[C:7]2[C:16](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15](=[O:17])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[CH3:19]
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Reactant: CCOC(CCCCl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CCCn1c2ccccc2c(=O)c2ccccc21)OCC
Reaction time: 2 h

Procedure:
A suspension of 1.44 g of sodium hydride in 100 ml of dimethylformamide is treated within 10 minutes with 9.75 g of 9-acridanone and held at 50° for 2 hours. At 120° there are then added 9.5 g of 4,4-diethoxybutyl chloride. After 16 hours, the mixture is cooled, poured into water and extracted with dichloromethane. The extract is dried over sodium sulfate and evaporated. The residue is extracted with hexane and crystallized twice from hexane. There is obtained 10-(4,4-diethoxybutyl)-9-acridanone of metling point 73°-74.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:41][C:42]1[CH:43]=[N:44][NH:45][CH:46]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([N:44]4[CH:43]=[C:42]([CH3:41])[CH:46]=[N:45]4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1cn[nH]c1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-n4cc(C)cn4)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 28 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) with 4-methyl-1H-pyrazole yielded the title compound (28% yield) as a white foam. MS (ISP): m/z=609.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:13]([NH2:17])(=[O:16])[CH:14]=[CH2:15]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:15][CH2:14][C:13]([NH2:17])=[O:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: SCCc1ccc2c(c1)OCO2
Reactant: C=CC(N)=O
Solvent: CCO
Product: NC(=O)CCSCCc1ccc2c(c1)OCO2
Yield: 60.4 %

Procedure:
5 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 4 g of acrylamide were dissolved in 100 ml of ethanol and the solution was heated under reflux to conduct the reaction for 20 h. The reaction mixture was cooled with ice. 100 ml of ethanol was added thereto and crystals thus formed were recovered by filtration to obtain 4.2 g of the intended compound in the form of colorless needles.
Reaction SMILES: [Na].[SH:2][CH:3]([CH2:6][SH:7])[CH2:4][OH:5].Cl[CH2:9][C:10]([CH2:12]Cl)=[CH2:11]>C(O)C>[OH:5][CH2:4][CH:3]1[CH2:6][S:7][CH2:12][C:10](=[CH2:9])[CH2:11][S:2]1
Reactant: C=C(CCl)CCl
Reactant: OCC(S)CS
Agent: [Na]
Solvent: CCO
Product: C=C1CSCC(CO)SC1
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Sodium metal (0.77 g) was dissolved in 35 mL of absolute ethanol at room temperature under nitrogen protection. Then 2,3-dimercapto-1-propanol (1.99 g, 1.6 mL, 16 mmoles) was added dropwise. The solution was taken up in a syringe and diluted to 44 mL. Solution 2. 2-(Chloromethyl)-3-chloro-1-propene (2 g, 16 mmoles) was dissolved in 30 mL of absolute ethanol. The solution was taken up into a syringe and diluted to a volume of 44 mL. Solutions 1 and 2 were added simultaneously (via syringe pump using separate teflon feed lines) to a 40 mL of absolute ethanol at room temperature under nitro:en protection over a period of one hour. After the addition was completed, the reaction was refluxed for one hour. The reaction was then worked up by evaporation of the solvent, dilution with water and extraction with ether. The ether extracts were dried and evaporated to give 2.6 g of oil. The oil was chromatographed on Silica gel using ether:hexane (1:3) to give 1.6 g (57%) of clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18]>C(O)(C)(C)C.C(O)(C)C>[ClH:1].[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:17]#[CH:18])[CH:20]=1)([O:14][CH3:15])=[O:13]
Reactant: C#Cc1cccc(N)c1
Reactant: COC(=O)c1ccc2ncnc(Cl)c2c1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3ccc(C(=O)OC)cc23)c1

Procedure:
4-Chloro-6-carbomethoxyquinazoline (100 mg, 0.450 mmol) and 3-ethynylaniline hydrochloride (53.4 mg, 0.456 mmol) were refluxed in 2 mL of tert-butyl alcohol for 2 hours, cooled, diluted with 2 mL of isopropyl alcohol and filtered to afford solid title product which was washed with 10 mL of diethyl ether and dried, in vacuo, at 70° C., 122 mg (80%); mp 232°-233° C. (dec).
Reaction SMILES: Br[C:2]1[N:3]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=2)[C:4]2[C:9]([C:10]=1[S:11][C:12]1[C:13]([F:23])=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=[C:6]([Cl:24])[C:5]=2[F:25].[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:24][C:6]1[C:5]([F:25])=[C:4]2[C:9]([C:10]([S:11][C:12]3[C:13]([F:23])=[C:14]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([CH:33]3[CH2:35][CH2:34]3)[N:3]2[C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cccc(Sc2c(Br)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of compound 11 (150 mg, 0.27 mmol) in toluene (10 mL) under inert atmosphere was purged with argon at RT for 10 min. To this, cyclopropylboronic acid (48 mg, 0.55 mmol), tricyclohexyl phosphine (16 mg, 0.05 mmol), Pd(OAc)2 (6 mg, 0.02 mmol) and potassium phosphate (202 mg, 0.01 mmol) were added at RT under argon. The resultant solution was purged again with argon at RT for 5 min. The reaction mixture was then heated to reflux temperature and stirred for 3 h. The reaction was monitored by TLC & LC-MS; after completion of the reaction, the reaction was cooled to RT, diluted with EtOAc (20 mL) and filtered. The filtrate was washed with water (2×10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified (silica gel chromatography; 6% EtOAc/Hexanes) to afford 7 as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.66-7.7.60 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (dd, J=8.4, 6.5 Hz, 1H), 6.93 (t, J=8.4 Hz, 1H), 6.79-6.75 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.26 (q, J=7.6 Hz, 2H), 1.74-1.68 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 1.41 (t, J=7.6 Hz, 3H), 1.08-1.04 (m, 2H), 0.89-0.84 (m, 2H); LC-MS (ESI): 92.9%; m/z 502.5 (M+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.85 min; 5 mM NH4OAc: ACN; 0.8 mL/min); HPLC: 93.1%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 3.44 min; ACN: 0.025% TFA (aq); 0.5 mL/min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[C:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1)#[CH:30].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:30]#[C:29][C:31]3[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC(C)C)c2)cc1C
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(SCc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC(C)C)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene (347.0 mg; 1.93 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 260 mg (72%). HPLC-MS: m/z: 567.6 (M+H)+; Rt: 2.77 min
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:18]([CH3:27])([C:23](OC)=[O:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:18]([CH2:23][OH:24])([CH3:27])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: C1CCOC1
Product: COC(=O)C(C)(CO)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 12 h
Yield: 60.2 %

