Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:24]C)=[C:14]3[C:19](=[O:20])[N:18]([CH2:21][CH3:22])[CH2:17][C@H:16]([CH3:23])[N:15]3[C:9]=2[C:8]([C:26]([NH:28][CH3:29])=[O:27])=[N:7]1.B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([OH:24])=[C:14]3[C:19](=[O:20])[N:18]([CH2:21][CH3:22])[CH2:17][C@H:16]([CH3:23])[N:15]3[C:9]=2[C:8]([C:26]([NH:28][CH3:29])=[O:27])=[N:7]1
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)NC)c32)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCN1C[C@H](C)n2c(c(O)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)NC)c32)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (6S)-2-(3-chloro-4-fluorobenzyl)-8-ethyl-10-methoxy-N,6-dimethyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-carboxamide (1.15 g, 2.41 mmol) in anhydrous dichloromethane (800 mL), a solution of boron tribromide in dichloromethane (3.14 mL, 3.14 mmol; 1 M) was added. After stirring at room temperature for 5 minutes, the reaction mixture was treated with anhydrous methanol, stirred for 30 minutes, and concentrated under vacuum. The procedure was repeated twice. The residue was dissolved in a mixture of methanol and acetonitrile and treated with aqueous sodium hydroxide. The mixture was subjected to purification on preparative reverse phase high pressure column chromatography. Collection and lyophilization of appropriate fractions provided the title compound as white amorphous solid.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]1(=[O:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1>>[CH:1]([C:6]1([OH:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: O=C1CCCc2ccccc21
Product: CC(C)C1(O)CCCc2ccccc21
Reaction time: 0.08 h

Procedure:
According to Example 2, i-PrMgCl (1.10 mL; 1.10 mmol; 1.10 equiv) was reacted with 3,4-dihydro-1(2H)-naphthalenone (146 mg; 1.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 3.00 mL, 1.00 mmol, 1.00 equiv), the conversion was complete after 5 min (GC monitoring). After workup and careful evaporation of the solvents under reduced pressure, the desired product was obtained as colorless oil (180 mg, 95%). The analytical data were found to be in accordance with the literature data.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)=[O:3].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>>[C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:14]=[CH:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:1]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)Nc1ccc(Br)cc1
Product: CCOC(=O)C=Cc1ccc(NC(C)=O)cc1
Yield: 10.4 %

Procedure:
The procedure described in Example 26 is repeated, but using 5.35 g (25 mmols) of 4-bromoacetanilide and 2.99 ml (27.5 mmols) of ethyl acrylate. After a reaction time of 12 hours at 130° C. and working up as described in Example 1, recrystallisation of the crude product from toluene gives 0.60 g (2.6 mmols) of ethyl 4-(N-acetylamino)-cinnamate as pale yellow crystals of melting point 133° C.; yield 10% of theory (conversion figure 1000; Pd content 0.01 mol %). Analysis for C13H15NO3 (molecular weight 233): calculated C 66.92; H 6.48; N 6.01; O 20.59, found C 66.52; H 6.38; N 6.07; O 20.59.
Reaction SMILES: C(O[CH:5]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)C>C(O)C.[Pd]>[NH:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1=[O:18]
Reactant: CC(=O)OC1CCCCC(=O)Nc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCCCc2ccccc2N1

