Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[C:3]=1[NH2:12].Br[C:14]1[S:15][CH:16]=[CH:17]N=1.N>O>[CH3:11][C:9]1[CH:8]=[C:4]2[C:3](=[C:2]([CH3:1])[CH:10]=1)[N:12]=[C:14]1[S:15][CH:16]=[CH:17][N:7]1[C:5]2=[O:6]
Reactant: Brc1nccs1
Reactant: Cc1cc(C)c(N)c(C(N)=O)c1
Agent: N
Solvent: O
Product: Cc1cc(C)c2nc3sccn3c(=O)c2c1
Temperature: 155 °C
Reaction time: 12 h
Yield: 57.2 %

Procedure:
A mixture of 13.1 g of 3,5-dimethylanthranilamide and 13.1 g of 2-bromothiazole was heated for 30 minutes at 155° C. and stirred for 12 hours. After the mixture had cooled to 25° C., the pH was adjusted to 9 by adding water and 25% strength ammonia solution, while stirring, and the resulting solution was stirred for 10 minutes. The solution was then suction filtered and the filtrate was washed with methanol and dried, 10.5 g of the above compound was obtained; m.p. 190°-192° C. The methanol filtrate was concentrated, taken up in ethyl acetate and chromatographed over aluminum oxide. After concentration a further 4.4 g of the above compound were obtained; total yield: 81%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[C:11]([O:23][CH3:24])=[CH:10][C:9]=1[F:25])=[O:7])[CH3:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:26])[C:5]([C:6](=[O:7])[C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[C:11]([O:23][CH3:24])=[CH:10][C:9]=1[F:25])=[CH:29][N:30]([CH3:32])[CH3:31])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Reaction time: 3 h

Procedure:
To a solution of 3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionic acid ethyl ester prepared in Step VI-2 in toluene was added dropwise at 75-85° C., N,N-dimethylformamide dimethyl acetal (5.08 g) with stirring, and the mixture was stirred for 3 hr. After cooling, a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylic acid ethyl ester in toluene was obtained. This was identified as the title compound by HPLC.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:17][OH:18].Cl>CCOC(C)=O.CN(C=O)C>[CH3:17][O:18][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)ccc1S(C)(=O)=O
Temperature: 100 °C
Yield: 95.7 %

Procedure:
To 3-fluoro-4-methylsulfonyl-benzoic acid (490 mg, 2.25 mmol), sodium hydride (270 mg, 6.74 mmol), methanol (1.55 g, 2.0 mL, 48.3 mmol) was added DMF (5 mL) and reaction mixture was heated at 100° C. for 1 hour. The reaction mixture was cooled and diluted with EtOAc and acidified using 1 M HCl solution. The organic layer was separated, washed with saturated aqueous brine solution (3×), dried over sodium sulfate and concentrated in vacuo to give 3-methoxy-4-methylsulfonyl-benzoic acid (496 mg, 95%). ESI-MS m/z calc. 230.0. Found 231.3 (M+1)+; Retention time: 0.49 minutes (3 min run).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: COC(=O)c1[nH]c2ccccc2c1CCSC(C)=O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(CCSC(C)=O)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.8 %

Procedure:
To a solution of methyl 3-[2-(acetylthio)ethyl]-1H-indole-2-carboxylate (0.364 g, 1.31 mmol), phenylboronic acid (0.239 g, 1.97 mmol), and copper(II)acetate (0.237 g, 1.31 mmol) in dichloromethane (10 mL) was added pyridine (0.91 mL, 6.55 mmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was passed through a column of silica gel (EtOAc/hexanes, 1:9) to afford 3-(2-acetylthioethyl)-1-phenyl-1H-indole-2-carboxylic acid, methyl ester (0.153 g, 0.43 mmol, 33%) as a clear oil: 1H NMR (CDCl3) δ 2.37 (s, 3H), 3.20–3.24 (m, 2H), 3.39–3.43 (m, 2H), 3.75 (s, 3H), 7.07 (d, J=8.2 Hz, 1H), 7.20–7.32 (m, 4H), 7.42–7.53 (m, 3H), 7.87 (d, J=7.9 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([NH:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 150 °C

Procedure:
90 mg (0.33 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90 mg (0.31 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.87 mmol) DIPEA were combined in 1.5 mL DMF and stirred at 150° C. After the reaction had ended the reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](Cl)=[O:7])[CH3:2].C[O:11][C:12](=O)[CH2:13][C:14]1([NH2:17])[CH2:16][CH2:15]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([NH:17][C:14]1([CH2:13][CH:12]=[O:11])[CH2:16][CH2:15]1)=[O:7])[CH3:2]
Reactant: COC(=O)CC1(N)CC1
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)NC1(CC=O)CC1
Yield: 40.3 %

