Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1.C(=O)(O)[O-].[K+]>CN(C=O)C>[Br:7][C:6]1[C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[C:3]([N+:8]([O-:10])=[O:9])[S:4][CH:5]=1
Reactant: O=[N+]([O-])c1scc(Br)c1Br
Reactant: c1c[nH]nn1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1scc(Br)c1-n1nccn1
Reaction time: 1 h

Procedure:
A mixture of 3,4-dibromo-2-nitrothiophene (1.5 g, 5.23 mmol), 1H-1,2,3-triazole (0.30 mL, 5.18 mmol) and potassium bicarbonate (0.54 g, 5.36 mmol) in DMF (13 mL) were stirred in an oil bath set at 110° C. under condenser with N2 (g) inlet for 1 h. The reaction mixture was quenched with H2O and extracted with ethyl acetate. The organic phase was collected, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, 30:70 ethyl acetate/hexane) gave the regio-isomer nitro intermediate of interest (0.518 g, 36%). Retention time (min)=1.950, method [4], MS (ESI) 276.9 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:20][CH:19]=[CH:18][CH2:17][O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:21]1([C:15]2([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C1=CCC(c2ccccc2)(c2ccc(OCc3ccccc3)cc2)OC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(C2(c3ccccc3)CCCCO2)cc1
Reaction time: 6 h
Yield: 101.9 %

Procedure:
2-(4-Benzyloxy-phenyl)-2-phenyl-3,6-dihydro-2H-pyran (4.1 g) was dissolved in methanol (25 mL) and ethyl acetate (5 mL). 5% Palladium on carbon (10 mg) was added. Nitrogen was bubbled through the solution. Ammonium acetate (4 g) was added. The mixture was stirred for 6 h, filtered through a block of celite and concentrated to a solid. NMR indicated full conversion to the title product (3.1 g, 12.2 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.CCOC(C)=O.O.[Fe]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccccn2)cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Sc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a solution of 4-(2-pyridinylthio)-1-nitrobenzene (Menai ST 3355A; 0.220 g, 0.95 mmol) and H2O (0.5 mL) in AcOH (5 mL) was added iron powder (0.317 g, 5.68 mmol) and the resulting slurry stirred for 16 h at room temp. The reaction mixture was diluted with EtOAc (75 mL) and H2O (50 mL), basified to pH 10 by adding solid K2CO3 in portions (Caution: foaming). The organic layer was washed with a saturated NaCl solution, dried (MgSO4), concentrated in vacuo. The residual solid was purified by MPLC (30% EtOAc/70% hexane) to give the desired product as a thick oil (0.135 g, 70%): TLC (30% EtOAc/70% hexanes) Rf 0.20. A13a. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C([OH:21])C>O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([OH:21])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1c(Cl)c(O)cnn1Cc1ccccc1

Procedure:
To the mixture of 60 g of 2-benzyl-4,5-dichloro-3(2H)-pyridazinone and 38.8 g of potassium hydroxide was added 250 ml of ethanol and 150 ml of water and heated in an oil bath to the refluxing temperature for 10 hours. After reaction the solvent was distilled off under reduced pressure, and to the residual solution was added 200 ml of water and washed twice with chloroform, the water layer was acidified with concentrated hydrochloric acid. The white solid thus separated was filtered off, washed with water and dried to obtain 55 g of 2-benzyl-4-chloro-5-hydroxy-3(2H)-pyridazinone. Subsequently, in aqueous sodium hydroxide solution (NaOH 1.82 g, water 20 ml) were added 5.0 g of 2-benzyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 200 mg of 5 % Pd/C , then 474 ml of hydrogen gas was absorbed in the solution under normal pressure. After reaction, Pd/C was filtered off and to the solution was added concentrated hydrochloric acid to be acidified. The white solid thus separated was filtered off, washed with water and dried to obtain 4.1 g of 2-benzyl-5-hydroxy-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.C(O[C:15]([S-])=[S:16])C.[K+]>C(O)C>[F:9][C:6]1[C:7]2[O:8][C:15]([SH:16])=[N:1][C:2]=2[CH:3]=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: CCOC(=S)[S-]
Reactant: COc1ccc(N)c(O)c1F
Agent: [K+]
Solvent: CCO
Product: COc1ccc2nc(S)oc2c1F
Temperature: 80 °C
Reaction time: 64 h
Yield: 52.7 %

