Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=O.[Cl:8][C:9]1[C:10]([NH:15][NH2:16])=[N:11][CH:12]=[CH:13][CH:14]=1>>[F:1][C:2]([F:7])([F:6])[C:3](=[N:16][N:15]=[C:10]1[C:9]([Cl:8])=[CH:14][CH:13]=[CH:12][NH:11]1)[CH3:5]
Reactant: CC(=O)C(F)(F)F
Reactant: NNc1ncccc1Cl
Product: CC(=NN=c1[nH]cccc1Cl)C(F)(F)F
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
1,1,1-Trifluoroacetone (7.80 g, 69.6 mmol) was added to (3-chloro-pyridin-2-yl)-hydrazine (10 g, 69.7 mmol) at 20–25° C. After the addition was complete, the mixture was stirred for about 10 minutes. The solvent was removed under reduced pressure, and the mixture was partitioned between ethyl acetate (100 mL) and saturated sodium carbonate solution (100 mL). The organic layer was dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate) gave the product as an off-white solid (11 g, 66% yield), m.p. 64–64.5° C. (after crystallization from ethyl acetate/hexanes).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH3:11])[CH3:2].[Se](=O)=[O:14]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]=[O:14])[CH3:2]
Reactant: CCOC(=O)c1cccnc1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1C=O
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A mixture of 11.3 g (0.069 mol) of 2-methyl-nicotinic acid ethyl ester and 8.4 g (0.076 mol) of selenium dioxide in 150 mL of dioxane is refluxed under nitrogen for 4 hours. The reaction mixture is cooled to room temperature and filtered. The filtrate is evaporated and the residue is chromatographed on 400 grams of silica gel using 50/50 ethyl acetate/hexanes as the eluant. Appropriate fractions are combined to yield 5 g of 2-formyl-nicotinic acid ethyl ester. 1H NMR (CDCl3) δ 10.3 (s, 1H), 8.8 (m, 1H), 8.0 (m, 1H), 7.5 (m, 1H), 4.30 (q, 2H), 1.4 (t, 3H). TLC (7/3 hexanes/ethyl acetate) Rf=0.2. Step 2:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([O-:19])=[O:18])=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[C:6]([F:8])[CH:7]=1.[Li+].[OH-]>>[NH2:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Yield: 79 %

Procedure:
Method 2 was followed using 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinate (1.0 equiv.) and LiOH (1.0 equiv.) to give 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid in 79% yield. LC/MS=269.0 (M+H), Rt=0.79 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.O.O.O.O.O.[OH-].C[N+](C)(C)C.Br[CH2:34][CH2:35][OH:36].Cl>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:34][CH2:35][OH:36])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Reactant: OCCBr
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Temperature: 50 °C
Yield: 95.7 %

Procedure:
To 4-(6-chloro-2,3-dihydro-indol-1-yl)-quinazolin-7-ol (125 mg, 0.42 mmol; from Example 65) in DMF (2 mL) was added H2O (50 μL), K2 CO3 (s) (116 mg, 0.84 mmol), and tetramethylammonium hydroxide pentahydrate (15 mg, 0.08 mmol) followed by 2-bromoethanol (39 μL, 0.46 mmol). The mixture was stirred at 50° C. under N2(g) and aliquots of 2-bromoethanol (3×20 μL) were added at 24 hour invervals. Extractive workup and chromatography analogous to that described in Example 1 followed by conversion to the HCl salt as outlined for Example 2 afforded 76 mg (53%) of product. (M.P. 215°-217° C.; LC-MS: 342 (MH+); anal. RP18-HPLC RT: 4.09 min.).
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>CC(O)C>[C:6]1([C@H:3]([OH:5])[CH3:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C[C@@H](O)c1ccccc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Into a pressure-resistant vessel was placed 11.1 mg (0.012 mmol) of RuCl2(DPEphos){(S,S)-DPEN} synthesized in Example 4, and then thereto were added 48 μl (0.024 mmol) of a 0.5M solution of potassium hydroxide in 2-propanol and 3.3 ml of 2-propanol. Under an argon atmosphere, the solution was stirred for 30 minutes. Thereafter, 350 μl (3.0 mmol) of acetophenone was added thereto, and then the solution was stirred under hydrogen atmosphere of 0.8 MPa (8 atm) for 4 hours to give (1R)-1-phenylethanol, which is an alcohol reductant of acetophenone, in a GC yield of not less than 99% and an asymmetric yield of 91% ee.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:16])[CH3:15])=[CH:12][CH:13]=2)[C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[CH:20][CH:19]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(=O)c1ccc(Nc2cncnc2)cc1
Product: CC(=O)c1ccc(N(Cc2ccc(Br)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 4'-[N-(pyrimidin-5-yl)amino]acetophenone and 4-bromobenzyl bromide
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=[O:2].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[CH:1]([NH:3][C:4]1[S:5][C:6]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=[O:2]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3cnc(NC=O)s3)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3cnc(NC=O)s3)[C@H]2SC1
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
A solution of benzhydryl 7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer)(2.7 g) in anisole (3.5 ml) and trifluoroacetic acid (10.8 ml) was stirred under ice-cooling for 15 minutes. The reaction mixture was poured into diisopropyl ether (140 ml), followed by stirring for 10 minutes. The precipitated solid was collected by filtration, washed with diisopropyl ether and then dried to give 7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer)(2.0 g), mp 147° C. (dec.).
Reaction SMILES: C1C=C2C=C[C:9](O)=[C:10]([C:11]3C4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][C:12]=3[OH:21])C2=CC=1.C([Sn](CCCC)(CCCC)CCCC)C=C.C(=O)CCCCCCC>>[CH2:9]=[CH:10][CH2:11][C@@H:12]([OH:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: CCCCCCCC=O
Product: C=CC[C@@H](O)CCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 188.2 %

