Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25](Cl)(=O)=O)[CH:24]=1.[ClH:30]>C(OCC)C>[S:25]([C:23]1[CH:24]=[C:19]([C:9]2[C:10]([Cl:30])=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])[CH:20]=[CH:21][C:22]=1[CH3:29])[C:23]1[CH:24]=[C:19]([C:9]2[C:8]([Cl:7])=[CH:13][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:10]=2[Cl:18])[CH:20]=[CH:21][C:22]=1[CH3:29]
Reactant: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S(=O)(=O)Cl
Reactant: Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1Sc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
To 0.7 g (18.4 mmol) of lithium aluminum hydride in 30 ml of diethyl ether, 7.2 g (17.8 mmol) of 5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylbenzenesulfonyl chloride in 30 ml of diethyl ether was added dropwise at −10° C. After 12 hours of stirring at room temperature, the reaction mixture was poured into 1N aqueous hydrochloric acid for separation. The organic layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography affored 4.3 g of 1,1′-thiodi-[5-(2,6-dichloro-4-trifluoromethylphenyl)-2-methylbenzene] (yield 75.0%) as a pale yellow dough (nD20 1.6066), which was used in Example 2 (1) as the starting material.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[OH-].[K+].ClC(OC(Cl)(Cl)Cl)=[O:16]>O>[CH3:11][C:4]1[S:3][C:2]2[NH:1][C:10](=[O:16])[O:9][C:7](=[O:8])[C:6]=2[CH:5]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(C)sc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(=O)oc(=O)[nH]c2s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
Methyl 2-amino-5-methyl-thiophene-3-carboxylate (16.8 g, 299 mmol) was added to a solution of potassium hydroxide (25 g, 146 mmol) in 300 mL water. The solution was heated at 90° C. until to yield a clear solution. The solution was heated at same temperature for another 30 min and then cooled to 0° C. Trichloromethyl chloroformate (26.42 mL, 219 mmol) was added slowly without allowing the temperature to rise beyond 10° C. The solution was further stirred for 2 h. The precipitated solid was collected by vacuum filtration to yield 21.6 g (83%) of 6-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione. 1H-NMR (DMSO-d6) δ 2.38 (d, J=1.2 Hz, 3H), 6.90 (q, J=1.2 Hz, 1H), 12.44 (b, 1H) ppm; EIMS m/z 184 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[NH:16][CH2:15][CH2:14]3)[O:5]1.[CH3:23]I>CN(C=O)C.C(OCC)(=O)C>[CH3:23][N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([B:6]3[O:5][C:4]([CH3:22])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]3)[CH:12]=2)[C:17]1=[O:21]
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36.2 %

Procedure:
Sodium hydride (29.3 mg, 0.732 mmol) was added to a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.366 mmol) in DMF (1.0 mL). The mixture was stirred at r.t. for 5 min, and then methyl iodide (57.0 μL, 0.915 mmol) was added. The mixture was stirred at 50° C. for 6 h, then diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.038 g, 36%). LCMS (M+H)+=274.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>O1CCOCC1>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Solvent: C1COCCO1
Product: O=Cc1cnn2c(NC3CC3)cc(Nc3cccc(Cl)c3)nc12
Temperature: 120 °C
Yield: 10.6 %

Procedure:
To 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (177 mg, 0.75 mmol) in 1,4-dioxane was added 3-chloroaniline (397 μl, 3.75 mmol). The mixture was heated in microwave at 120° C. for 60 minutes. Precipitate was filtered off, and the filtrate was prepared by TLC (1% methanol/dichloromethane) to yield 26 mg (11% yield) of 5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=328)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].C1(C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:30].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:30])=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1Cl
Temperature: 0 °C