Procedure:
Dissolved LiAl(OtBu)3H (509 mg, 2.0 mmol) in 2 mL THF and then added a solution of dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)-2-methylmalonate (215 mg, 0.48 mmol) in 2 mL of THF. After 12 h, the reaction was incomplete so more LiAl(OtBu)3H (509 mg, 2.0 mmol) was added. After 12 h, quenched with MeOH, poured into brine and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC using a 1:3 to 1:1 EtOAc/hexane gradient. Obtained 121 mg (60% yield) of methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(hydroxymethyl)-2-methyl-3-phenylpropanoate. MS found: (M+H)+=419.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(Cc3ccccc3F)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with 2-fluorobenzyl bromide and cesium carbonate in N,N-dimethylacetamide to give N-(2-fluoro-benzyl)-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 600.6 ([M+NH4]+)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C.O>CN(C)C=O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
Potassium phthalimide (20 g, 0.108 mol) was added to a solution obtained by dissolving 4-benzyloxybenzyl chloride (25 g, 0.107 mol) in N,N-dimethylformamide (75 mL), and the solution was stirred for 3 hours under reflux. The reaction solution was allowed to room temperature, then, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, and 2-(4-benzyloxybenzyl)-isoindol-1,3-dione (37 g, quantitatively) was obtained as a pale brown solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]=[CH2:27])=[CH:20][CH:19]=1>>[N:1]1([CH2:6][C:7]2([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH2:27][CH:26]([CH2:25][O:24][C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[O:10][N:8]2[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1cccs1
Reactant: C=CCOc1ccc(OC)cc1
Product: COc1ccc(OCC2CC(Cn3ccnc3)(c3cccs3)N(C)O2)cc1

Procedure:
Compound 6 (R=CH2OC6H4OCH3 -4) can be prepared by a method similar to that described in Example 1 by reacting 2-(1H-imidazol-1-yl)-N-methyl-1-(2-thienyl)ethanimine N-oxide (4) with allyl 4-methoxyphenyl ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: COc1cccc(O)c1
Product: COc1cccc(Oc2nc(Nc3cc[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-methoxy-phenol to give [6-methoxy-1-(3-methoxy-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 363(MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[F:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)=[CH:3][CH:4]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:22]([F:28])[CH:23]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 166, step 1, 5-{3-(4-bromo-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 237, step 5) was reacted with 4-carboxyphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)-ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound containing 12% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=502.8 [M−H]−.
Reaction SMILES: Br[C:2]1[C:21]([O:22][CH3:23])=[CH:20][C:5]2[NH:6][C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[CH3:23][O:22][C:21]1[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])=[CH:3][C:4]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[N:9][CH2:8][C:7](=[O:19])[NH:6][C:5]=2[CH:20]=1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2
Reactant: COc1ccccc1B(O)O
Agent: OB(O)c1ccccc1
Product: COc1ccccc1-c1cc2c(cc1OC)NC(=O)CN=C2c1cccc(C#N)c1
Yield: 88 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 5 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2-methoxy-benzene boronic acid. The title compound (474 mg) was obtained as a pale yellow solid, (yield=88%).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCCC(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1](=[O:7])([S:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Sc1ccccc1
Reactant: CCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC(=O)Sc1ccccc1
Yield: 94.8 %

Procedure:
Hexanoyl chloride (2.76 mL, 19.7 mmol) in 60 mL toluene was added to a solution of triethylamine (2.80 mL, 20.1 mmol) and thiophenol (2.04 mL, 20.0 mmol) in 40 mL toluene. Reaction monitoring was accomplished by TLC: iso-hexane/ethyl acetate 100:1, Rf=0.20. Workup yielded 3.89 g (95%) S-phenyl hexanethioate 4 as pale yellow oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:31]1[CH2:32][CH2:33][C@H:34]([OH:35])[C@@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:30]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CNCC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CN(C(C)=O)CC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*)-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f39) and commercially available acetyl chloride the title compound is obtained as colorless solid.