Procedure:
Chlorocarbonyl-acetic acid ethyl ester (2.75 ml; 22.1 mmol) is added dropwise under stirring and cooling to a solution of (1-amino-cyclopropyl)-acetic acid methyl ester (Chemstep Product List, 13926) (3.00 g; 23.2 mmol) in triethylamine (6.4 ml; 46.2 mmol) and CH2Cl2 (150 ml). After stirring at room temperature for 30 minutes, the reaction mixture is poured on a saturated solution of NaHCO3 and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness. Purification via chromatography (SiO2; hexane/acetone 6:4) yield the title compound as crystalline light-yellow solid (1.9 g; 34%) 1H-NMR (400 MHz; DMSO-d6): 8.40 (s, 1H); 4.07 (q, 2H); 3.60 (s, 3H); 3.12 (s, 2H); 2.58 (s, 2H); 1.17 (t, 3H); 0.71 (m, 2H); 0.66 (m, 2H). MS (m/z) ES+: 244 (MH+)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:26][C:27]1[O:28][C:29]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][C:30]=2[N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:34]3[CH:33]=[CH:32][C:30]4[N:31]=[C:27]([CH3:26])[O:28][C:29]=4[CH:35]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCCC3)nc(Cl)nc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 90 °C
Yield: 42 %

Procedure:
To a mixture of 2-chloro-4-(cyclopentyloxy)-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzooxazole (1 equiv), tripotassium phosphate trihydrorate (3 equiv) in 1,4-dioxane and water (8:1, 0.5 M) was added 1,1-bis(diphenylphosphion)ferrocene palladium dichloride (0.1 equiv). The mixture was refluxed at 90° C. for 2 h. Filtration and concentration gave the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (42% yield). MS (ESI) m/z 498.2 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]1=[O:19])[CH2:4][CH2:5][CH3:6].[CH2:20](I)[CH:21]=[CH2:22]>CN(C=O)C>[CH2:22]([C:7]1([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]1=[O:19])[CH:21]=[CH2:20]
Reactant: C=CCI
Reactant: CCCCC1CCc2cc(OC)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(CCCC)CCc2cc(OC)ccc2C1=O
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
NaH (0.32 g of a 60% dispersion in mineral oil, 8.0 mmol) was added to an ice-cold solution of 2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (1.55 g, 6.7 mmol) in anhydrous DMF (30 mL). The mixture was purged with N2 and stirred at 0-5° C. for 45 minutes. Allyl iodide (0.91 mL, 10.0 mmol) was added and, after a few minutes, the cooling bath was removed and the mixture was stirred overnight at room temperature. Additional NaH (0.16 g of a 61.1% dispersion in mineral oil, 4.1 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Allyl iodide (0.46 mL, 5.0 mmol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was partitioned between EtOAc and water, and the aqueous phase was back-extracted with several portions of EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40M (4×15 cm) silica gel column, eluting with 1% to 4% EtOAc in hexane, to afford 2-allyl-2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:4]=2[NH:5][C:6]2[CH:12]=[C:11](F)[CH:10]=[CH:9][C:7]=2[N:8]=1.Cl.CN(C)CCNC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[F:42]C1C=CC2N=C(N(CCN(C)C)C)C3C4C=CC=CC=4SC=3NC=2C=1>CS(C)=O>[NH2:1][C:2]1[C:3]2[C:16]3[CH:17]=[CH:18][C:19]([F:42])=[CH:20][C:15]=3[S:14][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CN(C)CCN(C)C1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Reactant: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Agent: CNCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Product: NC1=Nc2ccccc2Nc2sc3cc(F)ccc3c21