Procedure:
To a solution of 6-amino-2-fluoro-3-methoxyphenol (220 mg) in ethanol (10 mL) was added potassium ethylxanthate (450 mg), and the mixture was stirred at 80° C. for 64 hr. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in water, and the solution was acidified with 1 M hydrochloric acid. After stirring for 10 min, the mixture was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (147 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]I)=[CH:14][CH:13]=3)[CH:10]([CH2:30][CH2:31][CH:32]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[OH:33])[C:9]2=[O:41])=[CH:4][CH:3]=1.[CH3:42][NH:43][CH2:44][CH:45]([OH:54])[CH:46]([OH:53])[CH:47]([OH:52])[CH:48]([OH:51])[CH2:49][OH:50]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:43]([CH3:42])[CH2:44][CH:45]([OH:54])[CH:46]([OH:53])[CH:47]([OH:52])[CH:48]([OH:51])[CH2:49][OH:50])=[CH:14][CH:13]=3)[CH:10]([CH2:30][CH2:31][CH:32]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[OH:33])[C:9]2=[O:41])=[CH:4][CH:3]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCCCCCI)cc2)N1c1ccc(F)cc1
Reactant: CNCC(O)C(O)C(O)C(O)CO
Solvent: CN(C)C=O
Product: CN(CCCCCCCCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CC(O)C(O)C(O)C(O)CO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
170 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(10-iododecyloxy)phenyl]azetidin-2-one are dissolved in 5 ml of absolute dimethylformamide. 200 mg of 6-methylaminohexane-1,2,3,4,5-pentaol are then added, and the reaction solution is stirred at 50° C. for 2 h. After concentration using a rotary evaporator and oil pump pressure at 40° C., the residue is purified by preparative HPLC. The product is obtained as an oil. C41H56F2N2O8 (742) MS (ESI): M+
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([OH:27])=[O:26])[CH:21]=[CH:22][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([O:27][C@@H:47]2[CH:48]3[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]3)[CH2:46]2)=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C(Nc1ccccc1)c1cccc(F)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
PS-DCC (982 mg, 1.31 mmol, loading: 1.33 mmol/g) was suspended in dry THF (15 ml). 2-(3-Fluorophenyl)-2-(phenylamino)acetic acid hydrochloride (I17) (184 mg, 0.65 mmol), HOBT (200 mg, 1.31 mmol), and (R)-quinuclidin-3-ol (249 mg, 1.96 mmol) were added, and the mixture was shaken at room temperature overnight. PS-DCC was removed by filtration, and the filtrate is evaporated. The residue was dissolved in EtOAc and washed with NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The crude compound was purified by filtration through a pad of silica-gel using DCM/MeOH=9/1 as the eluent. The title compound was obtained (129 mg, 56% yield, mixture of diastereomers).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])=[CH:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].[C:19]([OH:22])(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])=[CH:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][C:8]=1[O:22][C:19](=[O:21])[CH3:20])[CH3:2]
Reactant: CCOC(=O)C(C)=Cc1ccc(OC)cc1OC
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)=Cc1c(OC)cc(OC)cc1OC(C)=O

Procedure:
3-(4,6-Dimethoxyphenyl)-2-methyl-2-propenic acid ethyl ester (1 g, 3.76 mmol) was dissolved in 5 ml of pyridine. To this was added 0.8 ml of anhydrous acetic acid and it was allowed to react at room temperature for 24 h. After the solvent was removed in vacuo, purification was carried out by silica gel column chromatography (toluene/ethyl acetate 93:7 as a developing solvent) to give 1.2 g of the desired product in a quantitative yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1.[OH-].[K+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][CH:14]1[C:15](=[O:19])[CH2:16][CH2:17][CH2:18][C:13]1=[O:20]
Reactant: O=C1CCCC(=O)C1
Reactant: ClCCCc1ccccc1CCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCCC(=O)C1Cc1ccccc1CCCCl

