Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[CH:14]=[C:15]3[C:20]=2[N:19]=[C:18](Cl)[N:17]=[C:16]3[OH:22])=[O:10])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35]>CN1CCCC1=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[CH:14]=[C:15]3[C:20]=2[N:19]=[C:18]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([F:26])=[C:28]([C:34]([F:37])([F:35])[F:36])[CH:29]=2)[N:17]=[C:16]3[OH:22])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(F)cc1)c1cc([N+](=O)[O-])cc2c(O)nc(Cl)nc12
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(F)cc1)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)c(C(F)(F)F)c3)nc12
Temperature: 130 °C

Procedure:
To a solution of N-(4-fluorophenyl)-2-chloro-4-hydroxy-6-nitroquinazoline-8-carboxamide (0.050 g) in 1-methyl-2-pyrrolidinone (1 mL) was added 4-fluoro-3-(trifluoromethyl)aniline (0.053 mL). The reaction mixture was heated at 130° C. for 4.5 h, then cooled to room temperature and diluted with water. The resulting mixture was cooled at 5° C. for 3 h and the precipitate which formed was isolated by filtration, washed with water and dried to afford the title compound as a grey solid (0.054 g). 1H NMR (300 MHz, DMSO-d6): 12.31 (s, 1H), 11.87 (s, 1H), 9.64 (s, 1H), 9.00 (d, J=2.9 Hz, 1H), 8.8. (d, J=2.9 Hz, 1H), 7.95-7.87 (m, 2H), 7.39-7.32 (m, 1H), 7.15-6.95 (m, 4H); HPLC (Method E): 4.3 min.; MS (APCI−): m/z 504.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:38])=[C:21]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1.[NH4+:39].[OH-]>>[NH2:39][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:38])=[C:21]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.256 mmol) and NH4OH (2.5 mL, 17.97 mmol) heated in a microwave reactor at 130° C. for 30 min the title compound was obtained as a light yellow solid (127 mg, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (br. s., 1H), 7.90 (d, J=5.3 Hz, 1H), 7.46-7.58 (m, 4H), 7.25 (t, J=8.8 Hz, 1H), 6.62 (br. s., 2H), 5.61 (d, J=5.1 Hz, 1H), 3.69-3.74 (m, 4H), 3.42-3.47 (m, 4H). MS (ESI): 566 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O)([CH3:13])[CH3:12]>>[CH:24]([C:20]1[CH:19]=[C:16]([CH:15]=[C:14]([CH:11]([CH3:13])[CH3:12])[C:21]=1[O:22][CH3:23])[CH:17]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10])([CH3:25])[CH3:26]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2ccccc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccccc32)cc1C(C)C

Procedure:
2-Oxindole was condensed with 3,5-diisopropyl-4-methoxybenzaldehyde using method B to give 3-(3,5-diisopropyl-4-methoxy-benzylidene)-1,3-dihydro-indol-2-one as a yellow-orange solid which was reduced using method E to give 2 g (100%) of 3-(3,5-diisopropyl-4-methoxybenzyl)-1,3-dihydroindol-2-one as a white solid.
Reaction SMILES: [C:1](#[N:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[C:9](O)(=O)[C:10]1C=CC(C(O)=O)=CC=1.P(=O)(O)(O)O>>[C:6]([C:5]1[CH:10]=[CH:9][C:2]([C:1]#[N:8])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: N#CCCCCC#N
Agent: O=P(O)(O)O
Product: N#Cc1ccc(C#N)cc1

Procedure:
650 g (6.0 mol) of a mixture of dinitriles (85% MGN, 12% ESN, 3% AdN by weight) which are by-products of adiponitrile synthesis are introduced into a 2000-ml reactor. 167 g of terephthalic acid (1.0 mol) are added to this heterogeneous medium, followed by 5 g of 85% orthophosphoric acid. The reaction medium is heated at the reflux of the dinitriles and these conditions are maintained for 5 h. Respective yields of imide mixture and of 1,4-dicyanobenzene of 96% and 95% are obtained by GC analysis.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]([CH2:13][C:14](=O)[CH3:15])[CH:11]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:21].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:13]=[C:14]([CH3:15])[N:21]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: COc1nc(Br)ccc1N(C=O)CC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1nc(Br)ccc1-n1cnc(C)c1
Temperature: 140 °C
Yield: 14.5 %