Procedure:
4-Hydroxy-8-(trifluoromethyl)-3-quinolinecarboxylic acid ethyl ester (compound of formula (V)), 11.27 g, 39.55 mmol) was taken into toluene (125 mL), then POCl3 (7.4 mL, 79.08 mmol) was added and the mixture was refluxed for 1.5 hours. The reaction was carefully poured into ice-water with vigorous stirring, then added carefully added saturated NaHCO3 until the solution was neutral. Dilute with ethyl acetate and separate the layers. The organic layer was dried over MgSO4, filtered and concentrated. The resulting material was passed through a short silica gel plug using 10% ethyl acetate in hexane. Concentration and drying under high vacuum yielded 9.93 g of the title compound as a white solid.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)([CH3:15])[CH3:14].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[C:23]([CH:22]([C:19]1[CH:20]=[CH:21][C:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[CH:17][CH:18]=1)[C:1]([C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)=[O:9])#[N:24]
Reactant: CCOC(=O)c1ccncc1
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)c1ccc(C(C#N)C(=O)c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
To a solution of ethyl isonicotinate (12 g) and 4-(1,1-Dimethylethyl)phenylacetonitrile (9.1 g) in tert-butyl alcohol (36 mL), was added potassium tert-butoxide (7.3 g), and the mixture was stirred at 100° C. for 3 h. After cooling, the resulting mixture was dissolved in water and washed with isopropyl ether. The aqueous phase was adjusted to pH 7.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, And the solvent was evaporated. The crystalline residue was recrystallized from ethyl acetate-isopropyl ether to obtain 2-cyano-2-[4-(1,1-dimethylethyl)phenyl]-1-(4-pyridyl)ethanone (5.09 g, yield 35%).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([I:12])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:13][CH:14]([CH3:17])[CH2:15][NH2:16].O>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:16][CH2:15][CH:14]([CH3:17])[CH3:13])[C:3]2[N:4]([C:9]([I:12])=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Reactant: CC(C)CN
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CNc1cc(Cl)nn2c(I)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 200 mg (0.558 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c in 4 mL N,N-dimethylformamide were added 122 mg 2-methylpropan-1-amine and the mixture was stirred at rt overnight. Water was added and the mixture was extracted with dichloromethane and methanol. The organic phase was washed with water and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 188 mg (96%) of the title compound.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=O)[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:45][C@@H:46]([C:59]([NH:61][C@H:62]([C:70]([N:72]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:73])=[O:71])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:60])[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([CH:57]=[O:58])[CH:49]=1>CN(C=O)C>[NH:1]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C@H:2]([C:19]([NH:45][C@@H:46]([C:59]([NH:61][C@H:62]([C:70]([N:72]([CH2:74][C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1)[CH3:73])=[O:71])[CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)=[O:60])[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([CH:57]=[O:58])[CH:49]=1)=[O:21])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:5]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](N)Cc1cn(C=O)c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc3cn(C=O)c4ccccc34)C(=O)N[C@@H](Cc3ccccc3)C(=O)N(C)Cc3ccccc3)c2)cc1

Procedure:
A solution of Boc-His(Tos)-OH (0.82 g) in DMF (10 ml) was cooled at -15° C. To the solution, NMM (0.22 ml) and isobutyl chloroformate (0.26 ml) were added successively and the mixture was stirred for ten minutes. On the other and, a solution of HCl.H-D-Trp(CHO)-Phe-NMeBzl in DMF (10 ml) was cooled at -15° C. and thereto was added NMM (0.22 ml). This solution was added to the above mentioned mixture and stirred for an hour at -15° C. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with 2% hydrochloric acid, water, 2% sodium hydrogencarbonate, water and saturated sodium chloride solution, and dried over magnesium sulfate to give Boc-His(Tos)-D-Trp(CHO)-Phe-NMeBzl. After evaporation, the residue was dissolved in DMF (20 ml). To the solution, pyridinium chloride (2.18 g) was added under stirring at room temperature. After an hour, additional pyridinium chloride (0.5 g) was added and stirred for additional fifty minutes. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with water, 2% hydrochloric acid, water, 2% sodium hydrogencarbonate, water, saturated sodium chloride solution and dried over magnesium sulfate. After evaporation, the residue was subjected to column chromatography on silica gel (60 g) and eluted with a mixture of chloroform and methanol (20:1). The fractions containing the object compound were combined and evaporated. The residue was pulverized with a mixture of ethanol, diethyl ether and n-hexane. The powder was filtered, washed with n-hexane and dried to give Boc-His-D-Trp(CHO)-Phe-NMeBzl (1.04 g).
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)=O.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].OS([O-])=O.[Na+]>CC(N(C)C)=O>[NH:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:29]=[C:1]1[C:3]1[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: CC(C)(C)C(=O)Nc1ncc(-c2ccccc2)cc1C=O
Reactant: Nc1ccccc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)C(=O)Nc1ncc(-c2ccccc2)cc1-c1nc2ccccc2[nH]1
Temperature: 250 °C
Yield: 27.8 %

