Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].CN[CH:27]1[CH2:29][CH2:28]1.[CH3:30][N:31](C=O)C>>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:31][CH2:30][CH:27]2[CH2:28][CH2:29]2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: CN(C)C=O
Reactant: CNC1CC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NCC1CC1

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.85 g (0.026 mol) of N-methylcyclopropylamine (60% pure) in 30 ml of DMF were reacted at room temperature affording 4.3 g of yellow semi-solid oil. Purification by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent afforded an oil which was kugelrohr distilled at 93 Pa, pot temperature 103° C. to give 1.36 g (24.3%) of product as a yellow solid; mp 56°-58° C.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:28]4[C:24](=[N:25][NH:26][N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:49]1[N:54]=[CH:53][CH:52]=[CH:51][N:50]=1.[H-].[Na+].CN(C)C=O>O>[C:8]1([N:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:28]4[C:24](=[N:25][N:26]([C:49]5[N:54]=[CH:53][CH:52]=[CH:51][N:50]=5)[N:27]=4)[C:23]([C:29]4[CH:34]=[CH:33][C:32]([N:35]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[CH:31][CH:30]=4)=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ncccn1
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4nn(-c5ncccn5)nc34)cc2)cc1
Temperature: 120 °C

Procedure:
A mixture of Intermediate A (500 mg, 0.82 mmol), 2-chloropyrimidine (343 mg, 3.0 mmol), 60% NaH (60 mg, 1.5 mmol), and dimethylformamide (10 mL) was stirred under argon and heated at 120° C. for 20 hours. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (4×100 mL). The extract was dried over anhydrous sodium sulfate, the volatiles were removed under reduced pressure, and the residue was chromatographed using silica gel and dichloromethane/ethyl acetate (95:5) as an eluent. The obtained product was recrystallized from ethanol to give 4,7-bis(4-(N,N-diphenylamino)phenyl)-2-(pyrimidin-2-yl)-2H-benzo[d][1,2,3]triazole (Compound 1), orange crystals, 340 mg (61%). 1H NMR (400 MHz, CDCl3): δ 8.99 (d, J=5.1 Hz, 2H, pyrimidine), 8.02 (d, J=8.8 Hz, 4H, p-phenylene), 7.66 (s, 2H, benzotriazole), 7.47 (t, J=4.8 Hz, 1H, pyrimidine), 7.28 (m, 8H, Ph), 7.21 (d, J=8.4 Hz, 4H, p-phenylene), 7.18 (m, 8H, Ph), 7.05 (tt, J=7.3 and 1.1 Hz, 4H, Ph). UV-vis spectrum (dichloromethane): λmax=451 nm. Fluorimetry (dichloromethane): λmax=600 nm.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#N)=[CH:20][CH:19]=1>C(C1C=CC(C#CCCCCCC)=CC=1)#CCCCCCC.C(#N)C1C=CC=CC=1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C#CCCCCCC
Agent: CCCCCCC#Cc1ccc(C#CCCCCCC)cc1
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccc(Cl)cc1
Reaction time: 23 h
Yield: 70.5 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 4-chlorobenzonitrile (0.275 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 23 h at 65° C. showed the presence of 1.41 mmol (70% yield) of 1-chloro-4-(1-octynyl)benzene, 0.11 mmol 1,4-bis(1-octynyl)benzene and no remaining 4-chlorobenzonitrile in the reaction mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9]([SH:11])=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18]Br>C(O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][S:11][C:9]1[NH:8][C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N:10]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: O=[N+]([O-])c1ccc2[nH]c(S)nc2c1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]c(SCc3ccc(Cl)c(Cl)c3)nc2c1
Yield: 64.9 %

