Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.[Br:33]C1C2SC(I)=NC=2C=CC=1>>[Br:33][C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: Brc1cccc2nc(I)sc12
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(Br)c2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 7-bromo-2-iodo-1,3-benzothiazole and conducting the Suzuki coupling at 60° C. for 4 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.20-9.09 (brm, 1H), 9.02-8.90 (brm, 1H), 8.61 (very brs, 1H), 8.60 (s, 2H), 8.52 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 4.57-4.47 (mc, 1H), 3.40 (brd, J=12.8 Hz, 2H), 3.11 (brq, J=11.2 Hz, 2H), 2.31-2.12 (m, 4H). MS(ES+): m/z=454.98/457.00 (79/83) [MH+], 371.94/373.95 (95/100) [MH+-piperidine]. HPLC: tR=2.22 min (polar—5 min, ZQ2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.CCN(C(C)C)C(C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:26]([O:16][C:7]1[N:8]=[C:9]([CH3:15])[C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2cc(OC(C)=O)nc(C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (3.11 g, 14.19 mmol) in dry CH2Cl2 (230 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added DIEA (2.46 mL, 14.88 mmol), DMAP (173 mg, 1.42 mmol) and acetic anhydride (1.39 mL, 14.80 mmol) and the reaction mixture was stirred overnight at RT. The organic solution was then washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was finally purified by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) to give 6,7-dimethoxy-1-methylisoquinolin-3-yl acetate SIL 32158 as an off-white solid (3.26 g, 88% yield).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[NH2:18][CH2:19][C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:18][CH2:19][C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:17])[CH3:16]
Reactant: NCC1(Nc2ccccc2)CCCCC1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(Nc2ccccc2)CCCCC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
620 mg (2.45 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide are added to 500 mg (2.45 mmol) of (1-aminomethylcyclohexyl)phenylamine in 10 ml of dimethylformamide. The reaction medium is stirred at 100° C. under microwave irradiation for 30 min. It is then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20, v/v). 580 mg of N-(2,6-diisopropylphenyl)-2-[(1-phenylaminocyclohexyl-methyl)amino]acetamide are obtained in the form of a beige solid. Yield=56%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31]([OH:34])(=O)=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[NH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31]([NH2:35])(=[O:34])=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Reactant: N
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(N)(=O)=O)n2C)n(CCC)c1=O
Yield: 70 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (1.96 mmol) of Compound 1 obtained in Example 1 and 0.6 ml of conc. aqueous ammonia. The resulting crude crystals were recrystallized from dioxane/water to give 670 mg (yield 70%) of Compound 9 as yellow needles.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[CH2:23](Br)[C:24]#[CH:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:25][C:24]#[CH:23])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1
Reactant: C#CCBr
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
A mixture of 2.0 g of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoro methyl-6(1H)-pyrimidinone, 1.06 g of propargyl bromide and 1.64 g of potassium carbonate in 5.0 ml of anhydrous acetone is heated at boiling point for 2.5 hours while stirring. The insoluble constituents are subsequently filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of ethyl acetate and the solution is extracted three times with 50 ml of water each time. The organic phase is then dried over anhydrous sodium sulphate and evaporated to dryness. The residue is recrystallized from diethyl ether/n-hexane. There is obtained 1-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 108°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O.CC(C)=O>[C:16]1(=[O:25])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]12
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1cc(Br)cc(Br)c1
Yield: 37.3 %

Procedure:
3,5-dibromophenol (970 mg, 3.85 mmol) was recrystallized from hexanes. After removal of solvent, N-(4-bromobutyl)phthalimide (1.38 g, 4.89 mmol), K2CO3 (1.88 g, 13.6 mmol), 18-crown-6 (53 mg, 0.20 mmol), and acetone (20 mL) were added. This was refluxed for 1 hour, and then poured into 100 mL of water. The aqueous layer was extracted with dichloromethane (4×30 mL). The organic layers were combined, washed with water, saturated NaHCO3, and brine, then dried over MgSO4 and filtered. Removal of solvent yielded a white solid, which was purified by column chromatography (4:1 hexanes:CH2Cl2) followed by recrystallization in hexanes to yield colorless needles (650 mg, 87%). 1H NMR (CDCl3): 7.860 (m, 2H); 7.733 (m, 2H); 7.220 (t, J=1.6 Hz, 1H); 6.964 (d, J=2.0 Hz, 2H); 3.962 (t, J=6.0 Hz, 2H); 3.770 (t, J=6.6 Hz, 2H); 1.846 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH2:12])[N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(CC)CC>CCO>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=[C:4]([NH2:12])[N:3]=2)[CH2:16][CH2:15]1