Procedure:
A solution of 7-acetoxy-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (7.4 g) in ethanol (250 ml) is hydrogenated at 3 atmospheres at 70° using 10% palladium on charcoal (1.5 g) as catalyst. The catalyst is filtered off and the solvent removed under reduced pressure. The residue is recrystallized to give 1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CN1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(C)CC2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
1-Methyl-4-piperidyl para-toluenesulphonate may be obtained in the following manner: para-toluenesulphonyl chloride (19.60 g) is added in the course of approximately 1 hour 30 minutes to a solution, cooled to 0° C., of 4-hydroxy-1-methylpiperidine (11.50 g) in pyridine (50 cc), and the mixture is stirred for 4 hours at 0° C. and then 12 hours at a temperature in the region of 20° C. After the addition of triethylamine (14.10 g) and stirring for a further 15 minutes, distilled water (300 cc) and ethyl acetate (300 cc) are added. The aqueous phase is separated after settling has taken place and washed with ethyl acetate (200 cc). The organic extracts are combined, washed with distilled water (500 cc in total), dried over anhydrous magnesium sulphate and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 45° C. The final traces of pyridine are removed under a higher vacuum (0.1 mm Hg; 13.5 Pa). 1-Methyl-4-piperidyl para-toluenesulphonate (19.6 g) is thereby obtained in the form of a brown oil [Rf=0.56; thin-layer chromatography on silica; eluent: acetonitrile/ammonia solution (d=0.92) (95:5 by volume)].
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)Nc2ccc([N+](=O)[O-])cc2O)c1
Yield: 46.2 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(3-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 3-methoxyphenylisocyanate(1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (140 mg, 46%). EI-MS m/z 302(M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>CC(C)=O>[CH2:18]([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Nc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 2-amino-4-chlorophenol (10 g, 69.65 mmol) and K2CO3 (14.53 g, 105 mmol) in acetone (160 mL) was treated with allyl bromide (9.03 mL, 104 mmol), stirred at room temperature overnight, and filtered. The filter cake was washed with acetone and the combined filtrates were concentrated. The residue was purified by flash column chromatography eluting with hexanes/ethyl acetate (10:1) to provide 8.31 g (65%) of the desired product. MS (DCI/NH3) m/z 184.02 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 4.51 (m, 2H), 5.02 (s, 2H), 5.24 (dd, J=10.53, 1.68 Hz, 1H), 5.42 (m, 1H), 6.04 (m, 1H), 6.47 (dd, J=8.54, 2.44 Hz, 1H), 6.66 (d, J=2.75 Hz, 1H), 6.75 (d, J=8.54 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[F:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:24]=1[C:25]([N:27]=[C:28]=[O:29])=[O:26].CCCCCC>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:24]=1[C:25]([NH:27][C:28]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[C:3]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:12]=2[Cl:21])=[CH:4][C:5]=1[F:9])=[O:29])=[O:26]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F

Procedure:
0.21 Gram of 5-chloro-2-fluoro-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline was dissolved in 6 ml of toluene, and to this solution was added dropwise a solution of 0.11 g of 2,6-difluorobenzoyl isocyanate in 4 ml of toluene with ice-cooling and stirring. After completion of addition, the reaction solution was stirred overnight at room temperature. Thereafter, 6 ml of n-hexane was added, the precipitated crystals were filtered off and dried to obtain 0.20 g of N-(2,6-difluorobenzoyl)-N'-[5-chloro-2-fluoro-4-{2-chloro-4-(trifluoromethyl)phenylthio}phenyl]urea as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:14]2[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: OC1CCNCC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(O)CC2)nc(Cl)n1
Yield: 57 %

Procedure:
To a solution of 2,4-dichloro-6-methylpyrimidine (998 mg, 6.0 mmol) in tetrahydrofurane (30 mL) was added under stirring N,N-diisopropyl ethyl amine (853 mg, 6.6 mmol) and 4-hydroxypiperidine (681 mg, 6.6 mmol) and the reaction was stirred over night at 20° C. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (1:1 v/v) as eluent to yield the title compound (779 mg, 57%) as white crystals. MS ISP (m/e): 228.2/230.2 (100/35) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=6.73 (s, 1H), 4.78 (d, 1H), 3.95 (br m, 2H), 3.75 (m, 1H), 3.25 (m, 2H), 2.22 (s, 3H), 1.75 (m, 2H), 1.33 (m, 2H).
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1)C.CC([O-])(C)C.[K+].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>C1COCC1.Cl>[I:11][C:7]1[CH:6]=[C:5]([C:4](=[O:12])[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cccc(I)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
Ethyl-3-iodobenzoate (25.4 g, 92.0 mmol) was dissolved in THF (60 mL) and cooled to 0° C. followed by the addition of KOt-Bu (20.6 g, 184 mmol). The mixture was stirred for 15 minutes followed by the addition of ethyl acetate (8.91 g, 101 mmol). The mixture was warmed to ambient temperature, stirred for 2 hours, diluted with aqueous HCl (10%, 200 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to provide the titled compound (29.3 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][N:2]=1.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.[ClH:54].C(N=C=NCCCN(C)C)C>ClCCl>[ClH:54].[ClH:54].[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[N:2][CH:3]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(O)c1ccnnc1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccnnc3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.8 %