Procedure:
In the same manner as in Example 42 and using 12-amino-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1 hydrochloride (1.3 g), N,N,N′-trimethylethylenediamine (13 g), dimethyl sulfoxide (5 ml) and citric acid, 8-fluoro-12-[N-(2-dimethylaminoethyl)-N-methylamino]-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1 citrate 1 hydrate (289 mg) was obtained.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[Cl:23].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:15]([Cl:23])=[CH:16][C:17]([C:18]#[N:19])=[CH:20][C:21]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(/N=C/c2cncc(F)c2N=[N+]=[N-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled (0° C.) solution of 4-azido-5-fluoro-pyridine-3-carbaldehyde (2.0 g, 12.0 mmol), 4-amino-3,5-dichlorobenzonitrile (2.25 g, 12.0 mmol) and triethylamine (5.0 mL, 36.1 mmol) in DCM (48 mL) was added titanium tetrachloride (1M in DCM, 7.2 mL, 7.2 mmol) dropwise over 20 minutes. The reaction mixture was stirred for 20 minutes, warmed to room temperature, and stirred for a further 30 minutes. The resultant mixture was concentrated to dryness under reduced pressure to afford the title compound, which was used without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:10]2[S:14][C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:12][C:11]=2[CH:21]=1)(=O)=O.[CH3:30][C:31]1([C:51]([O:53][CH2:54][CH3:55])=[O:52])[O:36][C:35]2[CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=[N:40][C:34]=2[NH:33][C:32]1=[O:50].ClC1N2N=C(N)N=C2C=C(Cl)C=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[CH2:19]([NH:18][C:16](=[O:17])[NH:15][C:13]1[S:14][C:10]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:8][C:7]([C:38]3[CH:39]=[N:40][C:34]4[NH:33][C:32](=[O:50])[C:31]([CH3:30])([C:51]([O:53][CH2:54][CH3:55])=[O:52])[O:36][C:35]=4[CH:37]=3)=[CH:21][C:11]=2[N:12]=1)[CH3:20]
Reactant: CCOC(=O)C1(C)Oc2cc(B3OC(C)(C)C(C)(C)O3)cnc2NC1=O
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3ccccn3)c2s1
Agent: Nc1nc2cc(Cl)cc(Cl)n2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc4c(c3)OC(C)(C(=O)OCC)C(=O)N4)cc(-c3ccccn3)c2s1
Temperature: 80 °C
Yield: 41.9 %

Procedure:
To the solution of 2-(3-ethylureido)-7-(pyridin-2-yl)benzothiazol-5-yl trifluoromethanesulfonate (0.5 g, 1.12 mmol) and ethyl 2-methyl-3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-2-carboxylate (0.4 g, 1.12 mmol) in 1,4-dioxane:MeOH (5:3 mL) was added potassium phosphate (0.36 g, 1.68 mmol) at rt and the mixture degassed for 15-20 min by purging N2 followed by the addition of dichloro(1,1-bis(diphenylphosphino)(ferrocene)palladium (II) (0.091 g, 0.11 mmol). The reaction was degassed for another 15-20 min then heated to 80° C. for 5 h. After completion of reaction (by TLC), the reaction was cooled to rt, diluted with EtOAc (500 mL), passed through celite, the filtrate concentrated under reduced pressure and the crude residue purified over 100-200 M silica-gel using eluent 2.3% MeOH: DCM to obtain the desired product as an off-white solid (0.25 g, 42%). 1H NMR (DMSO-d6): δ 1.06-1.13 (m, 6H), 1.77 (s, 3H), 3.21 (q, J=7.20, 2H), 4.14 (m, 2H), 6.87 (br s, 1H), 7.45 (m, 1H), 7.97-8.03 (m, 2H), 8.09 (s, 1H), 8.29 (s, 1H), 8.55 (s, 2H), 8.80 (d, J=4.0 Hz, 1H), 10.62 (br s, 1H) and 11.73 (br s, 1H). MS: 533.24 [M+H]+.
Reaction SMILES: [C:1]([NH:5][CH:6]([OH:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:4])[CH:2]=[CH2:3].CO.[CH3:14]OC.C1(C=CC(O)=CC=1)O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>>[CH3:14][O:11][CH:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC
Reactant: C=CC(=O)NC(O)C(=O)OC
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: Oc1ccc(O)cc1
Solvent: CO
Product: C=CC(=O)NC(OC)C(=O)OC
Yield: 85 %

Procedure:
Methyl acrylamidoglycolate, as prepared in Example I, in the amount of 100 parts (0.63 mole) is combined with 200 parts of methanol (6.3 moles), 0.10 parts of the methyl ether of hydroquinone and 0.005 part of ethylene-diamine tetraacetic acid and 5.0 parts of a 40% aqueous solution of paratoluenesulfonic acid is added as catalyst. The reaction mixture is heated for 4 hours at reflux temperature and then cooled and filtered. Vacuum stripping of the methanol results in crystallization of the product. An 85% yield of methyl acrylamidoglycolate methyl ether is obtained.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH:6]=1.C([Mg]Br)C.[CH3:17][O:18][C:19]1[C:20]([N+:30]([O-:32])=[O:31])=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[CH2:24][CH2:23][CH2:22]2.[Cl-].[NH4+]>ClCCl>[OH:29][C:25]1([C:2]2[N:3]=[CH:4][N:5]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH:6]=2)[C:26]2[C:21](=[C:20]([N+:30]([O-:32])=[O:31])[C:19]([O:18][CH3:17])=[CH:28][CH:27]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Reactant: CN(C)S(=O)(=O)n1cnc(I)c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc2c(c1[N+](=O)[O-])CCCC2(O)c1cn(S(=O)(=O)N(C)C)cn1
Reaction time: 0.5 h

