Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.O.[NH2:26][NH2:27]>C(Cl)(Cl)Cl.C1COCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]([NH:26][NH2:27])=[O:14])=[CH:11][C:10]=1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
To a solution of 4-benzyloxy-3-ethyl-5-methylbenzoic acid (4.38 g, 17.2 mmol) in chloroform (60 mL), thionylchloride (5 mL, 68.9 mmol) is added. The mixture is refluxed for 2.5 h before the solvent is evaporated in vacuo. The remaining red oil is dissolved in THF (150 mL) and then added dropwise to a solution of hydrazine hydrate (3.46 g, 69.3 mmol) in THF (80 mL). The mixture is stirred 2 h at rt, diluted with diethyl ether, washed with 1 N aq. HCl, dried over MgSO4, filtered, concentrated and dried to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide (1.16 g) as a white solid; LC-MS: tR=0.82 min, [M+1]+=285.47, 1H NMR (CDCl3): δ 0.98 (t, J=7.3 Hz, 3H), 1.98 (s, 3H), 2.39 (q, J=7.3 Hz, 2H), 4.49 (s, 2H), 7.20-7.32 (m, 5H) 7.57 (s, 1H), 7.65 (s, 1H), 11.23 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29].O>C1COCC1>[F:29][C:28]([F:30])([F:31])[C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:25])[F:26])[CH:22]=[CH:23][C:18]=1[CH2:17][N:8]1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCNC(=O)CC1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
To a solution of ethyl 7-oxoazepane-4-carboxylate (9.78 g) in THF (250 mL) was added 60% sodium hydride (2.33 g, containing mineral oil) under ice-cooling. The reaction mixture was stirred for 5 min under ice-cooling, and 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (17.9 g) was added. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (14.9 g).
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC=CC=1>[Zn].C(O)(=O)C>[Cl:1][C:2](=[CH2:3])[CH2:4][C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=C(Cl)CCl
Reactant: O=C1CCCCC1
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(Cl)CC1(O)CCCCC1
Yield: 99 %

Procedure:
56.53 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 25.00 g of cyclohexanone, 75 g of toluene, 100 g of 5% acetic acid and 34.35 g of zinc powder at 45° C., and then the mixture was allowed to react at the same temperature for 3 hours. After the reaction was completed, zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution and dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 44.05 g of 1-(2'-chloroallyl)-1-cyclohexanol. The results were as follows.
Reaction SMILES: [OH:1][CH:2]([C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1)C([O-])=O.C([NH+](CCCC)CCCC)CCC.C(O)C.S(=O)(=O)(O)O.C(OC(C)C)(=O)C>S([O-])([O-])(=O)=O.[Fe+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Fe+3].O>[OH:15][C:9]1[C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:6]([CH:2]=[O:1])=[CH:7][CH:8]=1
Reactant: O=C([O-])C(O)c1ccc(O)c2ccsc12
Agent: [Fe+3]
Agent: CCCC[NH+](CCCC)CCCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CC(=O)OC(C)C
Product: O=Cc1ccc(O)c2ccsc12
Temperature: 57.5 °C
Yield: 96.7 %

Procedure:
A 750 ml, 4-necked glass flask equipped with a mechanical stirrer, a thermometer, a dropping funnel and an argon inlet was charged under argon with 41.0 g (100 mmol) of tributylammonium hydroxy-(4-hydroxy-benzo[b]thiophen-7-yl)-acetate, 60.5 g (115 mmol) of iron(III) sulfate and a mixture prepared from 60 ml of dry ethanol and 300 ml of 0.4 N sulfuric acid aqueous solution. Then stirring was started and the reaction mixture was heated to 55-60° C. for 5 h. After cooling to room temperature, 300 ml of isopropyl acetate and 100 ml of water were added under stirring, then the organic phase was separated and transferred into a 500 ml glass flask equipped with a pH meter. After addition of 150 ml of water (pH was 3.0), ca. 58 ml of a 2 N sodium hydroxide aqueous solution were added dropwise at 20° C. until a pH of 12-12.5 was reached. The organic phase was removed and to the aqueous phase were added at 10-15° C. dropwise ca. 54 ml of a 2 N aqueous solution of sulfuric acid until a pH of 4-4.5 was reached. The product precipitated during the addition. The suspension was stirred over night at room temperature, 1.2 h in an ice bath and then filtered. The filter cake was washed with water and dried at 60° C./15 mbar to afford 17.23 g (94%) of 4-hydroxy-benzo[b]thiophene-7-carboxaldehyde as white crystals with m.p. of 204° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.C(N(CC)C(C)C)(C)C.Cl.Cl.[NH:42]1[CH2:45][CH:44]([N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[CH2:43]1.O>CN1CCCC1=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:42]3[CH2:45][CH:44]([N:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)[CH2:43]3)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: C1CCN(C2CNC2)C1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N3CC(N4CCCC4)C3)c21
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
150 mg (0.21 mmol, purity approx. 71%) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was dissolved in 1-methyl-2-pyrrolidone (3.1 ml) in a reaction vessel suitable for a microwave, and 0.29 ml (1.66 mmol) of N,N-diisopropyl ethylamine and 165 mg (0.83 mmol) of 1-(azetidin-3-yl)pyrrolidine-dihydrochloride were added. Then the reaction vessel was sealed with a septum and heated in the microwave at 150° C. for 6 h. After cooling, water was added to the reaction mixture. It was stirred for 30 min and filtered to remove the resultant solid. The filtrate was purified by preparative HPLC (acetonitrile:water (+0.1% trifluoroacetic acid) gradient). The product fraction was dissolved in dichloromethane and was washed twice with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated by evaporation. 52 mg of the title compound was obtained (46% of theor.; purity 94%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O.C(OCC)C>[C:1]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: C=C(C)C(=O)OC1CCCCO1

