Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H:10]1[C@@:14]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:15])[C@H:13]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:12]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:11]1)(=O)C1C=CC=CC=1.[NH2:44][C:45]1[N:53]=[C:52]2[C:48]([NH:49][CH:50]=[N:51]2)=[C:47]([Cl:54])[N:46]=1.CCCCCCC=CCCC.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:17]([O:16][C@:14]1([CH3:15])[C@H:13]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:12]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:11][C@H:10]1[N:51]1[CH:50]=[N:49][C:48]2[C:52]1=[N:53][C:45]([NH2:44])=[N:46][C:47]=2[Cl:54])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: CCCC=CCCCCCC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Temperature: 65 °C
Yield: 79 %

Procedure:
To a pre-cooled (0° C.) solution of (2S,3R,4R,5R)-5-(benzoyloxymethyl)-3-methyltetrahydrofuran-2,3,4-triyl tribenzoate (or 2,3,4,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose) (CarboSynth Ltd, 10.0 g, 17.22 mmol), 2-amino-6-chloropurine (Aldrich, 3.2 g, 18.87 mmol), and 1,8-diazabicycl[5.4.0]undec-7-ene (DBU) (7.7 mL, 51 mmol) in anhydrous acetonitrile (200 mL), was added trimethysilyl triflate (12.5 mL, 68.8 mmol) dropwise. The reaction mixture was then heated at 65° C. for 4 to 6 h, allowed to cool down to room temperature, poured into saturated aqueous sodium bicarbonate (300 mL), and extracted with dichloromethane (3×150 mL). The combined organic phase was dried over sodium sulfate and evaporated under reduced pressure. The residue was precipitated from dichloromethane and methanol, filtrated, the solid was washed 2 times with methanol and dried to give the desired compound (8.5 g, 79%) as a white solid (yields are from 65% (column) up to 90% (precipitation)).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:16]=[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:11]1([CH2:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[O:16])[CH:9]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: N#Cc1ccc(Cn2ccnc2)cc1F
Reactant: O=c1ccccn1-c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1Oc1ccccc1-n1ccccc1=O
Temperature: 70 °C

Procedure:
2-Fluoro-4-imidazol-1-ylmethyl-benzonitrile (as described in Example 9, Step E) (0.0276 g, 0.137 mmol), 2-(2-oxo-2H-pyridin-1-yl)-phenol (0.0257 g, 0.137 mmol) and cesium carbonate (0.089 g, 0.274 mmol) were combined in DMF (1.2 mL) and heated at 70° C. for 18 hr. The title compound was obtained after RP HPLC on aWaters Prep Pak column eluting with a 0.1% TFA/H2O: 0.1% TFA/CH3CN gradient followed by conversion to the free base.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([O:9][C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O-:25])=[CH:24][C:19]=4[O:18][C:12]4[CH:13]=[C:14]([O-:17])[CH:15]=[CH:16][C:11]3=4)[C:4]2=[CH:3][CH:2]=1)=[O:8].[Na+].[Na+].COC=C.C1(=O)OC(=O)C=C1>FC1(F)C2(F)C(F)(C(F)(F)C(F)(F)C(F)(F)C2(F)F)C(F)(F)C(F)(F)C1(F)F>[CH:2]1[CH:1]=[CH:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([C:10]2[C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[O:18][C:19]3[C:20]=2[CH:21]=[CH:22][C:23]([CH:24]=3)=[O:25])[CH:3]=1
Reactant: O=C1OC2(c3ccc([O-])cc3Oc3cc([O-])ccc32)c2ccccc21
Agent: C=COC
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: FC1(F)C(F)(F)C(F)(F)C2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C2(F)C1(F)F
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
In order to determine the temperature stability and release profile of the nonaqueous drug delivery vehicle suspensions of the present invention microparticulates containing 5% sodium fluorescein were prepared utilizing poly(methylvinylether/maleic anhydride) as the polymer matrix utilizing the manufacturing technique of Example 1 and were suspended in perfluorodecalin (PFC) as a 2% w/v suspension utilizing the technique of Example 4. This nonaqueous drug delivery vehicle suspension was divided in half and equal portions were stored at 23° C. and at 45° C. for thirty days. Samples were taken of each portion during the thirty days test period and fluorescein release profiles were obtained as is known in the art. More specifically, the dissolution tests were performed as follows. 500 ml of 7.4 pH phosphate buffer (0.05M) was added to the kettles in the standard USP dissolution apparatus set at 37° C. 10 ml of the 2% w/v suspension was slowly added to the dissolution medium and the propeller speed was set to 50 rpm. Over a seven hour time period, samples were taken from the dissolution medium and immediately centrifuged. The supernatant containing the released fluorescein was assayed for fluorescein content by UV spectrophotometry. Release profiles for the 23° C. and 45° C. samples are given in FIGS. 1 and 2. The control was freshly prepared microparticulates.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:10][CH:9]=1
Reactant: ClCC1CO1
Reactant: OCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCOc1ccc(OCC2CO2)cc1

