Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])/[CH:10]=N/O)=[CH:4][C:3]=1[O:14][CH3:15].[OH:16]S(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:14][CH3:15])[NH:8][C:9](=[O:13])[C:10]2=[O:16]
Reactant: O=S(=O)(O)O
Reactant: COc1cc(NC(=O)/C=N/O)ccc1Br
Product: COc1cc2c(cc1Br)C(=O)C(=O)N2
Temperature: 80 °C

Procedure:
Concentrated H2SO4 (400 mL) was heated to 50° C. and portions of (2E)-N-[4-bromo-3-(methyloxy)phenyl]-2-(hydroxyimino)ethanamide (75 g, 275 mmol) were added while keeping the internal temperature below 70° C. After complete addition, the mixture was heated to 80° C. for 1 h, then poured into ice, filtered and washed with H2O to yield 5-bromo-6-(methyloxy)-1H-indole-2,3-dione (75 g) of a red solid. MS (m/z) 257.9 (M+H+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[S:10][C:9]2[C:11](=[O:15])[CH:12]([CH3:14])[CH2:13][C:8]=2[CH:7]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][C:7]1[C:8]2[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[C:9]=2[S:10][C:6]=1[CH3:5]
Reactant: BrBr
Reactant: Cc1cc2c(s1)C(=O)C(C)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(c1Br)CC(C)C2=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To a suspension of 92.4 g (693 mmol) of AlCl3 (anhydrous powder) in 120 ml of CHCl3, 51.2 g (308 mmol) of 2,5-dimethyl-4,5-dihydro-cyclopenta[b]thiophen-6-one in 50 ml of CHCl3 was added at 0° C. over 0.5 hour. The reaction mixture was stirred for 10 minutes at this temperature; then a solution of 16.6 ml of Br2 (323 mmol) in 30 ml of CHCl3 was added dropwise over 1 hour. The resulting mixture was stirred for 1 hour at room temperature, and then poured over 1000 cm3 of ice. The organic layer was separated. The aqueous layer was extracted with 4×200 ml of CH2Cl2. The combined organic fractions were washed with 1000 ml of saturated aqueous Na2CO3, dried over K2CO3, passed through a short Silica Gel 60 column (40-63 um, d 40 mm, l 50 mm), and evaporated to dryness. Fractional distillation gave white crystalline product, b.p. 130° C./0.4 mm Hg. Yield 69.2 g (92%) of the title product contaminated with ca. 12% of 3-bromo-2,5-dimethyl-5,6-dihydro-cyclopenta[b]thiophen-4-one.
Reaction SMILES: [CH2:1]([C:11]1[C:16](N)=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N+:18]([C:21]1C=C(S(O)(=O)=O)C=[CH:25][CH:26]=1)([O-])=O.S(=O)(=O)(O)O.B(O)(O)O>OCC(CO)O.[Fe]=S.O>[CH2:1]([C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[N:18]=[CH:21][CH:26]=[CH:25]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Reactant: CCCCCCCCCCc1ccccc1N
Agent: S=[Fe]
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: O
Solvent: OCC(O)CO
Product: CCCCCCCCCCc1ccc2ncccc2c1
Temperature: 140 °C
Reaction time: 6 h
Yield: 30.2 %

Procedure:
12.5 g of 6-decylaniline, 5.0 g of 3-nitrobenzenesulfonic acid, 1.5 g of iron (II) sulfide, 10 ml of sulfuric acid, and 2.8 g of boric acid were dissolved in 13 ml of glycerin (glycerol), followed by stirring for 6 hours at 140° C. After the reaction, the reaction mixture was poured into water and alkalinized by adding thereto an appropriately amount of sodium hydroxide aqueous solution, followed by extraction with diethyl ether. The organic layer was washed with water, dried with anhydrous sodium sulfate and subjected to distilling-off of the solvent, followed by purification by silica gel column chromatography to obtain 2.0 g of 6-decylquinoline.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](COCC[Si](C)(C)C)[N:11]=[C:10]2[N:24]([CH2:26][CH2:27][O:28][CH3:29])[CH3:25].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[N:24]([CH2:26][CH2:27][O:28][CH3:29])[CH3:25]
Reactant: COCCN(C)c1nn(COCC[Si](C)(C)C)c2ccc(C3OCCCO3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: COCCN(C)c1n[nH]c2ccc(C3OCCCO3)cc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 245 mg (0.583 mmol) 5-(1,3-dioxan-2-yl)-N-(2-methoxyethyl)-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-amine (Example 46A) in anhydrous THF (12 ml) were added 8.5 ml (8.5 mmol) tetrabutylammonium fluoride solution (1 M in THF) and ethane-1,2-diamine (200 μl). The solution was stirred at 50° C. for 3 h. After addition of further 8.5 ml tetrabutylammonium fluoride solution (1 M in THF), stirring at 50° C. was continued for 24 h. After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution and with water. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The remaining solid (200 mg, 87% of th.) was used in the next step without further purification.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.[CH2:9]([O:16][CH:17]([C:22](=O)[C:23]([O:25][CH3:26])=[O:24])[C:18](OC)=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1CCN2C(=NCCC2)CC1.CCOC(C)=O>CO>[CH2:9]([O:16][C:17]1[C:18](=[O:19])[N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:3]2=[N:2][C:22]=1[C:23]([O:25][CH3:26])=[O:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(=O)C(OCc1ccccc1)C(=O)OC
Reactant: N=C1CCCCN1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCC2
Reaction time: 48 h