Procedure:
In this embodiment, 0.1 mol of methacrylic acid and 8.6 grams (0.11 mol) of 3,4-dihydro-2H-pyran was dissolved in 150 ml of CH2Cl2. Small amounts of p-toluene sulfonic acid were then added to the resultant solution. The resultant solution was allowed to react at room temperature for four hours to form a reaction product. Then, the reaction product was dissolved in an excess amount of water to which diethyl ether was added to extract the reaction product. After drying the reaction product with a magnesiumsulfate solution, tetrahydropyranyl methacrylate was obtained through vacuum distillation.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]#[N:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][CH2:15][C:16]1OC(=O)[S:18][N:17]=1.O>CCCCCCCCCCCC>[CH3:13][O:14][CH2:15][C:16]1[N:12]=[C:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[S:18][N:17]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: COCc1nsc(=O)o1
Solvent: CCCCCCCCCCCC
Solvent: O
Product: COCc1nsc(S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 150 °C

Procedure:
4-Methylbenzenesulfonyl cyanide (16.26 g) was added to an emulsion of 5-methoxymethyl-1,3,4-oxathiazol-2-one (6.6 g) in dodecane (60 cm3). The reaction mixture was stirred and heated at 150° C. for 18 hours, then cooled. Water was added and the product extracted into ethyl acetate. The combined organic phases were dried (MgSO4) and ethyl acetate was removed by evaporation under reduced pressure. The residue separated into a brown liquid and a clear dodecane layer which was removed and discarded. Chromatography of the brown liquid on silica gel (Sorbsil C30) using 3:7 ethyl acetate:hexane as eluant give a pale orange oil which solidified on standing (6.94 g). M+ =284; 1H NMR: δ 2.40(3H,s); 3.45(3H,s); 4.7(2H,s); 7.4(2H,d); 8.0(2H,d); (mp 43.4-45-4° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]3[N:13]([N:15]=[CH:16][C:17]=3[C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:28]=3)[C:23](OCC)=[O:24])[CH:14]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl.C(Cl)(=O)C(Cl)=O.Cl.CN.[CH:41]([N:44](CC)C(C)C)(C)C>CC(O)(C)C.COCCOC.ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][C:12]3[N:13]([N:15]=[CH:16][C:17]=3[C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:28]=3)[C:23]([NH:44][CH3:41])=[O:24])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cncc(-c2cnn3cc(-c4ccc(OC)cc4)cnc23)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CNC(=O)c1cncc(-c2cnn3cc(-c4ccc(OC)cc4)cnc23)c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]nicotinate (2-2, 150 mg, 0.40 mmol, 1 equiv) and aqueous sodium hydroxide solution (1N, 1.0 mL), 1.0 mmol, 2.5 equiv) in a mixture of t-BuOH (2 mL) and DME (2 mL) was heated at reflux for 1 hour. The reaction mixture was allowed to cool to 23° C., and then it was acidified with aqueous 1 N hydrogen chloride solution. The precipitate was filtered, washed with water, and air dried. Oxalyl chloride (150 TL, 1.7 mmol, 4.3 equiv) followed by a catalytic amount of DMF (4 TL) was then added to a suspension of the filtered solid in dichloromethane (10 mL), and the resulting mixture was stirred for 30 minutes, then concentrated. A suspension of one-tenth of this residue (approximately 15 mg, 0.040 mmol), methylamine hydrochloride (27 mg, 0.40 mmol, 10 equiv) and N,N-diisopropylethylamine (200 TL, 1.1 mmol, 30 equiv) in dichloromethane (3 mL) was stirred at 23° C. for 30 minutes. The reaction mixture was partitioned between half-saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated. The residue was suspended in methanol (3 mL) and filtered to give 5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-methylnicotinamide (2-3) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (d, 1H, J=2.2 Hz), 9.45 (d, 1H, J=2.2 Hz), 9.12 (d, 1H, J=2.2 Hz), 8.91 (s, 1H), 8.88 (t, 1H, J=2.0 Hz), 8.83 (d, 1H, J=2.0 Hz), 8.66 (br m, 1H), 7.84 (d, 2H, J=8.8 Hz), 7.10 (d, 2H, J=8.8 Hz), 3.82 (s, 3H), 2.84 (d, 3H, J=4.4 Hz).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:8]=[N:9][N:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:14]([C:25](OCC)=[O:26])[CH:13]=[N:12][C:11]=12)(=[O:6])=[O:5])[CH3:2].Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>>[CH2:1]([NH:3][S:4]([C:7]1[CH:8]=[N:9][N:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:14]([C:25]([N:41]3[CH2:42][CH2:43][CH:38]([C:35]4[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=4)[CH2:39][CH2:40]3)=[O:26])[CH:13]=[N:12][C:11]=12)(=[O:5])=[O:6])[CH3:2]
Reactant: CCNS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)OCC)cnc12
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: CCNS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 7.9 %