Procedure:
N-(3-formyl-5-phenylpyridin-2-yl)-2,2-dimethylpropanamide (0.1 g, 0.35 mmol), o-phenylenediamine (0.038 g, 0.35 mmol), and NaHSO3 (0.039, 0.53 mmol) were combined in 3 mL of dimethylacetamide and heated to 250° C. in the SmithSynthesizer™ microwave instrument for 10 minutes. Upon cooling, the solvent was removed and the residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (0 to 100% EtOAc over 20 minutes) to afford N-[3-(1H-benzimidazol-2-yl)-5-phenylpyridin-2-yl]-2,2-dimethylpropanamide (0.036 g). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.37 (s, 9H) 7.32 (m, 2H) 7.45 (m, 1H) 7.56 (t, J=7.60 Hz, 2H) 7.65 (d, J=7.87 Hz, 1H) 7.72 (d, J=7.87 Hz, 1H) 7.86 (dd, J=8.33, 1.19 Hz, 2H) 8.81 (d, J=10.07 Hz, 2H) 12.87 (s, 1H) 13.38 (s, 1H) MS m/z 371 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[O:34][CH3:35].O>CN(C=O)C>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[O:34][CH3:35])[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reaction time: 0.5 h

Procedure:
A solution of 1.13 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one in 7 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.120 g of sodium hydride as an 80% dispersion in oil is added. After stirring for 30 minutes, 1 g of methyl 4-bromomethyl-3-methoxybenzoate is added and the reaction mixture is stirred for 1 hour at 0° C. It is poured into water and the precipitate formed is filtered off, washed with water, taken up with AcOEt, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (93/7; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=1.88 g. M.p.=152° C.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:28](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:29])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:18][C:19]=3[CH3:20])=[CH:11][C:10]=2[CH:27]=1)[CH3:2].[OH-:43].[Li+]>O1CCCC1>[CH2:1]([O:3][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:18][C:19]=3[CH3:20])=[CH:11][C:10]=2[CH:27]=1)[C:28]([OH:29])=[O:43])[CH3:2]
Reactant: [OH-]
Reactant: CCO[C@@H](Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(=O)O
Temperature: 0 °C

Procedure:
5-{(S)-2-Ethoxy-3-[(S)-4-benzyl-2-oxo-3-oxazolidinyl}-3-oxopropyl}-2-[(5-methyl-2-phenyl-4-oxazolyl)methyl]benzofuran (0.15 g, 0.26 mmol) was dissolved in tetrahydrofuran (5 ml). The solution was cooled to 0° C. and 0.5N lithium hydroxide (1.1 ml, 0.52 mmol) was added. After 15 minutes the bulk of the ethanol was removed, the residue was acidified with 1N HCl, diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried over sodium sulfate and concentrated. The product was purified by flash-chromatography (hexanes/ethyl acetate/acetic acid, 10:10:1) then recrystallized from hexanes/ethyl acetate and obtained as a white solid (48 mg, mp 129° C., [α]D =-12.5° (c 0.99, CDCl3)).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:13][N:11]1[CH:12]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:15][NH2:16])=[CH:7][CH:6]=2)[CH:9]=[N:10]1
Reactant: NN
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2ccc(NN)nn2)cn1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a suspension of 3-chloro-6-(1-methyl-1H-pyrazole-4-yl)-pyridazine (21.0 g, 108 mmol) in ethanol (370 mL) was added hydrazine monohydrate (36 mL). The reaction mixture was stirred at reflux for 18 h, then cooled to room temperature. The precipitate was collected via filtration, washed with cold ethanol and dried in vacuo to provide 18 g of [6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine as a beige solid (87% yield): 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 4.28 (s, 2H), 7.02 (d, 1H), 7.59 (d, 1H), 7.83 (s, 1H), 7.91 (s, 1H), 8.19 (s, 1H); MS (m/z) 191 [M+H+]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20]C(=O)C)=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:47]([C:50]1[N:51]=[CH:52][NH:53][CH:54]=1)([O-:49])=[O:48]>CN1CCCC1=O.C(OCC)(=O)C>[C:35]1([CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][NH:26][C:4]2[N:3]=[C:2]([N:53]3[CH:54]=[C:50]([N+:47]([O-:49])=[O:48])[N:51]=[CH:52]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:18])[CH2:19][OH:20])[C@@H:13]([OH:24])[C@H:12]2[OH:25])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cnc([N+](=O)[O-])c4)nc32)[C@H](O)[C@@H]1O
Temperature: 150 °C