Procedure:
A solution of 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide (3.0 g, 10 mmol) (R. M. Turner, J. Org. Chem. (1991), 56, 5739-5740) in dichloromethane (40 mL) was treated with ethyl magnesium bromide (3.0M in diethyl ether, 3.3 mL) over 5 minutes, stirred for 30 minutes, treated with 6-methoxy-5-nitro-1-tetralone (2.6 g, 11.8 mmol), stirred for 16 hours, treated with ammonium chloride solution and extracted with dichloromethane. The extract was dried (MgSO4), filtered and concentrated to provide the desired compound.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])[CH3:29].O>CN(C)C(=O)C.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>[CH3:21][N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:34]4[CH:35]=[CH:36][C:31]([C:28](=[O:30])[CH3:29])=[CH:32][CH:33]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Reactant: CC(=O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Temperature: 120 °C
Yield: 96.9 %

Procedure:
Dissolve 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (921 mg, 3.0 mmol) in N,N-dimethylacetamide (6 mL). Add potassium carbonate (996 mg, 7.2 mmol), 4-acetylbenzene boronic acid (590 mg, 3.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0174 g, 0.015 mmol), then water (3 mL). Heat at 120° C. for 17 hr., then cool to room temperature, add water (15 mL) and extract with DCM (3×20 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®. Concentrate the filtrate and purify by SCX-2® chromatography washing with methanol then eluting with 3.5 M ammonia in methanol. Further purify (silica gel chromatography, eluting with 5:95 to 20:80 methanol:DCM), to give 1-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-ethanone as a yellow powder (1.135 g, 97%). MS (ES): m/z=391 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:11]([C@H:16]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:17][C:18](=[O:20])[CH3:19])[O:12][C:13](=[O:15])[CH3:14])[C:6](=[O:10])[CH:7]=[N+]=[N-])(=[O:3])[CH3:2].[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[C:26]([O:29][CH2:7][C:6]([C@@H:5]([C@H:11]([C@H:16]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:17][C:18](=[O:20])[CH3:19])[O:12][C:13](=[O:15])[CH3:14])[O:4][C:1](=[O:3])[CH3:2])=[O:10])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OC[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)C=[N+]=[N-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](COC(C)=O)OC(C)=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 156.9 %

Procedure:
A solution of 10 grams of 1-deoxy-1-diazo-keto-L-fructose tetracetate and 0.01 gram of cupric acetate in 300 ml. of anhydrous acetic acid in a 2 liter flask was heated gently and after the initial violent evolution of gas had subsided, was brought just to the boiling point. The solvent was removed by distillation under reduced pressure, the final portion was removed by distillation with ethanol. The resulting syrup was dissolved in 15 ml. of ethanol, filtered and allowed to crystallize overnight in a refrigerator. This yielded 4 grams of crystals, m.p. 65° C. The syrup obtained from mother liquid was dissolved in 50 ml. of acetic anhydride containing 0.5 gram of zinc chloride (fresh fused), allowed to stand overnight at room temperature and heated 90 minutes at 50° C. Excess acetic anhydride was hydrolyzed by pouring into 200 ml. of ice-water and stirred for 2 hours. The acetylated sugar was extracted from the water with 200 ml. of chloroform. The chloroform solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to a syrup. This syrup was crystallized from 10 ml. of ethanol and yielded an additional 3 grams of product.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1([CH3:14])[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C.C(OCC)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:14])[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)Oc1ccccc1C
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 102.3 %

Procedure:
Cesium carbonate (53.86 g, 165.3 mmol) was added to a solution of 2-cresol (10.0 g, 92.5 mmol) in anhydrous DMF (500 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (16.7 mL, 92.5 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir at 90° C. for 18 h. The reaction mixture was diluted with diethyl ether, then extracted twice with 1N HCl and twice with water. The organic layer was dried over MgSO4 and concentrated in vacuo to provide the title compound (19.7 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.16 (d, 1H, J=7.43 Hz), 7.11 (t, 1H, J=7.43 Hz), 6.89 (t, 1H, J=7.48 Hz), 6.70 (d, 1H, J=7.43 Hz), 4.75 (q, 1H, J=6.65 Hz), 4.23 (q, 2H, J=6.65 Hz), 2.30 (s, 3H), 1.64 (dd, 3H, J=7.04 Hz, 0.78 Hz), 1.26 (td, 3H, J=7.04 Hz, 0.78 Hz). Rf=0.37 in 25% ether in hexanes.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:21][N:20]=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Yield: 79.7 %

Procedure:
Prepared as in Example 104 from (2,3-difluorophenyl)-(4-methoxy-phenyl)-methanone (1.1 g, 4.4 mmol), hydrazine hydrate (1.37 mL, 44 mmol) and DMAP (0.54 g, 4.4 mmol) to give the product (0.85 g) as a white solid.