Procedure:
Using ethyl 3-(N-ethylsulfamoyl)-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.483 g, 1.145 mmol) obtained in Example 2 step 1 and 4-(4-fluorophenyl)piperidine hydrochloride (0.099 g, 0.458 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.020 g, 3%) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].Cl.[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:20]=[CH:21][CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:18]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: CN(C)CCNc1cccc(CN)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CN(C)CCNc1cccc(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1
Yield: 27.7 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (204 mg, 0.785 mmol), N-(3-Aminomethyl-phenyl)-N′,N′-dimethyl-ethane-1,2-diamine hydrochloride (198 mg, 0.86 mmol), Pd2(dba)3 (72 mg, 0.0785 mmol), rac-BINAP (162 mg, 0.260 mmol) and NaOtBu (266 mg, 2.77 mmol) in DMA (6 mL) was heated at 85° C. for 3 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Preparatory HPLC afforded 4-chloro-6-[3-(2-dimethylamino-ethylamino)-benzylamino]-2H-phthalazin-1-one hydroformate (81 mg) as a yellow solid. 1H (400 MHz, d6-DMSO) δ: 1.95 (s, 6H), 2.40 (m, 1H), 2.46 (m, 1H), 2.87 (m, 2H), 4.10 (d, 2H), 5.20 (bs, 1H), 6.26 (dd, 1H), 6.34 (d, 1H), 6.37 (s, 1H), 6.62 (s, 1H), 6.82 (t, 1H), 6.93 (dd, 1H), 7.40 (t, 1H), 7.70 (d, 1H), 7.95 (s, 1H), 12.12 (s, 1H) ppm; m/z (M+1) 372.04.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH:24]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:28]([CH:24]2[CH2:27][CH2:26][CH2:25]2)=[O:29])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: O=C(O)C1CCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C3CCC3)c2c1N