Procedure:
A solution of 155 g (0.75 mol) of 2-(3-chloropropyl)benzyl chloride 2 [Page, et al., J. Amer. Chem. Soc. 75:2053 (1953)], 91 g (0.81 mol) of 1,3-cyclohexanedione 1 [Aldrich Chem. Co. 10,160-5; Beilstein 7, 554], and 47 g of 85% KOH in 400 ml of methanol was refluxed 16 hours. After concentrating, the residue was partitioned between benzene and dilute aqueous NaOH solution. Acidification of the aqueous phase gave a solid that was recrystallized from ethyl acetate to give 34 g of the dione 3, mp 143°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Br[CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH:19]2[CH2:24][CH2:23][Si:22](C3C=CC=CC=3)([CH2:25][CH2:26][CH2:27][CH:28]([F:30])[CH3:29])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH2:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([C@H:19]3[CH2:20][CH2:21][Si@H:22]([CH2:25][CH2:26][CH2:27][CH:28]([F:30])[CH3:29])[CH2:23][CH2:24]3)[CH2:17][CH2:18]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: CC(F)CCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](CBr)CC2)CC1
Product: CC(F)CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](COc3cc(F)c(F)c(F)c3)CC2)CC1

Procedure:
The general procedure of Example 39 was repeated using 3,4,5-trifluorophenol and 4-(trans-4-bromomethylcyclohexyl)-I-phenyl-1-(4-fluoropentyl)-1-silacyclohexane thereby obtaining the intended product.
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:15])[C@H:11]\1[CH2:10][CH2:9][C@@H:8]2[C:12](=[O:14])[CH3:13].C[Si](C)(C)N[Si](C)(C)C.I[Si](C)(C)C.C(N(CC)CC)C.[Br-:37].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.O1CCCC1.C(OCC)C.C(=O)([O-])O.[Na+]>[Br:37][C@@:8]1([C:12](=[O:14])[CH3:13])[C@:7]2([CH3:15])[C@H:11](/[C:3](=[CH:2]/[Br:1])/[CH2:4][CH2:5][CH2:6]2)[CH2:10][CH2:9]1
Reactant: CC(=O)[C@H]1CC[C@H]2/C(=C/Br)CCC[C@]12C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)I
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)[C@@]1(Br)CC[C@H]2/C(=C/Br)CCC[C@@]21C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
1-{(E,3S,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-1H-indene-3-yl}ethanone (Compound 11: 100 mg, 0.369 mmol) was dissolved in methylene chloride (400 μl), and hexamethyldisilazane (160 μl, 0.758 mmol) and iodotrimethylsilane (80 μl, 0.562 mmol) were added thereto at −20° C., followed by stirring the resulting mixture for 10 minutes. The mixture was warmed to room temperature and stirred for another 100 minutes. The solvent was removed by evaporator, and the residue was dissolved in hexane. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution and the resulting mixture was extracted with hexane. The combined organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated to obtain a crude product of silylenol ether (143 mg). The obtained crude product was dissolved in tetrahydrofuran (700 μl), and a solution of triethylamine (50 μl, 0.359 mmol) and tetra-n-butylammonium tribromide (179 mg, 0.371 mmol) in tetrahydrofuran (400 μl) was added thereto at 0° C. After stirring the resulting mixture for 15 minutes, the mixture was warmed to room temperature and stirred for another 1 hour. The reaction solution was diluted with diethyl ether, and saturated aqueous sodium hydrogen carbonate was added thereto. The aqueous layer was extracted with diethyl ether. The combined organic layer was washed with aqueous sodium thiosulfate solution, aqueous potassium hydrogen sulfate solution and with saturated brine, and dried over sodium sulfate, followed by evaporation to obtain a crude product. The product was purified by flash column chromatography to obtain 1-{(E,1R,3aS,7aS)-1-bromo-4-(bromomethylene)-octahydro-7a-methyl-1H-indene-1-yl}ethanone as a white solid (99.2 mg, 76.9%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1.[NH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[NH2:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1
Reactant: CCOC(=O)c1cn2nc(I)ccc2n1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2nc(Oc3cccc(N)c3)ccc2n1
Temperature: 150 °C
Reaction time: 6 h
Yield: 39.1 %

