Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[CH2:15]2)[C:10](O)([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[FH:40].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O.ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[CH2:15]2)[C:10]([F:40])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(O)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 41 °C
Reaction time: 16 h

Procedure:
A mixture of 6.90 g (13.07 mmol) of 3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}(4 chlorophenyl)methyl]benzonitrile, 50 mL of hydrogen fluoride pyridine (HF 70%), and 60 mL of 1,2-dichloroethane was stirred at 40-42° C. for 16 h. Then the reaction mixture was poured slowly to a mixture of 250 mL of water, 74 g of NaOH, 300 mL of aq NaHCO3, 300 g of ice and 500 mL of CH2Cl2 with rapid stirring. The pH of the mixture was adjusted to 7-8, and the mixture was filtered to remove solids. The aqueous layer was extracted with three 300 mL portions of CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexane/ethyl acetate to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.25 (t, 6H, J=11.8 Hz), 2.32(t, 1H, J=7.5 Hz), 2.83-2.89(m, 2H), 3.09-3.17(m, 2H), 3.59 (m, 1H), 4.26(s, 1H), 6.85 (d, 1H, J=9.1 Hz), 7.10-7.14(m, 2H), 7.28-7.33 (m, 4H), 7.36 (t, 1H, J=7.2 Hz), 7.46 (d, 1H, J=7.8 Hz), 7.56 (d, 1H, J=7.7 Hz), 7.67 (s, 1H); Mass Spectrum: m/e=529, (M+1, 35Cl 79Br), 531 (M+1, 37Cl79Br/35Cl 81Br), 533 (M+1, 37Cl81Br).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].[CH2:7]([Mg]Br)[CH2:8][CH2:9][CH3:10].P([O-])([O-])([O-])=O>O1CCCC1>[CH2:2]([C:8]([CH:9]=[CH2:10])=[CH2:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[Mg]Br
Reactant: C=CC=CCBr
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C=CC(=C)CCCCC
Reaction time: 4 h

Procedure:
n-bromosuccinimide (5.34 g) is added to a solution of isoprene (2.45 g) in carbon tetrachloride (100 ml), and the solution is stirred for 24 hours. The product and solvent are then fractionally distilled away from the succinimide, resulting in a partially concentrated solution of c-bromomethylbutadiene. The bromomethylbutadiene solution is chilled (-20° C.), and a 2N tetrahydrofuran solution of butylmagnesium bromide (15 ml) is then added. After stirring for 4 hours, the solution is treated with a 1 M phosphate buffer solution (pH 7). The organic layer is dried over sodium sulfate, and the reaction mixture is fractionally distilled to produce the product, 2-pentyl-1,3-butadiene, as a non-viscous liquid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].P([O-])([O-])([O-])=O>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To 1 of an aqueous solution containing glucose, MgSO4.7H2O and phosphate buffer at a concentration of 0.1 M, 0.005 and 0.05 M, respectively, is added a given amount of insolubilized glucose isomerase and the mixture thus obtained is slowly stirred at a temperature of 70° C. for 60 minutes to effect the conversion. Then, the insolubilized isomerase is separated from the reacted solution and the amount of fructose so produced is determined according to the cystein carbazol method. The activity is calculated as in 3 above.
Reaction SMILES: I[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1.CN(C)CC(O)=O.C([O-])([O-])=O.[K+].[K+].[F:42][C:43]([F:54])([F:53])[C:44]1[C:52]2[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=2[NH:46][N:45]=1>CS(C)=O.CCOC(C)=O.[Cu]I>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([C@:13]23[CH2:14][C@H:15]2[CH2:16][N:11]([CH2:10][CH2:9][CH2:8][N:6]2[CH:7]=[C:2]([N:46]4[C:47]5[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=5[C:44]([C:43]([F:42])([F:54])[F:53])=[N:45]4)[C:3](=[O:28])[NH:4][C:5]2=[O:27])[CH2:12]3)=[CH:18][CH:19]=1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-n1nc(C(F)(F)F)c2c1CCCC2
Temperature: 150 °C
Reaction time: 18 h
Yield: 4.99 %