Procedure:
A mixture of N-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (7072 mg, 24.63 mmol) and ammonium acetate (8714 mg, 113 mmol) in 16 mL of acetic acid was heated at 140° C. for 1 h. The reaction mixture was cooled to rt and poured into a mixture of icewater and ethyl acetate. The pH of the resulting mixture was brought to pH 9 with a 50% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (959.0 mg, 3.58 mmol, 14.52% yield) as brown solid. LC-MS (M+H)+=270.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C-:6]1[CH2:10][CH:9]=[CH:8][S:7]1.O.[CH2:12]([O:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18])[CH3:13]>>[CH2:12]([O:14][P:15]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: BrCCCC[C-]1CC=CS1
Solvent: O
Product: CCOP(=O)(CCCCc1cccs1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A solution of 1d (4.58 g, 0.02 mol) in 20 mL of triethylphosphite was heated at 160° C. for 20 hours, with nitrogen bubbling directly into the solution. The solution was cooled to room temperature and 50 mL of water was added; the resulting mixture was stirred for 4 hours. The product was extracted with methylene chloride, the organic layer was separated and washed with brine, then dried over anhydrous magnesium sulfate. Evaporation of the solvent yielded an oily residue, which was distilled under vacuum (0.12 mm Hg, 135° C.) to give 1e as a colorless oil (6.0 g, 82%). 1H NMR (250 MHz, 25° C., CDCl3): δ 7.06 (m, 1H, Ar—H), 6.85 (m, 1H, Ar—H), 6.72 (m, 1H, Ar—H), 4.03 (m, 4H, POCH2CH3), 2.79 (t, 2H, Ar—CH2), 1.72 (m, 6H, CH2CH2CH2P), 1.26 (t, 6H, POCH2CH3).
Reaction SMILES: [CH:1]1([N:7]([CH2:15][CH:16]([OH:18])[CH3:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:21]=1[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:21]=1[C:22]([O:18][CH:16]([CH3:17])[CH2:15][N:7]([C:8]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:14])[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:23]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CC(O)CN(C(=O)OC(C)(C)C)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(=O)OC(C)CN(C(=O)OC(C)(C)C)C2CCCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl cyclohexyl(2-hydroxypropyl)carbamate (1 g, 3.89 mmol) in dry toluene (10 ml), 2,4,6-trimethyl-benzoyl chloride (0.510 mL, 4.280 mmol) was added. The resultant reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulphate, and concentrated to dryness to obtain 1-((tert-butoxycarbonyl)(cyclohexyl)amino)propan-2-yl 2,4,6-trimethylbenzoate. Yield: 1 g (64.10%); LCMS: m/z=404.4 [M+H], RT=2.76 min, (Column: Y, Program: P1)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[N:26][C:27]#[N:28])OC4C=CC=CC=4)=[CH:13][CH:12]=3)=[C:9]([CH3:29])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[C:31]([CH3:30])[CH:32]=4)=[N:26][C:27]#[N:28])=[CH:13][CH:12]=3)=[C:9]([CH3:29])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(NC(=NC#N)Oc2ccccc2)cc1
Reactant: Cc1cccc(N)c1
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=NC#N)Nc2ccc(-c3c(C)sc4ncnc(N)c34)cc2)c1
Yield: 362.8 %

Procedure:
A solution of Example 132 (40 mg, 0.01 mmol) and 3-methylaniline (0.012 mL, 0.01 mmol) in DMF (1 mL) was heated in a Smith synthesizer microwave to 180° C. for 22 minutes and partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with 8% methanol/dichloromethane to provide the desired product (15 mg). MS(ESI(+)) m/e 414 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H); 9.48 (s, 1H); 8.26 (s, 1H); 7.45 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.23 (t, J=7.8 Hz, 1H); 7.15-7.10 (m, 2H); 6.96 (d, J=7.8 Hz, 1H); 2.29 (s, 6H).
Reaction SMILES: [C:1]1([P:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])[O:8]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O-].[K+:27]>O1CCCC1>[C:1]1([P:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:8])[O-:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[K+:27]
Reactant: O=P(Oc1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=P([O-])(c1ccccc1)c1ccccc1
Yield: 87 %