Reactant: Nc1nc(Cl)c2c(n1)CCCC2
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(c2nc(N)nc3c2CCCC3)CC1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of 4-chloro-5,6,7,8-tetrahydro-quinazolin-2-ylamine (100 mg, 0.55 mmol), N-methyl piperazine (91 uL, 1.5 mmol) and Et3N (140 uL, 1.1 mmol) in EtOH (2 ml) was heated at 70° C. for 16 h. The mixture was cooled to rt and concentrated, and the crude residue was purified (2 M NH3 in MeOH/CH2Cl2) to yield a white solid (31 mg, 23%). MS (ESI): mass calcd. for C13H21N5, 247.3; m/z found, 248.2 [M+H]+. 1H NMR (MeOD): 3.30-3.23 (m, 4H), 3.21 (dt, J=3.3, 1.6, 1H), 2.49 (t, J=6.7, 2H), 2.47-2.41 (m, 4H), 2.36 (t, J=5.9, 2H), 2.23 (s, 3H), 1.77-1.67 (m, 2H), 1.62-1.52 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=2[CH:27]=[N:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=3[CH:27]=[N:26][CH:25]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CCS(=O)(=O)NC1CCCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c21
Product: CCS(=O)(=O)NC1CCCc2c(-c3cc(F)c4c(c3)CCC(=O)N4C)cncc21
Yield: 25 %

Procedure:
In analogy to the procedure described for the preparation of example 28, 8-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-7) and (rac)-ethanesulfonic acid (4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-yl)-amide (intermediate B-4) were used to give the title compound (10.3 mg, 25%) as a white solid. MS: 418.2 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:30]1[C:35]([F:36])=[C:34]([F:37])[N:33]=[C:32]([F:38])[C:31]=1[F:39]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[C:35]([F:36])=[C:34]([F:37])[N:33]=[C:32]([F:38])[C:31]=5[F:39])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1nc(F)c(F)c(Br)c1F
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4c(F)c(F)nc(F)c4F)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 4-bromo-2,3,5,6-tetrafluoropyridine. Mass spectrum (ESI) 465.5 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.S(O)([O:9][C:10]1[C:11]([NH2:17])=[N:12][C:13]([NH2:16])=[N:14][CH:15]=1)(=O)=O>O>[NH2:16][C:13]1[N:12]=[C:11]([NH2:17])[C:10]([OH:9])=[CH:15][N:14]=1
Reactant: Nc1ncc(OS(=O)(=O)O)c(N)n1
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ncc(O)c(N)n1
Yield: 114.7 %

Procedure:
A stirred solution of 23.0 grams ((:).235 mole) of concentrated sulfuric acid and about 18 mL of water was heated to reflux, and 48.5 grams (0.235 mole) of 2,4-diamino-5-pyrimidinyl hydrogen sulfate was added in one portion. Upon completion of addition, the reaction mixture was heated at reflux for ten minutes and then was immediately cooled in an ice-water bath. The resultant solid was collected by filtration, and the filter cake was washed with 100 mL of cold water. The solid was dried, yielding 34.0 grams of 2,4-diamino-5-hydroxypyrimidine hydrosulfate salt, mp 290° C., dec. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][S:12](=[O:17])(=[O:16])[NH:13][CH2:14][CH3:15])[C:8]([CH3:18])=[CH:7][C:6]=1[S:19]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[OH:30][C:31]1[CH2:32][C:33]([CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([NH:58]C(=O)[O-])=[CH:54][CH:53]=2)([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46]C(=O)[O-])=[CH:42][CH:41]=2)[O:34][C:35](=[O:37])[CH:36]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[C:1]([C:5]1[C:6]([S:19][C:36]2[C:35](=[O:37])[O:34][C:33]([CH2:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([NH2:46])=[CH:44][CH:45]=3)([CH2:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([NH2:58])=[CH:56][CH:57]=3)[CH2:32][C:31]=2[OH:30])=[CH:7][C:8]([CH3:18])=[C:9]([O:11][S:12](=[O:16])(=[O:17])[NH:13][CH2:14][CH3:15])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])Nc1ccc(CCC2(CCc3ccc(NC(=O)[O-])cc3)CC(O)=CC(=O)O2)cc1
Reactant: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccc(N)cc3)(CCc3ccc(N)cc3)OC2=O)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-ethylsulfamoyloxy-5-methyl-phenyl) ester (prepared in Example VVV; 0.218 g, 0.470 mmol), (1,1-dimethylethyl)[(3,6-dihydro-4-hydroxy-6-oxo-2H-pyran-2,2-diyl)bis[2,1-ethanediyl-(4,1-phenylene)]-biscarbamate (prepared in Example OO; 0.200 g, 0.380 mmol), K2CO3 (0.260 g, 1.88 mmol), and DMF (8 mL), as described in General Method 9. The reaction was stirred at room temperature for 3 hours and then worked up in the usual fashion. The residue was submitted to flash chromatography (100% EtOAc). The product form chromatography was taken up in EtOAc, triturated with hexane, filtered, and then taken up in CH2Cl2 (20 mL). Gaseous HCl was bubbled into this solution for 30 minutes. The solids that formed were filtered, washed with Et2O and dried under high vacuum to yield the title compound, m.p. 194° C. 1H NMR (DMSO-d6) δ 1.14 (t, 3 H), 1.49 (s, 9 H), 1.88 (s, 3 H), 2.09 (br m, 4 H), 2.70 (br m, 4 H), 3.12 (s, 2 H) 3.13 (m, 2 H), 6.79 (s, 1 H), 7.11 (s, 1 H), 7.27 (d, 4 H), 7.33 (d, 4 H), 8.40 (t, 1 H).