Procedure:
5-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione (Prep10, 150 mg, 0.282 mmol), copper (1+) iodide (59.1 mg, 0.310 mmol), N,N-dimethylglycine (32.0 mg, 0.310 mmol) and K2CO3 (86 mg, 0.620 mmol) were dissolved in Dimethyl Sulfoxide (DMSO) (2 ml) to give a light blue solution with a white precipitate. To this mixture, 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (commercially available from ABCR, 177 mg, 0.931 mmol) was added. After 18 h shaking at 150° C., the reaction mixture was diluted with EtOAc (5 ml) and the organic phase was washed with water (4×10 ml), then brine (5 ml), dried over Na2SO4, then filtered and the solvent evaporated. The obtained crude was passed through an SCX cartridge and eluted with 2M solution of ammonia in MeOH. The obtained mixture was iteratively purified (two times) by preparative LC-MS. The obtained fraction was passed through an SCX cartridge and eluted with 2M solution of ammonia in MeOH. 9.4 mg (4.99% yield) of the title compound were obtained.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH2:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:1][C:2]#[CH:3])[CH2:9][CH2:8]1)[CH3:6]
Reactant: C#CCBr
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CCN(CC)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Propargyl bromide (20.8 g, 175 mmol) was added dropwise to a mixture of 1-ethyl piperazine (20 g, 175 mmol) and cesium carbonate (57 g, 175 mmol) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered off, and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were then evaporated to give 19 g of 1-ethyl-4-prop-2-ynyl-piperazine: mass spectrum (m/e): M+H 153.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21].Cl>>[OH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([B:17]([OH:18])[OH:19])=[CH:13][C:12]=1[C:20]([F:23])([F:21])[F:22]
Reactant: OB(O)c1ccc(OCCOC2CCCCO2)c(C(F)(F)F)c1
Agent: Cl
Product: OCCOc1ccc(B(O)O)cc1C(F)(F)F
Temperature: 60 °C

Procedure:
4-(2-(Tetrahydro-2H-pyran-2-yloxy)ethoxy)-3-(trifluoromethyl)phenylboronic acid (8 g) was added to hydrochloric acid (1M in MeOH) and the mixture was heated at 60° C. for 60 minutes. Solvent and HCl was then removed under reduced pressure and residue (5.52 g) was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][N:17]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cn3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Absolute ethanol was degassed by applying a vacuum while simultaneously bubbling nitrogen through it. A solution of 188 mg (0.5201 mmol) ethyl 6-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronapth-2-yl)ethynyl]-nicotinoate in 2 ml absolute ethanol was treated with 800 ml of a 1.65M (1.32 mmol) solution of potassium hydroxide in ethanol and water. The mixture was stirred at room temperature for 18 hours and then the solvent removed in vacuo. The residue was dissolved in water and extracted with 50 ml ether, which was discarded. The aqueous layer was then acidified with glacial acetic acid and extracted with 4×50 ml ether. The ether extracts were combined, washed with water, saturated NaCl solution and then dried (MgSO4). Solvent was removed in vacuo to give the title compound as a pale yellow solid. PMR (CDCl3): δ 1.31 (12H, s), 1.71(4H, s), 7.34 (1H, d, J~7.8 Hz), 7.40 (1H, d, J~7.8 Hz), 7.62 (1H, s), 8.39 (1H, dd, J~7.3 Hz, 2.1 Hz), 9.33 (1H, d, J~2.1 Hz).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:35]=[CH:34][C:10]([C:11]([NH:13][NH:14][C:15]([C:17]2[O:18][CH:19]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:16])=[O:12])=[CH:9][C:8]=1[NH:36][S:37]([CH3:40])(=[O:39])=[O:38].[OH-].[Na+].Cl>C(Cl)(Cl)Cl.ClCCl>[OH:6][C:7]1[CH:35]=[CH:34][C:10]([C:11]([NH:13][NH:14][C:15]([C:17]2[O:18][CH:19]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])=[O:12])=[CH:9][C:8]=1[NH:36][S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1NS(C)(=O)=O
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
Boron tribromide (1 M dichloromethane solution; 5.10 ml) was added to a dichloromethane (10 ml) solution of the compound of Example 70 (0.86 g) at 0° C. and stirred at 25° C. for 3 hours. The reaction solution was mixed with 2 M aqueous sodium hydroxide solution, stirred for 0.3 hours, and mixed with 2 M hydrochloric acid and chloroform. The organic layer was washed with saturated brine and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0→15% methanol/chloroform gradient) and recrystallized from isopropyl alcohol, thereby giving 0.29 g of the desired compound. Melting point: 230-231° C.
Reaction SMILES: [OH:1][C@@:2]12[CH2:19][C@@H:18]([O:20]C(=O)C(C)(C)C)[CH2:17][CH2:16][C@:15]1([CH3:27])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C:9](=[O:28])[C@H:8]1[CH2:29][C@@H:7]31)[CH:4]=[CH:3]2.[OH-].[K+].Cl([O-])(=O)(=O)=O.[Na+].S(=O)(=O)(O)O>O1CCCC1.O.CO>[OH:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:27])[C@:2]([OH:1])([CH:3]=[CH:4][C@@H:5]3[C@@H:14]2[CH2:13][CH2:12][C@@:10]2([CH3:11])[C@H:6]3[C@@H:7]3[CH2:29][C@@H:8]3[C:9]2=[O:28])[CH2:19]1
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3C=C[C@]2(O)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Reaction time: 2.5 h
Yield: 94.3 %