Procedure:
Commercially available 2-iminopiperidine hydrochloride (1.5 eq) was added at room temperature to a solution of oxosuccinate prepared in Step 1b (1 eq) in MeOH. After dropwise addition of neat DBU (4.5 eq), the reaction mixture was stirred for 2 days. Evaporation of the solvent gave a residue that was taken into EtOAc and washed with 1N HCl and brine; the organic layer was dried on Na2SO4 and the solvent removed. The crude was used without further purification.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[S:13]1[CH:17]=[C:16]([S:18][C:19]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:20]=2[C:21](O)=[O:22])[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]1=2.CN.C(OCC)(=O)C>C1COCC1>[S:13]1[CH:17]=[C:16]([S:18][C:19]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:20]=2[C:21]([NH:3][CH3:1])=[O:22])[C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]1=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(Sc2csc3ccccc23)c(C(=O)O)c1
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(C)ccc1Sc1csc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (324 mg, 2 mmol) is added to 2-(benzo[b]thiophen-3-ylsulfanyl)-5-methyl-benzoic acid (300 mg, 1 mmol) in mL dry THF and stirred for 2 hours at room temperature. 2.5 mL methyl amine (2M in THF, 5 mmol) is added and the reaction mixture is stirred for 16 hours at room temperature. Ethyl acetate is added and the organic phase is washed with 1 N HCl (aq) and brine, dried with MgSO4 and concentrated in vacuo to give the title compound, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:8]2[CH:9]3[CH2:12][CH2:13][CH:7]2[C:6](C)([C:10]3=[CH2:11])[CH2:5][CH2:4][CH2:3]1.B(F)(F)F.[C:20]1(C)C=CC=CC=1>>[CH3:15][C:2]1([CH3:1])[C:7]23[CH2:8][CH:9]([C:10]([CH3:11])([CH3:20])[C:6]2=[CH:5][CH2:4][CH2:3]1)[CH2:12][CH2:13]3
Reactant: C=C1C2CCC3C2C(C)(C)CCCC13C
Reactant: Cc1ccccc1
Agent: FB(F)F
Product: CC1(C)C2=CCCC(C)(C)C23CCC1C3
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Over a period of 30 minutes 240 g (0.79 mol ) of Longifolene (1) (80% ex Indian oil of turpentine [a]D=+39.4°) were dropped into a heated solution (60 ° C.) of 90 g toluene and 10 g (0.07 tool ) BF3 -etherate. This was stirred at 100 ° C. for 3 hours, than cooled down to room temperature and neutralized. After drying above Na2SO4 the solvent was distilled at reduced pressure. A raw product of 198 g (of 70.2% according to GLC) remained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].[Cl-].[NH4+].C(OP(CC)(=O)OCC)C>[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: CCOP(=O)(CC)OCC
Agent: [Cl-]
Agent: [NH4+]
Product: Clc1cc(Cl)c(Cl)nc1Cl
Yield: 94.1 %