Procedure:
A mixture of ethyl 6-iodoimidazo[1,2-b]pyridazine-2-carboxylate (951 mg, 3.00 mmol), 3-aminophenol (655 mg, 6.00 mmol), potassium carbonate (622 mg, 4.50 mmol) and N,N-dimethylformamide (9.0 mL) was stirred at 150° C. for 6 hr. After allowing the reaction mixture to cool to room temperature, ethyl acetate and water were added to the mixture and the insoluble material was filtered through celite. The organic layer was collected from the filtrate, washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/19→ethyl acetate alone) to give the title compound (350 mg, 39%).
Reaction SMILES: [ClH:1].Cl.FC1C=C(NC(NC(=O)CC2C=CC(F)=CC=2)=S)C=CC=1OC1C2=C(C)C(O[CH2:21][CH2:22][N:23]3[CH2:28]CN(C)C[CH2:24]3)=CN2N=CN=1.Cl.[F:46][C:47]1[CH:48]=[C:49]([NH:73][C:74](=[O:86])[CH2:75][C:76]([NH:78][C:79]2C=CC(F)=[CH:81][CH:80]=2)=O)[CH:50]=[CH:51][C:52]=1[O:53][C:54]1[C:59]2=[C:60]([CH3:72])[C:61]([O:63][CH2:64]CN3CCOCC3)=[CH:62][N:58]2[N:57]=[CH:56][N:55]=1>>[ClH:1].[ClH:1].[CH3:24][N:23]([CH3:28])[CH2:22][CH2:21][CH2:64][O:63][C:61]1[C:60]([CH3:72])=[C:59]2[N:58]([CH:62]=1)[N:57]=[CH:56][N:55]=[C:54]2[O:53][C:52]1[CH:51]=[CH:50][C:49]([NH:73][C:74](=[O:86])[C:75]2[CH:81]=[CH:80][CH:79]=[N:78][CH:76]=2)=[CH:48][C:47]=1[F:46]
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCCN(C)C)cn2ncnc(Oc3ccc(NC(=O)c4cccnc4)cc3F)c12
Yield: 11 %

Procedure:
4-(6-(3-(Dimethylamino)propoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)-3-fluorobenzenamine (54 mg, 0.15 mmol, Compound B of Example 32) as converted to the title compound (8.7 mg, 11 %) in a manner similar to the preparation of Compound D of Example 36. 1H NMR (CD3OD) δ 9.47 (s, 1H), 9.20-9.19 (m, 1H), 9.08-9.07 (m, 1H), 8.30-8.27 (m, 1H), 7.97-7.93 (m, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.64-7.61 (m, 1H), 7.43-7.39 (m, 1H), 4.26-4.11 (m, 2H), 3.43-3.39 (m, 2H), 2.98 (s, 6H), 2.46 (s, 3H), 2.34-2.30 (m, 2H); HRMS(ESI), 463.1894 (M−H)− calc, 463.1905 (M−H)− found.
Reaction SMILES: [NH2:1]C1C=CC=CC=1.[CH3:8][S:9][CH2:10][CH2:11][O:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].N([O-])=O.[Na+].O.O.Cl[Sn]Cl.[OH-].[Na+]>O.Cl.CCOCC.C(O)(=O)C>[CH3:8][S:9][CH2:10][CH2:11][O:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][NH2:1]
Reactant: CSCCOc1ccccc1N
Reactant: Nc1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CSCCOc1ccccc1NN
Reaction time: 4 h