Reaction SMILES: Cl.[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([CH2:32][C:33](=O)[CH3:34])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>>[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:33]([CH3:34])[CH2:32][C:30]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([O:23][CH3:22])[CH:31]=2)[CH2:7][CH2:6]1
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(CC(C)=O)ccc1C#N
Agent: Cl
Product: COc1cc(CC(C)N2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
4-(2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}propyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion as described for the preparation of EXAMPLE 38 starting from 5-[1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxopropyl)benzonitrile.
Reaction SMILES: [CH2:1]1[CH2:11][O:10][C:3]2([C:7]3([CH2:9][CH2:8]3)[CH2:6][NH:5][CH2:4]2)[O:2]1.[F:12][C:13]1[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=[C:17]([F:20])[C:18]=1F>C(#N)C>[F:12][C:13]1[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=[C:17]([F:20])[C:18]=1[N:5]1[CH2:4][C:3]2([O:2][CH2:1][CH2:11][O:10]2)[C:7]2([CH2:8][CH2:9]2)[CH2:6]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C1COC2(CNCC23CC3)O1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CC3(CC3)C3(C2)OCCO3)c(F)c1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of 7,7-ethylenedioxy-5-azaspiro[2,4]heptane in acetonitrile (50 mL) was dropwise added 3,4,5-trifluoronitrobenzene (5.3 g, 31.6 mmol) and the reaction mixture was refluxed for 3 hours. After the reaction was terminated, the reaction mixture was cooled to room temperature and the solvent was removed therefrom by vacuum distillation. It was diluted with ethyl acetate and water, and the organic phase thus formed was dried over magnesium sulfate. The residue was filtered, concentrated in a vacuum, and purified through column chromatography (n-hexane/ethyl acetate=4:1) to afford the target compound (3.5 g, yield 66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[C:19]([O:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:18][CH:17]=[C:16]([F:30])[C:13]=1[CH:14]=[O:15].[OH-].[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:14]([C:13]3[C:16]([F:30])=[CH:17][CH:18]=[C:19]([O:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:12]=3[F:11])[OH:15])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: O=Cc1c(F)ccc(OCCOC2CCCCO2)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1c(F)ccc(OCCOC2CCCCO2)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (67, 118 mg, 0.000597 mol) in methanol (9.0 mL) were added 2,6-difluoro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzaldehyde (541, 180.0 mg, 0.63 mmol) and potassium hydroxide (601.9 mg, 10.7 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound that was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]=[N:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)([O-:3])=[O:2].[CH3:23][C:24]([CH3:26])=[CH2:25].B(F)(F)F.CCOCC>C(#N)C>[CH3:23][C:24]1([CH3:26])[C:18]2[C:8](=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:17]=2)[NH:7][CH:6]([C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:25]1
Reactant: CCOC(=O)c1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Reactant: C=C(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1[N+](=O)[O-])N2
Temperature: 90 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
To a solution of ethyl 4-(2-nitrobenzylideneamino)benzoate (18.67 g, 62.6 mmol) in acetonitrile was added 2-methylpropene (80 mL, pre-cooled to −78° C.) and boron trifluoride etherate (1 mL) at ice-bath. The reaction mixture was stirred at 90° C. for 18 h in sealed tube. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography to give ethyl 4,4-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as yellow solid (13.4 g, yield 60.4%). %). LC/MS m/e obsd. (ESI+) [(M+H)+] 355.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([O:11][CH3:12])(OC)OC)[CH3:2].C(O)(=O)C.[N+:18]([C:21]1[C:22]([CH3:31])=[C:23]([NH:29][NH2:30])[C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27])([O-:20])=[O:19]>CO>[CH2:1]([O:3][C:4](=[O:13])[CH:5]=[C:6]([O:11][CH3:12])[NH:30][NH:29][C:23]1[C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]([N+:18]([O-:20])=[O:19])[C:22]=1[CH3:31])[CH3:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1NN