Procedure:
With stirring, 13 g of crude 4-(2-hydroxyethoxy)phenol, 35 m of epichlorohydrin and 23.5 g of potassium carbonate are heated for 11/2 hours to reflux temperature. The reaction mixture is filtered and the filtrate is concentrated by evaporation under reduced pressure. The residual oil gradually congeals to a crystalline solid, which is recrystallised from isopropanol, affording 1-(2,3-epoxypropoxy)-4-(2-hydroxyethoxy)benzene with a melting point of 65°-67° C. Working up of the mother liquor yields further crystalline product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:33])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:43][CH2:42][O:41]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:33])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:43][CH2:42][OH:41])=[CH:30][CH:31]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1OCCO1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(O)cc2)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCCO)cc2)C1c1cccc([N+](=O)[O-])c1
Yield: 91.1 %

Procedure:
A mixture of 1.0 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-[2-(4-hydroxyphenyl)ethoxycarbonyl]-1,4-dihydropyridine (11), 0.5 g of K2CO3, and 0.5 g of ethylene carbonate in 20 mL of toluene was heated at reflux for 18 h. The mixture was filtered and the filtrate evaporated to yield 1.0 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-hydroxyethoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine (1, R1 =A1, m=2, p=0) as an amorphous solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:11]=[C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)[CH:9]=[C:8]([F:23])[C:7]=1[OH:24].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:24][C:7]1[C:6]([F:5])=[CH:11][C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)=[CH:9][C:8]=1[F:23])(=[O:3])[CH3:2]
Reactant: CCCCC[C@H]1CC[C@H](c2cc(F)c(O)c(F)c2)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2cc(F)c(OC(C)=O)c(F)c2)CC1

Procedure:
8 g of acetyl chloride is added to a solution of 28.2 g of 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-phenol and 20 ml of pyridine in 300 ml of toluene, and the mixture is heated at 80° for 1 hour. Cooling and working up in the usual manner gives 2,6-difluoro-4-(trans-4-pentylcyclohexyl)-phenyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:24]([CH2:31][CH3:32])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])=[O:8].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([N:47]3[CH2:52][CH2:51][CH:50]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:49][CH2:48]3)=[N:45][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:31]([N:24]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:4]1[CH:3]=[C:2]([C:41]2[CH:42]=[CH:43][C:44]([N:47]3[CH2:52][CH2:51][CH:50]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:58])([CH3:57])[CH3:59])[CH2:49][CH2:48]3)=[N:45][CH:46]=2)[CH:22]=[C:6]([C:7](=[O:8])[NH:9][CH2:10][C:11]2[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=2[CH:17]([CH3:19])[CH3:18])[C:5]=1[CH3:23])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: [Na+]
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 64.1 %

Procedure:
A solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.35 g, 0.69 mmol), tert-butyl (1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidin-4-yl)carbamate (0.33 g, 0.83 mmol), and tetrakis (0.079 g, 0.069 mmol) in dioxane (5 mL) was purged with argon for 10 min. To this, aq. Na2CO3 (0.263 g, 2.48 mmol, 2 mL) was added and again degassed for 10 min. Reaction mixture was heated at 100° C. for 16 h. On completion, it was concentrated to obtain crude material which was column purified to afford the title compound (0.31 g, 63%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([CH2:12][C@@H:13]2[CH2:16][C@H:15]([OH:17])[CH2:14]2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:17][C@H:15]1[CH2:16][C@@H:13]([CH2:12][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH2:14]1)(=[O:4])=[O:3]
Reactant: O[C@H]1C[C@@H](CN2CCOCC2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)O[C@H]1C[C@@H](CN2CCOCC2)C1
Reaction time: 1 h

Procedure:
MsCl (0.27 mL, 3.5 mmol) was added dropwise to a solution of intermediate 40, cis-3-(Morpholin-4-ylmethyl)cyclobutanol (0.5 g, 2.9 mmol) and triethylamine (1 mL, 7.0 mmol) in CH2Cl2 (5 mL) in argon under stirring on an ice bath. The mixture was brought to room temperature for 1 h, water (10 mL) was added, and the layers were separated. The organic layer was washed with water. The water layer was washed with the saturated NaCl solution, dried over Na2SO4, and evaporated to give the title compound as a yellow oil in 99% (718 mg, 2.88 mmol) yield. This material was used without additional purification. 1H-NMR (400 MHz)-data (dmso-d6): 4.83 (dddd, 1H, J=7.5 Hz, CHOMs), 3.51-3.58 (m, 4H, CH2OCH2), 3.12 (s, 1H, Ms), 2.46-2.55 (m, 2H, cyclobutylCHH), 2.28-2.40 (m, 6H, (CH2)3N), 2.00-2.12 (m, 1H, CHCH2N), 1.80-1.89 (m, 2H, cyclobutylCHH).
Reaction SMILES: [F:1][C:2]([C:17]([F:20])([F:19])[F:18])([O:6][C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3](F)=[O:4].C[Si](C)(C)[O-:23].[Na+:26]>O1CCCC1>[F:1][C:2]([C:17]([F:18])([F:19])[F:20])([O:6][C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:12])([F:10])[F:11])[C:3]([O-:4])=[O:23].[Na+:26]
Reactant: C[Si](C)(C)[O-]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C([O-])C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 69.3 %