Procedure:
0.25 g of 4-pyridazine-carboxylic acid (2.01 mmol) and 0.7 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.01 mmol) were dissolved in 25 ml of dichloromethane. 1.04 g of diisopropylethylamine (8.04 mmol), 0.19 g of hydroxybenzotriazole (HOBt, 1.4 mmol), and 0.46 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.4 mmol) were added at 0° C. and the reaction mixture was stirred for 16 h at room temperature. 0.09 g of hydroxybenzotriazole and 0.23 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the reaction mixture was stirred 5 h. 25 ml of dichloromethane were added, the organic layer was washed with aqueous saturated sodium chloride, the aqueous phase re-extracted once with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (10%). Fractions containing the product were combined, the solvent evaporated, and the residue re-dissolved in 20 ml of ethyl acetate. Treatment with 3.3 ml of 1 N hydrochloride acid in diethyl ether yielded 0.69 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]#[N:19])[C:9]2=[O:20])=[CH:4][CH:3]=1.[OH2:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([NH2:19])=[O:21])[C:9]2=[O:20])=[CH:4][CH:3]=1
Reactant: O
Reactant: N#Cc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Product: NC(=O)c1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O

Procedure:
1-(4-Chlorophenyl)-3-cyano-1,2-dihydroquinoxalin-2-one (6.6 g) was heated at 110° C. for 1 hour with polyphosphoric acid (25 g). The mixture was diluted with water and extracted with chloroform. Evaporation of the solvent and recrystallisation of the residue from ethanol gave the title compound (3.8 g) mp 293°-297° (decomp).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([C:18](O)=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([C:18]([N:6]2[CH2:7][C:2](=[O:1])[CH2:3][CH2:4][CH:5]2[C:8]([O:10][CH3:11])=[O:9])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C1CCC(=O)CN1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: COC(=O)C1CCC(=O)CN1C(=O)c1ccccc1-c1ccccc1

Procedure:
Methyl 1-(biphenylcarbonyl)-5-oxopiperidine-2-carboxylate was prepared according to general procedure A using methyl 5-oxopiperidine-2-carboxylate and biphenyl-2-carboxylic acid. MS (ESI) 338 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:3]=[CH:2][CH:7]=[C:6]([C:27]4[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=4)[CH:5]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cnn(C)c3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (116 mg, 0.557 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 8.02 (s, 1H), 7.84 (s, 1H), 7.64 (d, 1H), 7.58 (m, 2H), 7.52 (s, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 7.02 (d, 1H), 4.4 (m, 2H), 3.96 (s, 3H), 3.8 (m, 1H), 3.58 (m, 1H), 3.0-3.2 (m, 5H), 2.41 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[C:7]([C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[C:7]([C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(N(CCO)CCO)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1c([N+](=O)[O-])ccc(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A solution of methyl 3-[bis(2-hydroxyethyl)amino]-2,6-dinitrobenzoate [Palmer et al., J. Med. Chem. 1996, 39, 2518] (7.24 g, 22 mmol) in CH2Cl2 (120 mL) was cooled in an ice-bath and Et3N (15 mL) and MsCl (8 mL) were added in one portion. After stirred for 10 min, satd. NaHCO3 (100 mL) was added, and after a further 30 min the aqueous phase was extracted with CH2Cl2 (2×70 mL), the combined organic phase were dried, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel. Elution with EtOAc/petroleum ether (1:1 to 1:0), gave crude methyl 3-(bis{2-[(methylsulfonyl)oxy]ethyl}amino)-2,6-dinitrobenzoate (16) (10.67 g, 100%) as a yellow oil;
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:10][C:11]([F:19])([F:18])[CH2:12][O:13][CH2:14][C:15](N)=[NH:16].C(OCC)(=O)C>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:12][C:11]([F:19])([F:18])[F:10])[N:16]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)COCC(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc(COCC(F)(F)F)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 7.2 g (0.060 mole) of 3-amino-2-pyrazinecarbonitrile and 14.2 g (0.091 mole) of 2-(2,2,2-trifluoroethoxy)acetamidine in 230 ml of absolute ethanol. Refluxing time: 7 hours. Yld: 6.5 g (42%), m.p. 145°-147° C. (ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](O)=[CH:7][N:6]=1)=[O:4].O=P(Cl)(Cl)[Cl:14]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Cl:14])=[CH:7][N:6]=1)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cnc(O)cn1
Product: COC(=O)c1cnc(Cl)cn1
Yield: 55.1 %