Procedure:
Using the method described in Example 1, 12.76 g (0.05 mol) of pentachloropyridine is reacted with 4.1 g (0.063 gram atom) of zinc dust and 7.22 g (0.135 mol) of ammonium chloride, the solvent being in this case diethylethanephosphonate instead of dimethylmethanephosphonate. There is obtained 10.2 g (93% of theory) of crude 2,3,5,6-tetrachloropyridine, m.p. 86° to 88° C., which contains, according to gas-chromatographical analysis, 92.7% of 2,3,5,6-tetrachloropyridine, 1.2% of 2,3,5-trichloropyridine, 2.2% of 2,3,6-trichloropyridine and 2.8% of pentachloropyridine.
Reaction SMILES: S(O)(=O)(=O)C.[Si]([O:13][CH:14]1[CH2:17][N:16]([CH2:18][C@H:19]([O:30][C:31]2[N:36]=[CH:35][N:34]=[C:33]3[N:37]([C:40]4[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=4[Cl:47])[N:38]=[CH:39][C:32]=23)[C:20]([NH:22][C:23]2[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[O:21])[CH2:15]1)(C(C)(C)C)(C)C.C1COCC1.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O.COC(C)(C)C>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[N:37]1[C:33]2[N:34]=[CH:35][N:36]=[C:31]([O:30][C@@H:19]([CH2:18][N:16]3[CH2:17][CH:14]([OH:13])[CH2:15]3)[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=3)=[O:21])[C:32]=2[CH:39]=[N:38]1
Reactant: Cc1cnc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Cl)cn1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CN2CC(O)C2)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Cl)cn1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)propanamide mesylate (16.5 g), THF (50.00 mL), water (20.0 mL) and methanesulfonic acid (2.62 g) was stirred for 19 hours at ambient temperature. tert-Butyl methyl ether (40.0 mL) was added followed by the dropwise addition of a solution of potassium carbonate (3.77 g) in water (20.0 mL) over 20 mins with stirring. The aqueous phase was removed and the organic phase was washed with water (20.0 mL) then evaporated under reduced pressure at 50° C. THF (80 mL) was added to the residue and then removed by evaporation under reduced pressure. This process was repeated. THF (20.0 mL) was added to the residue followed by tert-butyl methyl ether (60.0 ml). The mixture was filtered then stirred whilst cyclohexane (50.0 mL) was added dropwise. The solid was collected by filtration and washed with a mixture tert-butyl methyl ether (50.0 mL) and cyclohexane (50.0 mL) and dried to give (2S)-2-[1-(2,6-dichlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-(3-hydroxyazetidin-1-yl)-N-(5-methylpyrazin-2-yl)propanamide in an overall yield for steps a) and b) of 69%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11](=[O:13])[CH3:12].C(O[CH:19](OC(C)(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>CN1CCCC1=O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11](=[O:13])/[CH:12]=[CH:19]/[N:20]([CH3:22])[CH3:21]
Reactant: CC(=O)c1c(Cl)nc2ccccn12
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN1CCCC1=O
Product: CN(C)/C=C/C(=O)c1c(Cl)nc2ccccn12

Procedure:
In a 100 mL round bottom flask, a solution of EXAMPLE 1C (4.25 g, 21.84 mmol), 1,1-di-tert-butoxy-N,N-dimethylmethanamine (28.8 mL, 120 mmol), and N-methyl-2-pyrrolidinone (15 mL) was heated at 85° C. for 2 hours. The reaction was concentrated under high vacuum on a rotavap at 60° C. The residual solid was triturated with 5 mL ether, filtered and dried to provide the title compound. MS (ES r) m/e 249.8 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1(=[O:16])[NH:14][C:13](=[O:15])[CH:12]=[CH:11]1.O>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:12]2[CH2:11][C:10](=[O:16])[NH:14][C:13]2=[O:15])=[CH:2]1
Reactant: O=C1C=CC(=O)N1
Reactant: c1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(c2c[nH]c3ccccc23)C(=O)N1
Reaction time: 24 h

Procedure:
Indole (4.38 g, 40 mmole) and maleimide (7.84 g, 80 mmole) were dissolved in concentrated acetic acid (35 ml) and stirred under reflux for 36 hours. After cooling the reaction mixture water (10 ml) was slowly added dropwise. The solution was then kept for 24 hours in a refrigerator. The solid thereby formed was filtered off. 3-(1H-indol-3-yl)-pyrrolidine-2,5-dione was thereby obtained as a brown solid in a yield of 3.24 g (38%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:23]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:23][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21
Reactant: N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C)(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Temperature: 140 °C
Reaction time: 17 h
Yield: 49 %