Procedure:
A mixture of 5-nitro-1H-benzoimidazol-2-thiol (1.95 g, 0.01 mol) and 3,4-dichlorobenzylbromide (2.4 g, 0.01 mol) was heated at reflux in ethanol (100 mL) for a period of 20 hours. The mixture was then concentrated. The solid was collected by filtration. The solid was dissolved in a mixture of EtOAc/H2O. Sodium bicarbonate was added until basic. The organic phase was separated and the solvent evaporated. The residue was dissolved in ethanol. The solution was saturated with hydrogen chloride. The solution was then concentrated to the precipitation point. The solid was then collected to give the title compound (2.3 g, 59% yield) as a mono-hydrochloride, off-white solid, m.p. 232°-234° C. (dec.). Mass spectrum (EI; M+) m/z 353/355/347. Anal. Calcd. for C14H9Cl2N3O2 S.HCl: C, 43.04; H, 2.58; N, 10.76. Found: C, 43.24; H, 2.47; N, 10.69. 1H-NMR (DMSO-d6 ; 400 MHz): δ 8.32 (s, 1H), 8.07 (d, 1H), 7.78 (s, 1H), 7.62 (d, 1H), 7.56 (d, 1H), 7.49 (d, 1H), and 4.64 ppm (s, 2H).
Reaction SMILES: C(O)(C)C.[CH3:5][O:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=[O:8].Cl(O)(=O)(=O)=O>O>[CH3:5][O:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][NH:16]2)=[CH:11][CH:10]=1)=[O:8]
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(c1)NCCC2
Temperature: 85 °C
Reaction time: 17 h

Procedure:
To a solution of bis (pentamethyl-cyclopentadiene iridium dichloride) (32 mg, 0.02 equiv.) in a degassed mixture of isopropanol (9.5 ml) and water (0.5 ml) was added quinoline-7-carboxylic acid methyl ester (374 mg, 2.00 mmol) and perchloric acid (70% in water, 0.02 ml, 0.1 equiv.). The mixture was stirred at 85° C. for 17 hours, then the solvents were evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), yielding 1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester as a white solid, 305 mg (80%). MS (ISP): m/e=192.4 (M+H+); δH (300 MHz; CDCl3) 7.23 (1H, d), 7.13 (1H, s), 6.98 (1H, d), 3.86 (3H, s), 2.52 (2H, m), 3.32 (2H, t), 2.79 (2H, t), 1.94 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])(=[O:23])=[O:22])[C:16](=[O:34])[C:15]2([OH:41])[C:35]1[S:36][CH:37]=[CH:38][C:39]=1[CH3:40]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])(=[O:23])=[O:22])[C:16](=[O:34])[C:15]2([O:41][C:9](=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:35]1[S:36][CH:37]=[CH:38][C:39]=1[CH3:40]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3sccc3C)c3cc(Cl)ccc32)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(OC(=O)Nc3ccc(Cl)cc3)(c3sccc3C)c3cc(Cl)ccc32)c(OC)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
4-Chlorophenyl isocyanate (32 mg, 0.208 mmol) and DMAP (5 mg) were successively added to a solution of example 62 (100 mg, 0.21 mmol) in toluene (20 ml) and stirred at 90° C. for 30 min. The solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate. The organic phase was washed with dilute citric acid solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from methanol resulted in 80 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[CH:23])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[O:9][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]=1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: Oc1ccc(Cl)nc1I
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2nc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.07 g (12.0 mmol) sample of 6-chloro-2-iodo-3-pyridinol, from step 11c above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), CuI (0.380 g, 1.98 mmol) and triethylanue (1.7 mL, 12 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1.95 g (10.0 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1a above, dissolved in 5 mL of DMF, was added carefully. The reaction mixture was stirred at 60° C. for 16 hours, cooled to room temperature, diluted with ether, washed with 50% brine and dried over MgSO4, then the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 1.54 g of title compound: 1H NMR (DMSO, 300 MHz, 130° C.) δ 1.37 (two s, 9H), 1.89-2.07 (m, 3H), 2.37 (m, 1H), 3.40-3.54 (m, 1H), 4.98 (m, 1H), 6.72 (s, 1H), 7.26-7.29 (d, 1H, J=8.6 Hz), 7.93-7.96 (d, 1H, J=8.6 Hz); MS m/z: 323 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].CCOCC>C(Cl)Cl>[O:1]=[CH:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[C:7]([F:9])([F:10])[F:8]
Reactant: O=C(NCCCO)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(3-hydroxypropyl)trifluoroacetamide (1.6 g, 9.3 mmol) in anhydroud DCM (10 mL) cooled to 0° C. was added a solution of Dess-Martin periodinane (30 mL of 15 wt % in DCM; 14 mmol). Stirring was continued at 0° C. for 10 min, then the mixture was allowed to warm to room temperature and stirring was continued for 2 h. The mixture was poured onto a biphasic mixture of saturated aqueous NaHCO3 (60 mL) and Et2O (60 mL) and stirred vigorously for 20 min. The forming precipitate was eliminated by filtration and the layers separated. The aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried (MgSO4), filtrated, and evaporated. The product was purified by column chromatography (Hex:EtOAc 3:2) to provide N-(3-oxopropyl)trifluoroacetamide as a viscous liquid in a yield of 0.82 g (52%). The product decomposes at room temperature and was used within 24 h of preparation. 1H-NMR (500 MHz, CDCl3): δ=2.84 ppm (t, J=6.0 Hz, 2H), 3.64 ppm (dt, J=6.0, 6.0 Hz, 2H), 6.98 ppm (bs, 1H), 9.81 ppm (s, 1H); 13C-NMR (500 MHz, CDCl3): δ=33.36, 42.58, 115.74 ppm (q, J=1144 Hz), 157.42 ppm (q, J=146.5 Hz), 200.85 ppm.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:27])[C:25]=1[OH:26])[CH:21]=O>C(O)C.Cl.C(O)(C)C.O>[OH:26][C:25]1[C:24]([CH3:27])=[CH:23][C:20]([CH2:21][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=2)=[O:10])=[CH:19][C:18]=1[CH3:17]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CCc1sc(C(C)=O)cc1-c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CC(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Reaction time: 1.5 h
Yield: 58.2 %