Procedure:
A mixture of 5-hydroxy-pyrazine-2-carboxylic acid methyl ester (Preparation 40, 50 g, 324 mmol) and POCl3 (500 mL, 5.36 mol) was heated under reflux for 1.5 hours and then poured onto ice. The resulting mixture was extracted with ether (4×500 mL). The organic layers were concentrated in vacuo, and the residue was recrystallised from toluene to give the title compound (30.8 g) in a 55% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[CH:15]1(O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH:15]1([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[CH:12][CH:13]=[CH:14][C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:8])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: OC1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1C1CCCC1
Yield: 74.4 %

Procedure:
To a solution of 3-nitrophthalimide (3.85 g, 20.0 mmol), cyclopentanol (2.24 g, 26.0 mmol) and triphenylphosphine (6.87 g, 26.2 mmol) in tetrahydrofuran 30 ml was dropwise added 40% toluene solution (11.4 ml) of diethyl azocarboxylate under stirring in a nitrogen stream. The mixture was concentrated in vacuo, and the precipitate formed upon addition of ether was filtered off. After the filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography (hexane-ethyl acetate, 3:1) to give the title compound (3.87 g) as a colorless solid.
Reaction SMILES: [C:1]([O:7]C(C)(C)C)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[CH2:12]([NH:14][CH3:15])[CH3:13]>C(O)(C)(C)C>[CH2:12]([N:14]([CH3:15])[C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[O:4])[CH3:13]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CCNC
Solvent: CC(C)(C)O
Product: CCN(C)C(=O)CC(C)=O
Temperature: 130 °C
Yield: 97.8 %

Procedure:
Into a 1 l stainless steel autoclave are introduced 158 g (1 mol) of tert-butyl acetoacetate and 61 g of N-ethyl-N-methylamine (1.05) mol), followed by heating at 130° C. for 6 hours; the pressure does not exceed 10 bars. The contents of the autoclave are transferred to a round-bottomed flask and the tert-butanol formed is evaporated under reduced pressure to give 140 g (98%) of N-ethyl-N-methylacetoacetamide which is sufficiently pure to be used in the following reaction.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([CH2:8][C:9]([S:11][C@H:12]2[CH2:16][CH2:15][N:14]([C:17](=[N:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[CH3:18])[CH2:13]2)=[O:10])[N:6]([C:33]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])=[C:34]([CH3:36])[CH3:35])[C:5]1=[O:50])[CH3:3].[N+:51]([C:54]1[CH:64]=[CH:63][C:57]([CH2:58][O:59][C:60](Cl)=[O:61])=[CH:56][CH:55]=1)([O-:53])=[O:52]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:20]([N:19]=[C:17]([N:14]2[CH2:15][CH2:16][C@H:12]([S:11][C:9]([CH2:8][C@H:7]3[N:6]([C:33]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=4)=[O:38])=[C:34]([CH3:35])[CH3:36])[C:5](=[O:50])[C@@H:4]3[C@H:2]([O:1][C:60]([O:59][CH2:58][C:57]3[CH:56]=[CH:55][C:54]([N+:51]([O-:53])=[O:52])=[CH:64][CH:63]=3)=[O:61])[CH3:3])=[O:10])[CH2:13]2)[CH3:18])=[O:21])=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(C)C)C1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(C)C)C1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
56 mg (0.079 mmole) of (3S, 4R)-3-[(R)-1-hydroxyethyl]-4-([(S)-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl)-1-[2-methyl-1-(p-nitrobenzyloxycarbonyl)prop-1-enyl]-2-azetidinone were dissolved in 1.5 ml of methylene chloride. To the solution were added, in turn, 29 mg (0.24 mmole) of 4-(N,N-dimethylamino)pyridine and 51 mg (0.24 mmole) of p-nitrobenzyloxycarbonyl chloride, with stirring at 0° C. The reaction mixture was stirred at room temperature for 3 hours, diluted with methylene chloride, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulphate. The solvent was distilled off and the residue was subjected to thin layer chromatography using silica gel, developed with a 1:5 by volume mixture of hexane and ethyl acetate, to afford 30 mg (yield 42%) of the title product as an oily substance. 8 mg (14%) of the starting material was also recovered.