Procedure:
Copper sulfate pentahydrate (55 mg, 0.24 mmol) was added to (5-bromopyridin-3-yl)(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (292 mg, 0.81 mmol) (see Preparation 30) and concentrated ammonia solution (20 mL). The mixture was heated in a sealed vessel at 140° C. for 17 hours. The reaction mixture was evaporated in vacuo and the residue was stirred in aqueous hydrochloric acid (10 mL, 2M) at room temperature for 17 hours. The reaction mixture was basified to pH 9 using saturated aqueous sodium carbonate then extracted with DCM (3×20 mL). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to afford the title compound as a white solid in 49% yield, 240 mg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2>[OH-].[K+].CO>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH:12]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Brc1ccc2[nH]cc(C3=CCN(Cc4ccccc4)CC3)c2c1
Yield: 90.3 %

Procedure:
Freshly distilled 1-Benzyl-4-piperidone (11.7 g) was added to a stirred solution of 5-bromoindole (11.0 g) in 2M potassium hydroxide in methanol (81ml). The mixture was stirred at reflux for 8 h and then allowed to cool to 25° over 8 h. The solid was collected by filtration, washed with a mixture of methanol:water (2:1, 2×15 ml) and dried in vacuo at 50° for 18 h to give the title compound as a crystalline solid (18.6 g) m.p. 173°-175° (decomp).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:13]([O:14][CH3:15])=[C:12](Cl)[N:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[N:9]=1>C1COCC1>[Cl:7][C:8]1[N:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[N:11]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:13]=1[O:14][CH3:15]
Reactant: C1COCCN1
Reactant: COc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)nc1Cl
Solvent: C1CCOC1
Product: COc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)nc1N1CCOCC1
Reaction time: 4 h
Yield: 56 %

Procedure:
Morpholine (0.6 ml, 2.2 eq) was added to a stirred solution of 4,6-dichloro-5-methoxy-2-(4-nitrophenyl)pyrimidine (0.87 g, 1 eq) in THF, the mixture was stirred at r.t for 4 hrs, the solvent was evaporated, water was added to the solution and the solution was extracted with EA. The combined organic layers were washed with brine, dried and evaporated in vacuo, the product was obtained as a yellow solid (56%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO[C:23](/[N:25]=N/C(OCC)=O)=O.[C:32]1([CH:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(C)(O)C#N>C1COCC1>[C:32]1([CH:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[C:23]#[N:25])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OC(c1ccccc1)c1cccnc1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CC(c1ccccc1)c1cccnc1
Reaction time: 0.33 h
Yield: 52.1 %

Procedure:
To a solution of triphenylphosphine (3.83 g, 14.61 mmol) in THF (40 mL) at 0° C. was added DEAD (2.54 g, 14.61 mmol) drop wise and the reaction mixture was stirred for 20 minutes. Compound 76 (1.78 g, 9.61 mmol) was added to the reaction mixture and stirred for an additional 20 minutes. Then acetone cyanohydrin (1.319 mL, 14.42 mmol) was added, stirred for 1 h at 0° C. and 18 h at room temperature. The reaction mixture was concentrated then purified by flash chromatography to afford 77 (0.972 g, 52%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[NH2:40])[CH2:24][CH2:23]1.Cl.O1CCOCC1>CO>[N:25]1([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[NH:40][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:3]=2[CH3:21])[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)c(F)cc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2cc(F)c(F)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-6,7-difluoro-2-(2-fluorophenyl)-3-methylquinoline (100 mg, 325 μmol), 2,5-dimorpholinobenzenamine (86 mg, 325 μmol) and 4N hydrochloric acid solution in dioxane (0.081 mL, 325 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 7.91 (1H, dd, J=11.0, 7.8 Hz), 7.55-7.71 (2H, m), 7.43-7.54 (1H, m, J=7.9, 7.9, 5.4, 2.0 Hz), 7.31-7.40 (1H, m), 7.09-7.25 (3H, m), 6.46 (1H, dd, J=8.6, 2.7 Hz), 6.01 (1H, br. s.), 3.87-4.05 (4H, m), 3.73-3.83 (4H, m), 3.06 (4H, dd, J=2.5, 1.8 Hz), 2.90-3.01 (4H, m), 2.21 (3H, d, J=2.0 Hz). Mass Spectrum (ESI) m/e=535.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][CH2:17][C:18]#[N:19])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+].COC1C=C(C2(CCC#N)CCCCC2O)C=CC=1.P(Cl)(Cl)(Cl)=O.COC1C=C(C2(CC#N)CCCC=C2)C=CC=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][CH2:17][C:18]#[N:19])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(CCC#N)CCCCC2=O)c1
Agent: COc1cccc(C2(CC#N)C=CCCC2)c1
Agent: COc1cccc(C2(CCC#N)CCCCC2O)c1
Agent: [BH4-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cccc(C2(CCC#N)C=CCCC2)c1