Procedure:
To a flame dried flask under a N2 atmosphere was added 5.0 g of 4 Å molecular sieves and 100 mL of anhydrous CH2Cl2, followed by 1.9 g (7.8 mmol) of TiCl2(i-PrO)2 and 2.2 g (7.8 mmol) of (R)-(+)-1,1′-bi-2-naphthol. The solution immediately turned red and was stirred at room temperature for 2 h. To this solution was added 17.9 mL (58.3 mmol) of allyltributyltin. The reaction was cooled to −20° C. and 5.0 g (39.0 mmol) of octanal was added. The solution was allowed to stir for 48 h at −20° C. The solution was filtered through a plug of Celite and the solvent was removed under reduced pressure. The remaining residue was purified by flash chromatography eluting with 1:9 EtOAc-hexanes to give 2.5 g (38%) of allylic alcohol 27. 1H NMR (400 MHz, CDCl3) δ 5.85-5.75 (m, 1H), 5.11-5.07 (m, 2H), 3.60 (m, 1H), 2.29-2.22 (m, 1H), 2.14-2.07 (m, 1H), 1.91 (br s, 1H), 1.44-1.41 (m, 2H), 1.32-1.22 (m, 10H), 0.85 (t, J=6.5 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 133.6, 116.8, 70.8, 42.6, 37.6, 32.8, 30.6, 30.3, 26.7, 23.8, 15.4. [α]23 (c 1.04, CHCl3)=−7.7; lit. [α]25 (c 1.04, CHCl3)=−6.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.[Mg].Br[CH:17]([CH3:21])[C:18]([O-:20])=[O:19].[Na+].S(=O)(=O)(O)O>O1CCCC1.O>[F:14][C:4]1[CH:3]=[C:2]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CC(Br)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Mg]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
A solution of 4-bromo-2-fluorobiphenyl (2.51g;0.01 mole) in dry tetrahydrofuran (15ml) was aded dropwise, with stirring, to magnesium turnings (0.25g;0.0103g. atom) under a nitrogen atomosphere. When the addition was complete, the mixture was stirred and boiled under reflux for 30 minutes. The mixture was then cooled and a suspension of sodium 2-bromopropionate (1.75g;0.01 mole) in dry tetrahydrofuran (20ml) was added. Frothing occurred and when this had subsided the mixture was boiled under reflux with stirring, for one hour. The mixture was then cooled in an ice-bath and water (15ml) was added, followed by sulphuric acid (20%;5ml). The mixture was stirred for 10-15 minutes, and extracted with ether. The extract was washed with water and then extracted with aqueous potassium carbonate (1N). This extract was washed with ether and then added to a mixture of concentrated hydrochloric acid (10ml) and water (20ml). The mixture was cooled overnight and the precipitate filtered, washed with water and dried in vacuo to give 2 -(2-fluoro-4-biphenylyl)propionic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[OH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([CH3:36])[CH:28]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:31]([C:30]4[CH:34]=[CH:35][C:27]([OH:26])=[CH:28][C:29]=4[CH3:36])=[O:32])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1cc(O)ccc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(O)cc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-hydroxy-2-methylbenzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH2:20])=[C:6]([CH:21]([CH3:23])[CH3:22])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH3:20])=[C:6]([CH:21]([CH3:22])[CH3:23])[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6dusopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5ethenylpyridine (Example 22) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.15 (m, 4 H), 4.33 (d, J=3.6 Hz, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.26 (sept, J=6.6 Hz, 1 H), 2.34 (q, J=7.35 Hz, 2 H), 1.33 (d, J=6.6 Hz, 6 H), 1.31 (d, J=6.6 Hz, 6 H), 1.19 (m, 1 H), 0.93 (t, J=7.35 Hz, 3 H). FAB-MS: calculated for (C20H26FNO) 315, found 316 (M+H). Anal. Caled for C20H26FNO: C, 76.16; H, 8.31; N, 4.44. Found: C, 75.74; H, 8.50; N, 4.27. mp 126-129° C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=C)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C[O:34]CC1.C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[O:34])=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred mixture of 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (7A, 1.96 g, 4.80 mmol) and THF (20 mL) were added NMO (50% in water, 1.493 mL, 7.20 mmol) and osmium tetroxide (4% in water, 1.173 mL, 0.192 mmol) at room temperature. The mixture was vigorously stirred at room temperature overnight. A solution of sodium periodate (1.540 g, 7.20 mmol) in water (10 mL) was added. The mixture was stirred at room temperature under nitrogen for 30 min. Water (20 mL) was then added. The solid was filtered, washed with water (2×5 mL) and ethanol (2 mL) and dried to give 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (1.92 g, 4.68 mmol, 98%) as a white solid. The compound had an HPLC retention time=3.95 min (condition C); LC/MS M+1=410.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:18]1[O:19][C:20]([C:23](OC)=[O:24])=[CH:21][CH:22]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[C:18]1[O:19][C:20]([CH2:23][OH:24])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccc(N)cc23)o1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)c(-c1ccc(CO)o1)nn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 80 mg (0.23 mmol) of 5-amino-I-benzyl-3-(5-methoxycarbonyl-2-furyl)indazole in 5 ml of THF was added dropwise to 0.01 g (0.3 mmol) of lithium aluminum hydride in 5 ml of THF, and the mixture was stirred at RT. After 3 h, 10 ml of a 25% strength K2CO3 solution were added and stirring was continued for 30 min. The precipitate was filtered off with suction and extracted with boiling THF, the combined organic phases were dried and concentrated and the residue was chromatographed over silica gel using 95:5 dichloromethane/methanol. This gave 21 mg (29%) of the title compound. m.p.: 156° C.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([NH:5][C:6]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)=[N:7]2)=[N:3][CH:2]=1>C(O)C.O1CCCC1.[Ni]>[N:1]1[CH:9]=[C:8]2[C:4]([NH:5][C:6]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)=[N:7]2)=[N:3][CH:2]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cncnc2[nH]1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3nc4cncnc4[nH]3)cccc21
Reaction time: 20 h
Yield: 89.3 %