Procedure:
27.4 g of the aniline obtained under (b) are placed into 45 ml of glacial acetic acid and, with ice cooling, a mixture of 37 ml of concentrated HCl and 75 ml of H2O is added. The formed suspension is diazotised at 0°-5° C. with 10.3 g of NaNO2 in 22 ml of water. The diazonium solution is subsequently stirred at 0° C. for 10 minutes, and a solution of 80.7 g of SnCl2.2H2O in 112 ml of concentrated HCl is then quickly added with cooling. After 4 hours, water is added to the reaction mixture, and extraction is repeatedly performed with ether. The aqueous phase is afterwards rendered alkaline with a 10% aqueous sodium hydroxide solution, and extracted three times with ether. After customary further processing of the ether phases, there is obtained the compound of the formula ##STR61## having a melting point of 72.5°-74.5° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Br)=[O:7].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:7])[CH:9]=[CH:10][CH:11]=1
Reactant: C1CCNCC1
Reactant: O=C(Br)c1cccc(CBr)c1
Solvent: c1ccccc1
Product: O=C(c1cccc(CBr)c1)N1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
Into a 25 mL round bottom flask was added 3-bromomethyl-benzoyl bromide (1.39 g, 5 mmol) and benzene (5 mL). The flask was cooled to 0° C. with an ice bath and piperidine (852 mg, 2 eq) in benzene (3.3 mL) was added slowly. The reaction was stirred at 0° C. for three hours. The precipitate was removed by filtration on a Buchner funnel. The filtrate was concentrated to an oil which was purified by column chromatography with 20% ethyl acetate in hexanes to give the titled compound as a clear oil (578 mg, 41% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C[Sn](C)(C)[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][N:36]=1)[C:32]#[N:33]>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.CN(C=O)C>[NH2:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[C:31]([CH:34]=[CH:35][N:36]=3)[C:32]#[N:33])[CH:7]=[CH:6][CH:5]=2)([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[N:9]=1
Reactant: C[Sn](C)(C)c1cc(C#N)ccn1
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(C2(c3cccc(-c4cc(C#N)ccn4)c3)N=C(N)c3c(F)cccc32)ccn1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 8.4 %

Procedure:
1-(3-Bromophenyl)-4-fluoro-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine (0.200 g, 0.49 mmol), 2-(trimethylstannyl)isonicotinonitrile (0.194 g, 0.73 mmol), tetrakis(triphenylphosphine)palladium(0) (0.056 g, 0.05 mmol) and DMF (4 mL) were put in a microwave vial and heated in a microwave reactor at 110° C. for 20 min, then at 150° C. for 20 min. The reaction mixture was filtered through a syringe filter and purified by preparative HPLC. The desired fractions were pooled and concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (sat.) and ethyl acetate. The aqueous layer was extracted with EtOAc (×2), the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.018 g, 9%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.86 (dd, 1 H) 8.40 (t, 1 H) 8.11-8.15 (m, 1 H) 8.04 (d, 1 H) 8.01 (ddd, 1 H) 7.78-7.81 (m, 1 H) 7.66 (d, 1 H) 7.51-7.57 (m, 1 H) 7.42-7.47 (m, 2 H) 7.24-7.31 (m, 1 H) 6.88 (dd, 1 H) 6.59-6.71 (m, 3 H) 3.79 (s, 3 H); MS (ES+) m/z 436 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].O.[NH2:23][NH2:24]>CCO>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:23][NH2:24])=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(C#N)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
To a suspension of methyl 4-[(4-cyanobenzoyl)amino]benzoate (680 mg, 2.43 mmol) in EtOH (8 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (1×2 mL) and water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 432 mg of the title compound (64%) as a pale yellow solid in 94.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: FC1C=CC(CC(N2CCN([CH:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=4)[CH2:20][CH2:19][CH2:18]3)CC2)=O)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH2:35].[OH-].[Na+]>C1COCC1>[OH:35][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: O
Reactant: COc1ccc2c(c1)C(N1CCN(C(=O)Cc3ccc(F)cc3)CC1)CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)CCC2

Procedure:
1-[4-(4-Fluorophenylacetyl)piperazin-1-yl]-7-methoxy-1,2,3,4-tetrahydronaphthalene (0.41 g) and lithium aluminum hydride (0.05 g) were heated under reflux in THF (15 ml) for 6 hr. Next, the reaction solution was cooled and water (50 ml) a 5 N aqueous solution (50 ml) of sodium hydroxide and further water (150 ml) were successively added thereto. After stirring the resultant mixture at room temperature for 1 hr, the resulting precipitate was filtered through celite and washed with THF. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (toluene/acetone system) to give the title compound (0.38 g) as an oil.