Procedure:
A solution of 1-(5-ethyl-4-phenyl-thiophen-2-yl)-ethanone (64 mg, 0.278 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (53 mg, 0.334 mmol) in ethanol (1.2 mL) and 5 N HCl in isopropanol (0.6 mL) is stirred at rt for 1 h. The dark green solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in methanol (1 mL) and THF (1 mL), and treated with Pd/C (60 mg, 10% Pd). The slurry is hydrogenated under 1.4 bar of H2 for 1.5 h. The mixture is filtered over celite, the solvent is removed in vacuo and the crude product is purified on prep. TLC plates with heptane:EA 2:1 to give 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (59 mg) as a yellow oil; LC-MS: tR=1.11 min; 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.46-7.30 (m, 5H), 6.85 (s, 2H), 4.56 (s, 1H), 3.18-3.10 (m, 2H), 2.97-2.86 (m, 4H), 2.22 (s, 6H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH:55]1([C:58]2[O:62][N:61]=[C:60]([CH2:63][NH2:64])[N:59]=2)[CH2:57][CH2:56]1>CN(C)C=O>[CH:55]1([C:58]2[O:62][N:61]=[C:60]([CH2:63][NH:64][C:20]([C:10]3[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:9]=3)=[O:21])[N:59]=2)[CH2:57][CH2:56]1
Reactant: NCc1noc(C2CC2)n1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1noc(C2CC2)n1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Yield: 66.8 %

Procedure:
To a stirred solution of 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M, 100 mg, 0.300 mmol) in dimethylformamide (4 mL, dried), was added 4-methylmorpholine (CAS No. 109-02-4, 0.09 ml, 0.901 mmol), HBTU (CAS No. 94790-37-1, 171 mg, 0.450 mmol), 5-cyclopropyl-[1,2,4]oxadiazol-3-methanamine hydrochloride (Chembridge, MFCD09864586, 52 mg, 0.300 mmol) at rt and this mixture was stirred for 12 h at rt. Volatile were removed under reduced pressure and the residue was extracted with ethyl acetate. The combined organic layer was washed with aq. NaHCO3 soln, brine and concentrated to afford the crude residue which was purified by column chromatography (100-200 silica gel, elution with ethyl acetate/hexane). The title compound (91 mg, 66.0% yield) was obtained as a white solid; LC-MS (UV peak area/ESI) 96.8%, 454.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:11])=[C:8]([OH:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:24]I.Cl>[OH-].[Na+].C(O)C.O>[CH2:1]([O:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)c(OC)c1
Temperature: 60 °C