Procedure:
The title compound is prepared by dissolving acetic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1) in N-methyl-2-pyrrolidinone, followed by potassium carbonate (5 equivalents) and 4-nitro-1H-imidazole (10 equivalents). The mixture is heated by microwave irradiation to 150° C. for two hours, then diluted with ethyl acetate and washed consecutively with water (×2) and brine, before drying over magnesium sulfate. Filtration, removal of the volatile components under reduced pressure and purification by flash column chromatography/crystallisation affords the title compound.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].CN1C(=O)CCC1.[NH:34]([C:36](OCC)=[O:37])[NH2:35]>CCOC(C)=O>[O:37]=[C:36]1[NH:34][N:35]=[C:1]([C:3]2[N:4]=[C:5]([O:13][CH2:14][C@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(C#N)cc2ccccc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Temperature: 175 °C

Procedure:
To a crude reaction mixture containing (R)-tert-butyl 2-(((3-cyanoisoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (0.749 g) was added NMP (2 mL) and ethyl hydrazinecarboxylate (0.883 g, 8.48 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled, diluted with EtOAc, and washed with saturated aqueous NH4Cl followed by water. The organic layer was separated and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]12[CH2:9][CH:6]([NH:7][CH2:8]1)[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]2.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>C(OCC)C>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][N:7]1[CH2:8][C:2]2([CH3:1])[CH2:9][CH:6]1[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]2)[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: CC1(C)CC2CC(C)(CN2)C1
Solvent: CCOCC
Product: CCOC(=O)CCN1CC2(C)CC1CC(C)(C)C2
Reaction time: 8 h

Procedure:
15.3 g of 1,3,3-trimethyl-6-aza-bicyclo[3,2,1]octane (0.15 mol) are introduced into 50 ml of diethyl ether, and 15.1 g of ethyl acrylate are gradually added thereto while stirring. A clear solution forms with a slight increase in temperature. After standing overnight at room temperature, the ether is distilled off. The oil which remains is distilled in vacuo to give 3-(1,3,3-trimethyl-6-aza-bicyclo[3,2,1]oct-6-yl)-propionic acid ethyl ester, b.p. 77°/0.013 mbar.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:22](Cl)(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C)C=O>[C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][O:15][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:8][C@@H:6]1[OH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=O)[C@@H](O)[C@@H]1O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To 1 g of N-acetylglucosamine, 5 mL of pyridine and 15 mL of N,N-dimethylformamide were added, and the mixture was heated to 70° C. under stirring and 1.37 mL of palmitoyl chloride was dropwise added, and the reaction was carried out for 4 hours. On completion of the reaction, after extracting with ethyl acetate and washing with 2 mol/L hydrochloric acid, the ethyl acetate layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform:methanol=15:1) to obtain 710 mg of 2-acetamido-2-deoxy-6-O-palmitoyl-α-D-glucopyranose as a white crystal.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[N+:9]([C:12]1[CH:13]=[CH:14][C:15]2[NH:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)([O-])=O.[H-].[Na+]>CN(C=O)C>[CH3:1][N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([NH2:9])[CH:13]=[CH:14][C:15]1=2
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCOc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
Potassium carbonate (800 mg, 6 mmol) and methyl iodide (1.3 g, 9 mmol) were added to a solution of 3,4-dihydro-7-nitro-2H-benzo[b][1,4]oxazine (540 mg, 3 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight. Sodium hydride (100 mg, 95%) and methyl iodide (1.0 g) were added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was suspended in water. A solid precipitated which was filtered and washed with water. The bright yellow solid was then suspended in MeOH (20 mL) and Pd/C (10%) was added. The suspension was stirred under an atmosphere of hydrogen overnight, then filtered through celite and the filtrate concentrated under vacuum to give the product (470 mg) as a purple oil.