Procedure:
The procedure used in Example 6 is followed, in an autoclave, starting from 450 mg of 4-(9H-purin-8-yl)fluoren-9-one oxime (Z,E), obtained in the previous stage, in solution in a mixture of 25 ml of ethanol and 25 ml of tetrahydrofuran, in the presence of Raney activated nickel, under an initial hydrogen pressure of 1 bar, at 600 for 20 hours. After filtration of the catalyst over Celite, and concentration of the filtrate under reduced pressure, in this way, we obtain 384 mg of 4-(9H-purin-8-yl)-9H-fluorene-9(R,S)-amine, in the form of a beige powder with the following characteristics:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[CH:17]1([CH:22]=[CH:23][CH:24]([CH3:31])[CH2:25][C:26](OCC)=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[CH:17]1([CH:22]=[CH:23][CH:24]([CH3:31])[CH2:25][CH:26]=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CC(C)C=CC1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CCO
Product: CC(C=CC1CCCC1)CC=O
Temperature: 0 °C
Yield: 69 %

Procedure:
Diisobutylaluminum hydride (95 ml of 1.0 M solution in hexane) was added into a hexane (200 ml) solution of ethyl 5-cyclopentyl-3-methylpent-4-enoate (used in example 1; 20.0 g; 95 mmol), at −65° C. After 3 hours stirring at the same temperature, ethanol (3 ml) was added, and the reaction mixture was poured into an ice-cold NH4Cl solution (200 ml) and diluted with 2 NHCl (100 ml). The organic layer was separated, washed with brine (3×200 ml), dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (hexane/MTBE 15:1) to give 10.9 g (69% yield) of 5-cyclopentyl-3-methylpent-4-enal.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O-2].[Mg+2].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18]>O.C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][S:13]([C:11]1[S:12][C:8]([Cl:7])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: NCCO
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(S(=O)(=O)NCCO)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a stirred solution of ethanolamine (0.67 g, 11 mmol) in water (4 ml) was added at room temperature magnesium oxide (2.22 g, 55 mmol) and THF (12 ml). The suspension was stirred at room temperature for 30 min and a solution of 5-chloro-4-nitrothiophene-2-sulfonyl chloride (3.46 g, 13.2 mmol) in THF (4 ml) was added. The light yellow suspension was stirred at room temperature for 1 h and, after filtration on Dicalit, evaporated. Water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and subsequent crystallization from ethyl acetate/hexane to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (1.39 g, 44%) as a yellow solid. MS (ISP) 284.8 [(M−H)−], mp 99° C.
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[CH:19]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[N:28]=[N:29][C:30](Cl)=[CH:31][CH:32]=2)=[O:26])[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O1CCOCC1>[CH:19]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[N:28]=[N:29][C:30]([N:16]3[CH2:17][CH2:18][CH:13]([N:2]([CH3:1])[C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:9]([F:12])([F:11])[F:10])[CH2:14][CH2:15]3)=[CH:31][CH:32]=2)=[O:26])[CH2:21][CH2:20]1
Reactant: CN(c1ccccc1C(F)(F)F)C1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1COCCO1
Product: CN(c1ccccc1C(F)(F)F)C1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1
Yield: 60 %

Procedure:
A mixture of methylpiperidin-4-yl-(2-trifluoromethylphenyl)amine (0.130 g, 0.500 mmol), 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.113 g, 0.500 mmol), K2CO3 (0.100 g, 0.720 mmol) and n-Bu4NI (10 mg) in dioxane (10 mL) was heated to reflux overnight, then concentrated and purified by column chromatography to afford the title compound in 60% yield (0.147 g). 1H NMR (300 MHz, CDCl3) δ 8.30-8.26 (m, 1H), 8.10-7.95 (m, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.55-7.34 (m, 2H), 7.28 (d, J=7.8 Hz, 1H), 4.51 (s, br, 2H), 3.83-3.28 (m, 5H), 2.67 (s, 3H), 2.07-1.98 (m, 2H), 1.77 (s, br, 2H), 1.51-1.44 (m, 2H), 0.68-0.66 (m, 1H), 0.47-0.38 (m, 2H), 0.07-0.03 (m, 2H). MS (ES+) m/z 448.4 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:19][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)=[N+]=[N-].[H][H]>CN(C)C=O.[Pd]>[NH2:1][CH2:4][CH:5]1[O:19][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN=[N+]=[N-])C2
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Yield: 102.6 %

Procedure:
2-Azidomethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (759 mg) was dissolved in dimethylformamide (20 ml). To the solution, 10% palladium-on-carbon (455 mg) was added, and the solution was hydrogenated in the atmosphere of hydrogen at ambient temperature and under atmospheric pressure. After completion of the reaction, the catalyst was filtered off. When the solvent was evaporated, 0.7 g of the title compound was obtained as a crude product. This product was purified by silica gel column chromatography to obtain 409 mg of a free base (60.0%). The obtained free base was converted into a hydrochloric acid salt, followed by recrystallizing from a solvent mixture of methanol-diethylether, obtaining yellow powdery crystals having a melting point over 300° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:5]1=[O:24])(=O)C.[CH3:25][N:26]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:27].[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:26]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:24])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:34][CH:35]=1)[CH3:25]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-nitrophenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[CH:9][CH:10]=1)[C:5]([O:7][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:6]
Reactant: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of Example 104B (10 g, 30.3 mmol), potassium carbonate (6.3 g, 45.4 mmol), and DMF (300 mL) was treated with benzyl bromide (3.6 mL, 30.3 mmol), stirred for 5 hours, concentrated, and partitioned between water (1 L) and ethyl acetate (1 L). The organic layer was washed with water (2×1 L) and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 420, 422 (M+H)+, 437, 439 (M+NH4)+, 442, 444 (M+Na)+; (ESI(−)) m/e 418, 420 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.65 (d, 1H), 7.45 (m, 2H), 7.37 (m, 3H), 7.22 (d, 1H), 5.28 (s, 2H), 2.30 (s, 3H), 1.42 (s, 9H).