Procedure:
A solution of 3-(4-butoxy-2-hydroxybenzoyl)benzoic acid (0.85 g), prepared as described in Example 26, is heated under reflux in a mixture of 2N sodium hydroxide (2.8 ml) and ethanol (10 ml) for 30 minutes. The reaction mixture is then cooled to 60° C. and methyl iodide (10 ml) is added. The resulting mixture was heated at 60° for 72 hours, cooled, acidified with concentrated hydrochloric acid and diluted with water (100 ml). The product is extracted with ether (3×25 ml). The extracts are dried over magnesium sulfate, filtered and evaporated to dryness. 2N Sodium hydroxide (2 ml) is added to the residue and the mixture heated under reflux for 6 hours. The reaction mixture is acidified with concentrated hydrochloric acid, diluted with water (100 ml), and extracted with ether (3×25 ml). The residue is chromatographed on silica (hexane:ether:acetic acid at 90:10:1) to yield 3-(4-butoxy-2-methoxybenzoyl)benzoic acid (0.46 g), m.p. 144°-145° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.CC[O-].[Na+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1c[nH]cn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1cnc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.3 g (35.3 mmol) 1H-imidazole-4-carbonitrile [Matthews et al., J. Org. Chem. 1986, 51, 3228-3231] are initially introduced into 13.2 ml (11.5 g, 35.3 mmol) 21% strength sodium ethylate solution in ethanol and 4.3 ml (6.5 g, 38.9 mmol) ethyl bromoacetate are added. The reaction mixture is stirred at RT for 16 h. For working up, the solid which has precipitated out is filtered off, the residue on the filter is washed with ethanol and the filtrate is concentrated in vacuo. Diisopropyl ether is added to the residue, the mixture is filtered again, the filtrate is concentrated again on a rotary evaporator and the residue is dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl.CN(C)C=O.[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Reaction time: 8 h
Yield: 112.5 %

Procedure:
To a 0° C. solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.50 g, 0.0033 mol) and [β-(trimethylsilyl)ethoxy]methyl chloride (0.75 mL, 0.0043 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) was added sodium hydride (0.17 g, 0.0043 mol). The resulting mixture was stirred overnight and partitioned between ethyl acetate and water (×2), and the organic layer was washed with sat. NaCl. The organic layer was then dried under vacuum to produce 1.05 g of an orange oil which was chromatographed with 15% ethyl acetate/hex to give 830 mg of a colorless oil (89.6% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[C:15]([NH2:16])=[N:14][NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.[CH3:17][NH:18][CH3:19].[CH2:20]=O>C(O)C>[CH3:17][N:18]([CH2:20][N:13]1[C:9]2=[N:10][C:11]3[C:6]([CH:7]=[C:8]2[C:15]([NH2:16])=[N:14]1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH3:19]
Reactant: CNC
Reactant: C=O
Reactant: COc1ccc2cc3c(N)n[nH]c3nc2c1
Solvent: CCO
Product: COc1ccc2cc3c(N)nn(CN(C)C)c3nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 15 g 7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine (Example 3d) in 190 ml ethanol was added 16 ml 47% aqueous dimethylamine and 6.5 ml 37% aqueous formaldehyde. The reaction mixture was stirred at room temperature overnight, then concentrated by evaporation, and the residue was recrystallized from ethanol to give 10.8 g 1-[(dimethylamino)methyl]-7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine, bright-yellow solid, m.p. 156°-158° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S-:10])=[N:2]1.[K+].[OH-].[K+].Cl[CH:15]([F:17])[F:16]>O1CCOCC1.O>[F:16][CH:15]([F:17])[S:10][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: [S-]c1nsc2ccccc12
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)Sc1nsc2ccccc12
Temperature: 0 °C