Procedure:
134 g of 5-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androst-6-en-17-one is dissolved in 1340 ml of tetrahydrofuran and 670 ml of methanol and combined in succession with 40 g of pulverized potassium hydroxide and 13 g of sodium perchlorate. After 2.5 hours, the mixture is stirred into 8 l of water, neutralized with 20% sulfuric acid, and the precipitated solid product is removed by filtration. After dissolving in methylene chloride and drying with sodium sulfate, the product is concentrated under vacuum. By trituration of the resultant solid compound with ethyl acetate, 99.8 g of 3β,5-dihydroxy-15β,16β-methylene-5β-androst-6-en-17-one is obtained, mp 196.5°-198° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:25])[CH3:24])([OH:16])=[O:15]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:24][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:14]([OH:16])=[O:15])=[O:25])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: O=C(O)c1ccccc1C(=O)C=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 8 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.64 g of 2'-carboxyacetophenone. Yield 0.36 g (11%), m.p. 178°-180° C.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[N:13]=[C:12](Cl)[C:11]=12)=[O:6])[CH3:3]>C(Cl)(Cl)Cl.C(O)C>[CH2:2]([O:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[N:13]=[C:12]([NH2:1])[C:11]=12)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1ncn2c1c(Cl)nc1cc(C(F)(F)F)ccc12
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ncn2c1c(N)nc1cc(C(F)(F)F)ccc12
Yield: 57 %

Procedure:
A small stream of anhydrous ammonia was passed through a solution of 4-chloro-7-trifluoromethylimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (5.4 g) in chloroform-ethanol (100 ml each) for 30 minutes. The precipitate was collected and recrystallized from DMF to give the product as an off-white crystalline solid (2.9 g, 57% yield), m.p. >300° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OCC)=O)[CH2:19][CH2:18]2)[N:3]=[CH:2]1.[BrH:28]>>[BrH:28].[BrH:28].[BrH:28].[NH:20]1[CH2:19][CH2:18][CH:17]([CH2:16][C:8]2[N:7]([CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH2:22][CH2:21]1
Reactant: CCOC(=O)N1CCC(Cc2nc3ccccc3n2Cc2cscn2)CC1
Agent: Br
Product: c1ccc2c(c1)nc(CC1CCNCC1)n2Cc1cscn1

Procedure:
A mixture of 2 parts of ethyl 4-[[1-(4-thiazolylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinecarboxylate and 30 parts of a hydrobromic acid solution 48% was stirred and refluxed for 15 minutes. The reaction mixture was evaporated. The oily residue was crystallized from a mixture of ethanol and 2-propanone, yielding 2 parts of 2-(4-piperidinylmethyl)-1-(4-thiazolylmethyl)-1H-benzimidazole trihydrobromide; mp. 208.3°-226.3° C. (72).
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([Cl:19])=[N:9][C:8]=1[CH3:20].CN([CH:24]=[O:25])C>C1COCC1>[Cl:19][C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7]([CH:24]=[O:25])=[C:8]([CH3:20])[N:9]=1
Reactant: COc1ccc2c(Cl)nc(C)c(Br)c2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(Cl)nc(C)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 72.4 %