Procedure:
By reducing 1-(m-methoxyphenyl)-2-oxo-cyclohexane-propionitrile with sodium borohydride and subsequently dehydrating the resulting 1-(m-methoxyphenyl)-2-hydroxycyclohexane-1-propionitrile with phosphorus oxychloride in pyridine in analogy to the preparation of 1-(m-methoxyphenyl)-2-cyclohexene-1-acetonitrile described in Example 1, there is obtained 1-(m-methoxyphenyl)-2-cyclohexene-1-propionitrile in the form of a pale yellowish oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:24][O:25][CH2:26]Br.Cl>O1CCCC1.CCCCCC>[C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:24][O:25][CH3:26])(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCBr
Reactant: CC1Cc2cccc(S(=O)(=O)NC(C)(C)C)c2S1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCc1ccc2c(c1S(=O)(=O)NC(C)(C)C)SC(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.14 g of N-t-butyl-2,3-dihydro-2-methylbezo[b]thiophene-7-sulfonamide in 175 ml of dry tetrahydrofuran was added 34 ml of a 1.6M hexane solution of n-butyl lithium at -40° C. to -30° C. under an inert atmosphere. The mixture was allowed to warm and was stirred at room temperature for 30 minutes. It was recooled to -30° C. and was contacted with 2.2 ml of bromomethyl methyl ether. The mixture was allowed to come to room temperature overnight and was acidified with 10 ml of 6N hydrochloric acid. The organic layer was separated, was dried over magnesium sulfate, and was concentrated to give 7.4 g of the title compound as a brown oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].O.C([O-])(=O)C.[Na+]>ClCCCl.O>[CH:14]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][C:17]=1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:15]
Reactant: CN(C=O)c1ccccc1
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=Cc1c(C(=O)OCc2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A mixture of 6.5 ml (70 mmol) of phosphorus oxychloride and 9.3 ml (70 mmol) of N-methylformanilide was stirred at ambient temperature. The resulting mixture was diluted with 90 ml of 1,2-dichloroethane, treated with 15.0 g (59.8 mmol) of benzyl indole-2-carboxylate, and heated at reflux for 1 h. After being allowed to cool for 5 min, the warm solution was poured into an ice-cold solution of 60 g of sodium acetate hydrate in 200 ml of water. The resulting mixture was stirred for 1 h, filtered, and the yellow solid was washed twice with water and twice with ether, and air-dried. The filtrate was treated with 400 ml of hexane and filtered. The combined solids were digested with hot ethyl acetate, cooled to 0° C., and filtered to give 13.41 g (80%) of the desired compound as an off-white solid. 1H NMR (CDCl3 /CD3OD) δ 5.50 (s,2H), 7.3-7.55 (m, 8H), 8.38 (d,J=9 Hz,1H). Mass spectrum: (M+H)+ =280.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH2:24][CH2:25][C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[S:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH2:24][CH2:25][C:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCC1=CCCCC1)Oc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)s1
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: COCCOC
Solvent: O
Product: CCOC(=O)C(CCC1=CCCCC1)Oc1ccc(-c2ccc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
0.18 g (0.04 equivalent) of Pd(PPh3)4 and then 1.2 g (0.0084 mol) of 5-chloro-2-thiopheneboronic acid are added to a solution of 1.4 g (0.0038 mol) of ethyl 2-[(4-bromophenyl)oxy]-4-cyclohex-1-en-1-ylbutanoate in 20 ml of dimethoxyethane. 4.2 ml of 2M sodium carbonate solution are added at room temperature. The reaction mixture is stirred overnight and then refluxed for 2 hours. After cooling to room temperature, the mixture is taken up in water and extracted with ethyl acetate. The extract is washed with 1N sodium hydroxide and then with saturated aqueous NaCl solution and finally dried over Na2SO4. After concentrating, the black oil obtained is purified by flash chromatography (95/5 heptane/ethyl acetate). 1.1 g of a thick oil are obtained.