Procedure:
The procedure of Example 1 was followed adding neat solid phenyl diphenylphosphinate (5.88 g, 20 mmol) to a slurry of potassium trimethylsilanolate (2.56 g, 20 mmol) in dry tetrahydrofuran (50 mL); a 4 h reaction time was used. Potassium diphenylphosphinate (4.46 g, 87% yield) was isolated as a white solid: 1H NMR (D2O, DSS) δ 6.8-7.9 (m, Ar--H's, 10H). Anal. Calcd. for C12H10KO2P: C, 56.24; H, 3.93; K, 15.26; P, 12.09. Found: C, 52.57, 52.49, 54.53, 54.38; H, 4.00, 4.09, 4.02, 4.36; K, 14.78; P, 11.01, 10.89.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.C(O)(=O)C.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1C=CC=CC=1>[C:23]([C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:1][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cc(C(=O)OCC)c(=O)n2ccccc12)C(=O)OCC
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A 100 ml round-bottom flask equipped with a Dean-Stark trap was charged with 50 ml benzene, ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (8) (1.22 g, 5 mmol), acetic acid (5 g, 83 mmol), NH4OAc (5 g, 65 mmol), and diethyl malonate (2.3 g, 9 mmol). The reaction mixture was refluxed for 48 h. The reaction mixture was cooled to room temperature and washed three times with 50 ml water. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (ethyl acetate) to yield ethyl 1-(2,2-dicarboethoxyvinyl)-4-oxo-4H-quinolizine-3-carboxylate (12) as a yellow powder (1.58 g, 82%). M.p. 149-151° C. 1H NMR (δ, CDCl3): 1.31 (t, J=7 Hz, 3H), 1.36 (t, J=7 Hz, 3H), 1.42 (t, J=7 Hz, 3H), 4.34 (q, J=7 Hz, 2H), 4.36 (q, J=7 Hz, 2H), 4.41 (q, J=7 Hz, 2H), 7.34 (dd, J=7 Hz, J=7 Hz, 1H), 7.82 (dd, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 8.05 (s, 1H), 8.60 (s, 1H), 9.50 (d, J=7 Hz). MS: m/z 387.1331; required for C20H21NO7: 387.1318.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:27])=[CH:16][CH:17]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:3]=1
Reactant: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccc(O)cc3)coc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccc(OC)cc3)coc2c1
Yield: 87.6 %

Procedure:
In 150 ml of acetone was dissolved 5.5 g of ethyl {[5-chloro-3-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl]oxy}acetate under heating, and 4.8 g of anhydrous potassium carbonate was added thereto. To the solution was added 3.4 ml of methyl iodide, followed by refluxing for 2 hours. After cooling, the solvent was removed by distillation under reduced pressure. Water was added to the residue, and the insoluble material was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethanol-chloroform to obtain 5.0 g of the entitled compound having a melting point of 121° to 122° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12](=[N:14][OH:15])[NH2:13])=[CH:10][CH:11]=1)=[O:4].[C:16]1(=O)[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>CN(C)C=O.O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:16]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[O:15][N:14]=2)=[N:8][CH:7]=1)=[O:4]
Reactant: NC(=NO)c1ccc(NC(=O)CCl)cn1
Reactant: O=C1CCC(=O)O1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1nc(-c2ccc(NC(=O)CCl)cn2)no1

Procedure:
A mixture of compound of example 4 (0.228 g, 1 mmol) and succinic anhydride was stirred in dimethyl formamide (5 mL), at a temperature in the range of 115-120° C. for a period of 16 hours. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate (3×50 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product obtained was purified over silica gel using ethyl acetate as eluent. The pure fractions were concentrated and crystallized using ethyl acetate/petroleum ether, to obtain the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12]>N1CCCCC1.C(O)C>[CH2:18]1[N:13]([CH:11]=[O:12])[CH2:14][CH2:15][N:16]([C:19]2[CH:26]=[CH:25][C:22](/[CH:23]=[C:3]3\[C:4]4[C:9]([NH:1][C:2]\3=[O:10])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:21][CH:20]=2)[CH2:17]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc(N2CCN(C=O)CC2)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=CN1CCN(c2ccc(/C=C3/C(=O)Nc4ccccc43)cc2)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 59.8 %

Procedure:
A mixture of 133.15 mg (1 mmol) of 2-indolinone, 228.3 mg (1.2 mmol) of 4-(1-formylpiperazin-4-yl)benzaldehyde and 3 drops of piperidine in 2 ml of ethanol was stirred at 90° C. for 5 hr. After cooling, the precipitate was filtered, washed with cold ethanol and dried to yield 199.5 mg (65%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-]C(C)C)(C)C.[Li+].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C@H:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C:42](=O)[CH2:41][CH2:40]4)[CH:37]=[CH:36][C:35]=2[CH:34]=1.O>O1CCCC1>[F:1][C:2]([F:3])=[C:42]1[CH2:41][CH2:40][C@H:39]2[C@H:38]3[C@H:47]([CH2:46][CH2:45][C@:43]12[CH3:44])[C:48]1[CH:35]=[CH:34][C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:50][C:49]=1[CH:36]=[CH:37]3
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4C=C[C@H]3[C@@H]1CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A solution of 715 mg of difluoromethyldiphenylphosphine oxide in 36 ml of tetrahydrofuran is slowly mixed with 1.42 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 1 g of 3-tetrahydropyranyloxy-estra-1,3,5(10),6-tetraen-17-one in 10 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 2.5 hours. For working-up, it is added to water, extracted with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 1.1 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10), 6-tetraene is obtained as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[O:6])[CH2:3][CH2:2]1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: COC(=O)c1ccc(C)c(C(=O)CC2CC2)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)c(C(=O)C(Br)C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 3-(2-cyclopropylacetyl)-4-methylbenzoate (compound 4.5, 150 mg, 0.65 mmol) in chloroform (15 mL). Bromine (40 μL, 0.78 mmol) in chloroform (2 mL) was added drop-wise to the reaction mixture. The resulting solution was stirred for 2 h at room temperature, then concentrated under reduced pressure to yield the title compound as a yellow oil (200 mg, crude), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccccn2)C1
Temperature: 80 °C