Procedure:
The procedure of Example 1 was followed using perfluoro-2-methyl-3-oxahexanoyl fluoride (16.6 g, 50 mmol), sodium trimethylsilanolate (5.6 g, 50 mmol), and dry tetrahydrofuran (100 mL), and a 2 h reaction time. Sodium perfluoro-2-methyl-3-oxahexanoate (12.2 g, 69% yield) was isolated as a white solid: The 19F NMR data were the same as reported in Example 15.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[N:19]=[C:4]2[N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH2:63][C:64]1[S:65][CH:66]=[CH:67][N:68]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.C1(C)C=CC=CC=1>[S:65]1[CH:66]=[CH:67][N:68]=[C:64]1[NH:63][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[N:19]=[C:4]2[N:3]=1
Reactant: Nc1nccs1
Reactant: O=c1c2ccccc2nc2nc(Cl)c3ccccc3n12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=c1c2ccccc2nc2nc(Nc3nccs3)c3ccccc3n12
Reaction time: 17 h
Yield: 53 %

Procedure:
A pressure tube was charged with 5-chloro-quinazolino[3,2-a]quinazolin-12-one (200 mg, 0.71 mmol), Pd2(dba)3 (25 mg, 0.028 mmol), Xantphos (25 mg, 0.043 mmol), 2-aminothiazole (71 mg, 0.85 mmol), Na2CO3 (fine powder, 71 mg, 0.85 mmol) and anhydrous dioxane/toluene (1:1, 5 mL). The mixture was stirred with heating at 100 deg C. for 17 hours. After this period the mixture was cooled, concentrated in vacuo and purified by preparative chromatography, to yield the desired product (TFA salt) as a yellow powder (130 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:9](Cl)([Cl:11])[Cl:10].[Cl-].C[NH+](C)CCCCCCCCCCCCCC1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[C:9]([Cl:10])[Cl:11]
Reactant: Clc1ccccc1C(c1ccccc1Cl)C(Cl)(Cl)Cl
Agent: C[NH+](C)CCCCCCCCCCCCCc1ccccc1
Agent: [Cl-]
Product: ClC(Cl)=C(c1ccccc1Cl)c1ccccc1Cl
Reaction time: 2 h

Procedure:
990 kg of solid 1,1-bis(chlorophenyl)-2,2,2-trichloroethane were charged into the basic aqueous phase emanating from an upstream dehydrochlorination operation. The charging period was 2 hours to avoid the formation of solid masses inside the reactor. 5 kg of dimethylbenzyllaurylammonium chloride were added, while intense stirring was continued for 4 hours at 100°. After 1 hour at rest, the aqueous phase was separated off and 268 kg of 50% strength sodium hydroxide were added and the dehydrochlorination was continued with stirring at 100° C. for 10 hours. After dilution with 560 kg of water and 1 hour at rest, the organic phase was drawn off and the aqueous phase was retained for the following operation. The organic phase was then washed 3 times with 250 kg of a 1N solution of sulfuric acid and 879 kg of 1,1-bis(chlorophenyl)-2,2-dichloroethylene were obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:23](=O)[C:24]#[C:25][CH2:26][CH2:27][CH2:28][N:29]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]4=[O:39])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:11]=[N:10]1.C(=O)(O)O.[NH2:45][C:46]([NH2:48])=[NH:47]>COCCO>[NH2:48][C:46]1[N:47]=[C:25]([CH2:26][CH2:27][CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH:24]=[C:23]([C:22]2[C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:12]4[CH:11]=[N:10][N:9]([CH3:8])[CH:13]=4)[CH:15]=3)[NH:20][CH:21]=2)[N:45]=1
Reactant: N=C(N)N
Reactant: Cn1cc(-c2cnc3[nH]cc(C(=O)C#CCCCN4C(=O)c5ccccc5C4=O)c3c2)cn1
Agent: O=C(O)O
Solvent: CCN(CC)CC
Solvent: COCCO
Product: Cn1cc(-c2cnc3[nH]cc(-c4cc(CCCN5C(=O)c6ccccc6C5=O)nc(N)n4)c3c2)cn1