Procedure:
4.1 g (0.02 mol) Potassium 1,2-benzoisothiazole-3-thiolate was suspended in 25 ml dioxane and treated with a solution of 5.6 g (0.10 mol) potassium hydroxide in 9 ml water. At a temperature of 60°-70° C., a slow stream of chlorodifluoromethane was passed through over 30 minutes. The mixture was added to 500 ml ice/water and extracted several times with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residual oil was purified by silica gel column chromatography (eluent: hexane/diethyl ether 9:1).
Reaction SMILES: N#N.[F:3][C:4]([F:15])([CH2:12][CH:13]=[CH2:14])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=O.B.C1C[O:20]CC1>C1COCC1>[F:3][C:4]([F:15])([CH2:5][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:12][CH:13]([OH:20])[CH3:14].[F:3][C:4]([F:15])([CH2:5][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:12][CH2:13][CH2:14][OH:20]
Reactant: C=CCC(F)(F)C(=O)N1CCCC1
Reactant: C1CCOC1
Agent: B
Agent: N#N
Product: CC(O)CC(F)(F)CN1CCCC1
Product: OCCCC(F)(F)CN1CCCC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2,2-difluoro-1-(pyrrolidin-1-yl)pent-4-en-1-one (260 mg, 1.37 mmol) in dry THF (15 mL) was added BH3-THF (6.6 mL of a 1M solution in THF, 6.60 mmol) at rt. The reaction mixture was stirred at reflux for 18 h, cooled down to rt and concentrated under reduced pressure. The residue was redissolved in MeOH (slow addition) and concentrated under reduced pressure (2×). The resulting oil was then redissolved in THF (5 mL), treated with aq. 2N NaOH (0.8 mL) and aq. 30% H2O2 (0.8 mL). The mixture was stirred at rt for 2 h. Water was then added, the layers separated and the aq. layer extracted with EA. The combined org. extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 1:1→3:7) to give 4,4-difluoro-5-(pyrrolidin-1-yl)pentan-2-ol as a colorless oil and 4,4-difluoro-5-(pyrrolidin-1-yl)pentan-1-ol as a yellow oil. LC-MS-conditions 08: tR=0.38 min; [M+H]+=194.39 and tR=0.51 min; [M+H]+=194.38.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[C:1]([C:5]1[CH:9]=[C:8](/[N:10]=[CH:13]/[N:14]([CH3:16])[CH3:15])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)c1cc(N)[nH]n1
Product: CN(C)/C=N/c1cc(C(C)(C)C)n[nH]1
Yield: 98.7 %

Procedure:
A mixture of 3-tert-butyl-1H-pyrazol-5-amine (5 g, 36 mmol, Alfa-aesar) and N,N-dimethylformamide dimethylacetal (153 mL, 1078 mmol, Aldrich) was refluxed overnight. The reaction mixture was then cooled, concentrated under reduced pressure and the residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-5% methanol in dichloromethane) to provide 6.9 g (99%) of the title compound. MS (ESI+) m/z 195 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:19]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:21])[CH3:20]>CC#N>[CH:19]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:25][CH:24]=1)([CH3:21])[CH3:20]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)Oc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)C)C2=O)cc1
Temperature: 160 °C
Yield: 59.2 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.2 g, 0.7 mmol), 4-isopropoxyaniline (0.106 g, 0.7 mmol) and TEA (0.071 g, 0.7 mmol) was dissolved in dry MeCN (3 ml). The reaction mixture was heated at 160° C. for 30 min in a microwave reactor. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 70:30 mixture of heptane:EtOAc as eluant to give the title compound (0.166 g, 59%). 1H NMR (500 MHz, CDCl3): δ 7.21-7.15 (m, 1H), 7.13-7.09 (m, 4H), 7.06 (brs, 1H), 6.65-6.59 (m, 2H), 6.53-6.48 (m, 2H), 4.48 (hep, 1H), 4.35 (hep, 1H), 1.63 (d, 6H), 1.23 (d, 6H); 13C NMR (125 MHz, CDCl3): δ 159.0, 155.5, 131.6, 129.5, 128.9, 128.1, 125.0, 124.1, 124.0, 116.0, 109.7, 70.4, 47.8, 21.9, 20.4.