Procedure:
A stirred solution comprising (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.0 g, 10.7 mmol), 2-bromopyridine (1.7 g, 10.7 mmol) and TEA (1.1 g, 10.7 mmol) in DMF (40 ml) is heated to 80° C. for 50 hours. The solvent is removed in vacuo the purification of the crude residue by chromatography on silica eluting with ethyl acetate:hexane (1:9 increasing to 1:4) yields the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:22][NH2:23].C1COCC1>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]([S:12]([NH:23][CH3:22])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CN
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CNS(=O)(=O)c1cccc(C(=O)OC)c1Cl
Yield: 72 %

Procedure:
To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added a 2M solution of methylamine in THF (5.6 mL, 11.2 mmol). Purification of the product (2:1 hex:EtOAc) provided methyl 2-chloro-3-[(methylamino)sulfonyl]benzoate (430 mg, 72%) as a solid. 1H NMR (400 MHz, CDCl3), δ 8.23 (dd, 1H, J=7.9, 1.7 Hz), 7.90 (dd, 1H, J=7.8, 1.7 Hz), 7.48 (t, 1H, J=7.9 Hz), 5.16 (q, 1H, J=5.2 Hz), 3.94 (s, 3H), 2.62 (d, 3H, J=5.3 Hz); ESI-MS 264 (M+H). Methyl 2-chloro-3-[(methylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(methylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 250 (M+H), 272 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[NH:11][N:10]([CH2:20][CH2:21][CH2:22][OH:23])[N:9]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1.CN(C1C=CC=CN=1)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[NH:11][N:10]([CH2:20][CH2:21][CH2:22][O:23][C:36](=[O:37])[NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)[N:9]=1
Reactant: Cc1cccc(C=NNC2=NN(CCCO)NC(N3CCOCC3)=C2)c1
Reactant: COc1cccc(N=C=O)c1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: COc1cccc(NC(=O)OCCCN2N=C(NN=Cc3cccc(C)c3)C=C(N3CCOCC3)N2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-triazin-2-yl}-propan-1-ol (1 mmol) is dissolved in acetonitrile (4 mL). To the mixture is added m-methoxyphenylisocyanate (149 mg., 1 mmol) and a catalytic amount of dimethylaminopyridine. The reaction is stirred at 60° C. for 16 hours. The reaction is then cooled to 4° C., and the precipitate is filtered, washed with acetonitrile (1 mL) and dried to give Compound 103, (3-methoxy-phenyl)-carbamic acid 3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-triazin-2-yl}-propyl ester.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([O:11][C:12]([C:14]1[S:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:21][CH2:20]2)=[N:17][N:18]=1)=O)C>>[CH2:1]([NH:8][C:12]([C:14]1[S:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:23][CH2:24]2)=[N:17][N:18]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: CCCCCCCN
Product: CCCCCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-heptylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.053 g, yield 90%). 1H NMR (300 MHz, CDCl3) δ 7.69-7.76 (m, 1H), 7.63-7.50 (m, 2H), 7.30-7.38 (m, 1H), 7.05 (br. t, 1H), 4.07-4.01 (m, 1H), 3.91-3.83 (m, 1H), 3.75-3.6 (m, 2H), 3.54-3.5 (m, 2H), 3.43-3.31 (m, 4H), 1.59-1.52 (m, 2H), 1.32-1.21 (m, 8H), 0.85 (t, J=6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.5, 158.2, 156.0, 133.9, 133.9, 132.4, 129.6, 127.1, 126.9, 126.8, 125.3, 121.7, 49.5, 48.9, 45.9, 40.7, 39.6, 31.6, 29.4, 28.8, 26.7, 22.5, 14.0. MS (ES+) m/z 484 (M+1).