Procedure:
8.5 0.92 ml (6.7 mmol) of triethylamine is added to a solution of 116 mg (0.265 mmol) of 2-{6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-6-oxohex-4-ynyl}isoindole-1,3-dione and 70 mg (0.39 mmol) of guanidine carbonate in 4 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 6 hours. After cooling, the mixture is evaporated, and the residue is purified by preparative HPLC, giving 2-(3-{2-amino-6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrimidin-4-yl}propyl)isoindole-1,3-dione as brown solid; ESI 479, EMD 1183586.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][CH2:6][N:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1.[CH3:20]COCC.[N+](=C)=[N-].C(O)(=O)C>C(O)C>[CH3:20][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][CH2:6][N:7]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15]1
Reactant: Oc1ccccc1C=CCN1Cc2ccccc2C1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccccc1C=CCN1Cc2ccccc2C1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. 236.2 milligrams of the N-(o-hydroxycinnamyl)-isoindoline of the hereinafter-given Example 24 is dissolved in 10 milliliters of ethanol. After adding an ether solution of diazomethane thereto, the resulting mixture is left standing overnight at room temperature. The excess diazomethane is then decomposed with acetic acid, the solvent is distilled off, and the residue is recrystallized from acetone as a maleic acid salt to obtain 220.2 milligrams (yield 61.2%) of N-(o-methoxycinnamyl)-isoindoline.maleic acid salt as crystals having a melting point of 147°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[CH:27][C:28]=4[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1n[nH]cc1-c1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnc3c(-c4ccccc4)cnn3c1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-4-phenylpyrazole
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.[OH-].[Na+].[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.[BH4-].[Na+]>C(O)C.C(OCC)C>[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][N:1]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]1[C:8]([OH:10])=[O:9]
Reactant: CC(C)(C)C=O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)CN1C(=O)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
L-glutamic acid (1.47 g, 10 mmol) was dissolved in 2N aqueous sodium hydroxide (10 ml, 20 mmol) and treated with a solution of trimethylacetaldehyde (1.09 ml, 10 mmol) in ethanol (5 ml) and then stirred at room temperature for 30 minutes. The mixture was cooled to 0° C. and treated with sodium borohydride (0.130 g). The mixture was allowed to warm to room temperature with stirring over 4 hrs and then acidified to neutral pH. Concentration in vacuo was followed by slurrying in ethanol and azeotroping three times with more ethanol. Finally the remaining material was suspended in ethanol (50 ml) and heated at reflux for 48 hrs. The mixture was then cooled to room temperature, salts were filtered off and the solvent was evaporated in vacuo to give a gum. Trituration with diethyl ether followed by drying afforded pure solid 1-(2,2-dimethylpropyl)-5-oxoproline (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH2:15][OH:16])[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.IC.[C:19](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:13][C:12](=[O:14])[CH:11]([CH2:15][OH:16])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(CCC(CO)C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CO)CCc1ccc(OC)cc1
Temperature: 70 °C

Procedure:
A mixture of [4-(4-methoxyphenyl)]-2-hydroxymethyl butanoic acid (6.0 g, 0.027 mol), iodomethane (5.68 g, 0.04 mol) and potassium carbonate (7.45 g, 0.054 mol) in dimethylformamide (40 ml) was heated at 70° C. for 1 h. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (400 ml), washed with water (3×200 ml), sodium hydrogen carbonate solution (2×200 ml) and again with water (2×200 ml). Drying (MgSO4) and removal of solvent at reduced pressure gave the product as a pale yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([C:16]#[N:17])[CH:15]=1)[O:12][C:11]([CH3:19])([CH3:18])[CH2:10][C:9]2([CH3:21])[CH3:20])=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:16]([C:14]1[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:18])([CH3:19])[CH2:10][C:9]2([CH3:20])[CH3:21])#[N:17]
Reactant: CCOC(=O)c1cc(C#N)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(C#N)c2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
A solution of ethyl-8-cyano-2,2,4,4-tetramethylchroman-6-carboxylate (Compound 29, 1.36 g, 4.73 mmol) in ethanol (14 mL) was treated with 3N aqueous sodium hydroxide solution (3 mL, 15 mmol) and was stirred at ambient temperature for 3 h. The resulting solution was adjusted to pH˜5 with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid (1.15 g, 94%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20]>>[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[CH:24]=[CH:23][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Product: COc1ccc(C(=O)C#Cc2ccc(C(=O)O)c(O)c2)cc1C(C)(C)C
Yield: 85.1 %

Procedure:
Following the basic procedure of Example 1(b), by reacting 4.2 g (0.02 mol) of 3-tert-butyl-4-methoxybenzoyl chloride with 5 g (0.02 mol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate, 6 g (81%) of the expected compound were obtained, after purification by chromatography on a silica column eluted with dichloromethane, in the form of a brown oil.