Reactant: CCOC(=O)CC(OC)(OC)OC
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C=C(NNc1c(C)cc(C)c([N+](=O)[O-])c1C)OC
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
26.9 g (0.14 mol) of trimethoxypropionic acid ethyl ester (prepared according to DT-OS 2,042,920 ) are dissolved in 100 ml of absolute methanol, 7 ml of glacial acetic acid are added and the mixture is heated to the boil. 23.4 g (0.12 mol) of 3-nitro-2,4,6-trimethylphenylhydrazine (prepared according to DT-OS 2,156,913) are introduced in portions into the mixture over the course of 10 minutes. The mixture is stirred for a further 10 minutes at the boil and is allowed to cool whilst stirring. The orange crystals which have precipitated are filtered off, washed with a little methanol and dried (18 hours in vacuo at 50° C.). 14.4 g of β-methoxy-β-(3-nitro-2,4,6-trimethylphenylhydrazino)-acrylic acid ethyl ester of melting point 82° - 83° C. are obtained.
Reaction SMILES: [CH2:1]([C:3]1[S:27][C:6]2=[N:7][C:8]([CH3:26])=[C:9]([CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[C:5]2[C:4]=1[CH3:28])[CH3:2].[OH-].[Na+]>CO.C(O)C>[CH2:1]([C:3]1[S:27][C:6]2=[N:7][C:8]([CH3:26])=[C:9]([CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20])[C:10]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[C:5]2[C:4]=1[CH3:28])[CH3:2]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc(CC)c(C)c2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc(CC)c(C)c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
To a solution of methyl 2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.119 g; 0.301 mmol) in methanol (6.4 mL) and ethanol (3.2 mL) was added a 5% sodium hydroxide solution (8.2 mL; 10.25 mmol). The reaction mixture was heated under reflux for 5.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.059 g (51%) of the title compound as a white powder.
Reaction SMILES: [CH:1]1([C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[I:25]I>C1COCC1>[CH:1]1([C:7]2[C:12]3[O:13][C:14]4[C:19]([I:25])=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: II
Reactant: c1ccc2c(c1)oc1c(C3CCCCC3)cccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Ic1cccc2c1oc1c(C3CCCCC3)cccc12
Temperature: -90 °C
Reaction time: 6 h
Yield: 57.9 %

Procedure:
4-Cyclohexyldibenzo[b,d]furan (11.3 g, 45.0 mmol) and THF (1000 mL) were cooled down to −90° C. After that, n-BuLi (56.2 mL, 90.0 mmol, 1.6 M in THF) was added at −90° C. The mixture was stirred for 6 h and allowed to warm from −90° C. to room temperature. The mixture was then cooled to −90° C., and iodine (22.9 g, 90.0 mmol) was added at −90° C. The resultant mixture was stirred for 17 h and allowed to warm from −90° C. to room temperature. The reaction mixture was then quenched by the addition of saturated Na2S2O3 solution and extracted with DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography using 5% DCM/hexane to yield 4-cyclohexyl-6-iododibenzo[b,d]furan (9.8 g, 58% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[CH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:16]1([CH2:22][O:23][C:24]([NH:26][CH:27]([PH:29](=[O:31])[OH:30])[CH3:28])=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([CH2:15][P:29]([OH:31])([CH:27]([NH:26][C:24]([O:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:25])[CH3:28])=[O:30])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: C=C(Cc1ccc(Br)cc1)C(=O)OCC
Reactant: CC(NC(=O)OCc1ccccc1)[PH](=O)O
Product: CCOC(=O)C(Cc1ccc(Br)cc1)CP(=O)(O)C(C)NC(=O)OCc1ccccc1
Yield: 90 %

Procedure:
The process is performed according to the operating conditions described in 5.3., starting with 2.6 g (9.67 mmol) of ethyl 4-bromo-α-methylenebenzenepropanoate and 2 g (8.23 mmol) of [1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinic acid. 3.79 g of product are recovered (yield=90%).