Procedure:
Prepared as in Example Da from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example Db) and cyclobutanecarboxylic acid as an off-white solid (61%). MS 400 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C([O:26][C:27](=O)[C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([N:35]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]=1[F:50])C1C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH2:43]([N:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]1[C:29]([F:50])=[C:28]([C:27](=[O:26])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)[C:33]([F:34])=[CH:32][CH:31]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=C(OCc1ccccc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(F)c1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-fluoro-4-methyl-pyridine (5.76 mL, 0.056 mol) in anhydrous tetrahydrofuran (200 mL) at 0° C. sodium hexamethyldisilazide (NaHMDS, 2 M in tetrahydrofuran, 36 mL, 0112 mol) was added and the reaction was stirred for 1 hour. A solution of 3-dibenzylamino-2,6-difluoro-benzoic acid benzyl ester (25 g, 0.056 mol) in tetrahydrofuran (80 mL) was then added dropwise to the reaction mixture, which was stirred at 0° C. for one hour and allowed to warm at room temperature. The reaction mixture was then poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with ethyl acetate 15% in hexane (40.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH2:14]=O>O>[CH3:12][C:9]1([CH3:13])[C:5]2[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][NH:11][CH2:10]1
Reactant: C=O
Reactant: COc1cccc(C(C)(C)CN)c1
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)CNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture of 2-(3-methoxyphenyl)-2-methylpropylamine (7.5 g, 0.042 mol), 40% aqueous formaldehyde (3.2 g, 0.043 mol) and water (3.2 ml) was stirred at room temperature for 3 hours then heated on a steam bath for 0.5 hour. On cooling the mixture was partitioned between water (100 ml) and dichloromethane (50 ml) and the aqueous layer extracted with dichloromethane (3×50 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo. The residue was mixed with water (3.6 ml) and concentrated hydrochloric acid (5 ml) and heated on a steam bath under argon for 2 hours. On cooling, water (300 ml) was added and the mixture washed with dichloromethane (2×50 ml). The aqueous layer was basified with solid potassium carbonate and extracted into dichloromethane (3×75 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a pale yellow oil (6.5 g, 85%).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[O:42])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[C:43]([Mg]Br)#[C:44][CH3:45].C([Mg]Br)#C>O1CCCC1>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]([OH:42])[C:43]#[C:44][CH3:45])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Reactant: CC#C[Mg]Br
Agent: C#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(O)c1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 71-(a) except for using 1.01 g (1.62 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 15-(a), and using 3.6 ml of tetrahydrofuran solution containing 0.5M propynyl magnesium bromide in place of tetrahydrofuran solution containing ethynyl magnesium bromide, whereby 1.07 g of the title compound was obtained as a pale brownish foam substantially quantitatively.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH:10]=[CH:11][C:12](=O)[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:16][NH:17][CH3:18].[ClH:19]>C(OCC)(=O)C>[ClH:19].[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH:10]([N:17]([CH3:18])[CH3:16])[CH:11]=[CH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CNC
Reactant: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C1C=Cc2cc([N+](=O)[O-])ccc2CC1

Procedure:
Using the procedure of Example 1, 3-nitro-8,9-dihydro [5H] benzocycloheptene-5-one and dimethylamine were reacted to obtain a non-salified product which was treated in ethyl acetate with a solution of ethyl acetate saturated with gaseous hydrogen chloride to obtain a product which was crystallized from isopropanol to obtain 2-nitro-7-dimethylamino-6,7-dihydro [5H] benzocycloheptene hydrochloride melting at 202° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20].[CH:21]([OH:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([O:24][CH:21]([CH3:23])[CH3:22])=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20]
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)Cl)c(Cl)cc2F)C1=O
Reactant: CC(C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(c2cc(C(=O)OC(C)C)c(Cl)cc2F)C1=O

Procedure:
6 g of N-(2-fluoro-5-chlorocarbonyl-4-chlorophenyl)-2,3-dimethylmaleic acid imide are added dropwise, while stirring at room temperature, to a mixture of 4 ml of isopropanol, 4 ml of triethylamine and 100 ml of toluene. After a reaction time of 6 hours, the triethylamine hydrochloride is separated off by filtration and the filtrate is concentrated by evaporation. By recrystallising the residue from ethanol/water, 4.2 g of N-(2-fluoro-4-chloro-5-isopropoxycarbonylphenyl)-2,3-dimethylmaleic acid imide having a melting point of 161°-162° are obtained.
Reaction SMILES: [CH2:1]1[C:10]2[N:5]([C:6](=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl>C(O)C.[Pd]>[CH2:1]1[CH:10]2[N:5]([C:6](=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2ccccc2cc2n1CCCC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1c2ccccc2CC2CCCCN12
Reaction time: 72 h
Yield: 93.5 %

Procedure:
To a solution of 1,3,4,6-tetrahydro-2H-benzo[b]quinolizin-6-one (4.02 g, 20.2 mmol) (M. A. Haimova, V. I. Ognyanov, and N. M. Mollov, Synthesis, 1980, 845) in ethanol (250 ml) and 2.5M hydrochloric acid (10 ml) was added 10% palladium-on-carbon (0.8 g) and the solution was shaken on a Parr Hydrogenator for 72 h. The catalyst was filtered off and the filtrate was concentrated to give an oil which was partitioned between ethyl acetate and dilute base. The dried (magnesium sulfate) organic phase was concentrated in vacuo and then placed on a high vacuum system to give the title compound as a white solid (3.8 g, 94%), m.p. 88-92° C.