Procedure:
n-BuLi (12 ml of 1.6 M in hexane) is added dropwise to a solution of 4-bromo-1-chloro-6-methoxy-3-methyl-isoquinoline (4.8 g, 17 mmol) in THF (60 ml) at −78° C. After stirring for 40 min, DMF (4 ml, 51 mmol) is added slowly. The reaction is allowed to warm to 0° C. and the stirring is continued for 1 h. The mixture is then quenched with 1N—HCl (30 ml) and extracted with EtOAc. The combined extracts are dried over Na2SO4 and evaporated. The residue is chromatographed on silica gel eluting with EtOAc/hexane (1:4) to give 2.9 g of 1-chloro-6-methoxy-3-methyl-isoquinoline-4-carbaldehyde. 1H NMR (CDCl3) 10.8 (s, 1H), 8.61 (s, 1H), 8.24 (d, 1H), 7.29 (d, 1H), 4.01 (s, 3H), 2.99 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3=[C:12]4[S:18][CH:17]=[CH:16][C:13]4=[N:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@H:19]([OH:21])[CH3:20])[CH2:3][CH2:2]1.[F:22][C:23]([F:29])([F:28])[CH2:24][CH2:25][CH2:26]O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>C(Cl)Cl.CN(C)C=O>[F:22][C:23]([F:29])([F:28])[CH2:24][CH2:25][CH2:26][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3=[C:12]4[S:18][CH:17]=[CH:16][C:13]4=[N:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@H:19]([OH:21])[CH3:20])[CH2:3][CH2:2]1
Reactant: OCCCC(F)(F)F
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(CCCC(F)(F)F)CC1
Reaction time: 8 h
Yield: 34.2 %

Procedure:
To a mixture of (1R)-1-(1-piperidin-4-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol (15.0 mg, 0.0496 mmol) and 4,4,4-trifluorobutanol (9.4 mg, 0.0744 mmol) in methylene chloride (0.3 mL) and N,N-dimethylformamide (0.2 mL) was added resin of tetramethylammonium triacetoxyborohydride (48.4 mg, 0.0992 mmol). The resulting mixture was stirred overnight. The mixture was filtered and concentrated then purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 7 mg (34%) of the desired product. LCMS calculated for C19H24F3N4OS (M+H)+: m/z=413.2. Found: 413.1. 1H NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 7.71-7.60 (m, 2H), 5.21 (s, 1H), 4.72-4.58 (m, 1H), 3.70-3.57 (m, 6H), 3.13 (d, J=9.8 Hz, 2H), 2.89-2.66 (m, 1H), 2.49 (t, J=6.9 Hz, 2H), 2.34-2.18 (m, 2H), 1.96 (s, 1H), 1.86-1.74 (m, 2H), 1.67 (s, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH2:24])=[N:20]1>>[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ccn(Cc2cccc(F)c2)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4cccc(F)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3-fluoro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a yellow oil (yield=73%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[CH2:8][C:9]3[CH:14]=[N:13][C:12](S(C)=O)=[N:11][C:10]=3[C:4]=2[CH:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[CH2:8][C:9]3[CH:14]=[N:13][C:12]([N:22]([CH3:21])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CS(=O)c1ncc2c(n1)-c1cc(Br)ccc1NC(=O)C2
Reactant: CNc1ccccc1
Solvent: O
Product: CN(c1ccccc1)c1ncc2c(n1)-c1cc(Br)ccc1NC(=O)C2
Temperature: 150 °C

Procedure:
A mixture of 10-bromo-2-methanesulfinyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (100 mg) was stirred with N-methyl aniline (1 mL) and refluxed overnight at 150° C. Water was added and the product was extracted with methylene chloride, dried over MgSO4, filtered and concentrated. Purification by C-18 RP LC-MS chromatography afforded I-85 (10%): MS m/z═395 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH2:14][C:11]3([O:13][CH2:12]3)[CH2:10][CH2:9]2)[CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:12][C:11]2([OH:13])[CH2:14][CH2:15][N:8]([C:4]3[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=3)[CH2:9][CH2:10]2)[C:25](=[O:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Clc1cc(N2CCC3(CC2)CO3)ncn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(CC2(O)CCN(c3cc(Cl)ncn3)CC2)C(=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 6-(6-chloropyrimidine-4-yl)-1-oxa-6-azaspiro[2,5]octane (4.00 g) and 4-(tert-butoxycarbonyl)-2-piperazinone (3.38 g) in tert-butylalcohol (50 ml) was added potassium tert-butoxide (0.57 g), and the mixture was stirred at 80° C. overnight. The reaction solution was concentrated, and the residue was diluted with ethyl acetate (100 ml), washed with 0.5N hydrochloric acid and saturated brine, dried and concentrated. The residue was purified with silica gel column chromatography (eluent: ethyl acetate) and crystallized from a mixture of ethyl acetate and diethylether to give colorless crystals of 4-(tert-butoxycarbonyl)-1-[1-(6-chloro-4-pyrimidinyl)-4-hydroxypiperidin-4-ylmethyl]piperazin-2-one (5.51 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:8]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:6].C(O)(=O)C.N([O-])=O.[Na+]>O>[CH2:5]([C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=[C:9]([CH2:13][CH3:14])[C:8]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:17])=[O:18])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc([N+](=O)[O-])cc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 115 ml nitric acid (d=1.42) in water (900 ml) are added successively 129.9 g (0.43 moles) of N-(2,6-diethylphenyl)-p-toluenesulfonamide, glacial acetic acid (900 ml) and sodium nitrite (3.2 g). The mixture is boiled on a steam bath for 1.5 hours, then poured into ice water (2 l). The precipitate is filtered, washed with water and air-dried to give crude N-(2,6-diethyl-4-nitrophenyl)-p-toluenesulfonamide.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:14](O)[CH2:15][OH:16].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:12][C:11]1([CH2:10][CH2:9][C:7]2[S:8][C:4]([C:1]([CH3:2])=[O:3])=[CH:5][CH:6]=2)[O:16][CH2:15][CH2:14][O:13]1
Reactant: CC(=O)CCc1ccc(C(C)=O)s1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Product: CC(=O)c1ccc(CCC2(C)OCCO2)s1

Procedure:
4-(5-Acetyl-2-thienyl)-2-butanone (Tetrahedron 35, 1979, 329) was reacted with ethylene glycol, triethyl orthoformate and p-toluenesulphonic acid in methylene chloride to give methyl 5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-2-thienyl ketone. Oxidation with sodium hypobromite and subsequent hydrolysis gave 5-(3-oxobutyl)-2-thiophenecarboxylic acid. With sodium borohydride there was obtained therefrom 5-(3-hydroxybutyl)-2-thiophenecarboxylic acid which was converted in dimethylacetamide with methyl iodide and sodium carbonate into the methyl ester. Treatment with p-toluenesulphochloride in pyridine and reaction with sodium azide in dimethyl sulphoxide gave methyl 5-(3-azidobutyl)-2-thiophenecarboxylate from which there was obtained by saponification the corresponding acid. The acid was treated with thionyl chloride to give the acid chloride from which there was obtained with concentrated ammonia in ether 5-(3-azidobutyl)-2-thiophenecarboxamide. Reduction of the azido group with triphenylphosphine and subsequent hydrolysis gave (RS)-5-(3-aminobutyl)-2-thiophenecarboxamide of melting point 65°-75°; ε256 =7780; ε275 =9900.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[C:16]([OH:20])(=[O:19])[CH:17]=O>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:17]2[C:16]([OH:20])=[O:19])([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: O=CC(=O)O
Product: O=C(O)C1Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Yield: 69 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with glyoxylic acid as described in Example 11 to give 1-nitro-5,6-dihydropyrazolo[1,5-c]quinazoline-5-carboxylic acid with a yield of 69%. M.p.: 203°-205° C.