Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH2:5][C:6](Cl)([Cl:8])[Cl:7])[CH:3]1[C:10]([O:12]C)=[O:11].[OH-].[Na+].CO>O>[CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Yield: 81.7 %

Procedure:
In similar way to that in Stage IV-1 Example 3 above except that 5 g of methyl 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropanecarboxylate (purity: 95.8%, cis/trans: 92.7/7.3) were added to a mixture of 4 g of sodium hydroxide, 20 ml of methanol and 30 ml of water to heat the resulting mixture for 10 hours under reflux, 3.31 of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid, cis/trans ratio 98.8/1.2, purity 96.4%, yield 81.7% were obtained.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=O.N1C=CC=CC=1C1C=CC=CN=1.[Li]CCCC.[CH3:27][C:28](C)([CH:32]=[CH2:33])[C:29](Cl)=O>C1COCC1.CCOCC>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C:28]([CH3:29])([CH3:27])[CH:32]=[CH2:33])[CH3:9]
Reactant: CCOC(=O)CC(=O)O
Reactant: C=CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(C)(C)C(=O)CC(=O)OCC
Reaction time: 3 h
Yield: 101.3 %

Procedure:
Monoethyl hydrogen malonate (7.2 g, 0.05 mol) and bipyridyl (few milligrams) were dissolved in THF (90 ml) and the system was flushed with nitrogen. The solution was cooled to −70°, then BuLi (2.5 M in hexanes, 37 ml, 0.09 mol) was added. After the addition of only ˜10 ml of BuLi the solution turned pink and additional THF (15 ml) was required to enable magnetic stirring. The cooling bath was removed and the remaining BuLi was added, the temperature was allowed to reach −10°, upon which the solution turned colorless. The mixture was again cooled to −60° and a solution of 2,2-dimethyl-but-3-enoyl chloride (4.1 g, 0.03 mol) in THF (12 ml) was added dropwise. After addition was complete the mixture was allowed to warm to 0° and stir for 3 h, then it was added to a 1:1 mixture of ether/1M HCl (260 ml) at 0° and stirred for a further 1.5 h. The organic layer was removed, washed with HCl (1 M), sodium bicarbonate solution, brine then dried and evaporated to give 4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (5.6 g, 98%). (Hayashi et al., J. Org. Chem., 65:8402-8405 (2000). Distillation with a Kugelrohr oven (160°/1 mmHg) afforded pure material.
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[O:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:18]C(=O)C4C=CC=CC=4)[C:11]=3[CH:10]=2)[C:7]([C:27]#[N:28])=[C:6]([CH3:29])[NH:5][C:4]=1[CH3:30])#[N:2].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[NH2:18][C:12]1[C:11]2[CH:10]=[C:9]([CH:8]3[C:7]([C:27]#[N:28])=[C:6]([CH3:29])[NH:5][C:4]([CH3:30])=[C:3]3[C:1]#[N:2])[O:17][C:16]=2[CH:15]=[CH:14][N:13]=1
Reactant: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cc3c(N)nccc3o2)C(C#N)=C(C)N1
Temperature: 100 °C
Reaction time: 24 h
Yield: 17.5 %

Procedure:
A solution of 43 mg (0.11 mmol) N-[2-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)furo[3,2-c]pyridin-4-yl]benzamide (Example 4) in acetic acid (3 ml) was treated with 0.2 ml hydrochloric acid (37%) and stirred for 24 h at 100° C. Then, further 0.2 ml hydrochloric acid (37%) were added, and stirring was continued for 48 h at 100° C. Upon cooling, saturated aq. sodium carbonate solution was added until a neutral pH was reached. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and water, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (silica, eluent dichloromethane/methanol 10:1 v/v) to afford the title compound (5.6 mg, 18% of th.) as a white solid.
Reaction SMILES: C([O:8][C:9]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:25])[N:13]2[CH3:24])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:25])[N:13]2[CH3:24]
Reactant: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2O
Reaction time: 1 h

Procedure:
To a solution of 4-benzyloxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one (0.3 g, 0908 mmol) in ethanol (20 mL), was added 10% palladium on carbon (0.2 g, 0.28 mmol). The atmosphere over the reaction mixture was evacuated and the reaction was placed under an atmosphere of hydrogen gas via a balloon. The reaction was permitted to stir for 1 hour. The reaction mixture was then filtered through a plug of Celite®. The Celite pad was washed with hot ethanol (200 ml). The combined filtrate was then concentrated to afford 4-hydroxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; MS: (E 5÷) m/z 241.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][OH:18])[CH:10]=2)[N:3]=1>O=[Pt]=O>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:23][CH:24]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C#CCO)c2)N=C1N
Agent: O=[Pt]=O
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(CCCO)c2)N=C1N
Reaction time: 4 h

Procedure:
A mixture of an ethanolic solution of 1 (1 g, 2.6mmol) and PtO2 (50 mg, 10%) is hydrogenated at 15 psi on a Parr hydrogenator for 4 h and filtered through celite. The filtrate is concentrated to dryness under reduced pressure to afford 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxypropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one, 830 mg, identified by NMR and mass spectral analyses.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]1([CH3:27])[NH:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:9]1=[O:26]>O.O1CCCC1>[CH3:21][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:10]2[C:9](=[O:26])[C:8]([CH3:27])([CH3:7])[NH:12][C:11]2=[O:13])=[CH:15][C:16]=1[C:22]([F:25])([F:24])[F:23])=[O:2]
Reactant: CSc1ccc(N2C(=O)NC(C)(C)C2=O)cc1C(F)(F)F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1ccc(N2C(=O)NC(C)(C)C2=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
470 mg of sodium periodate were dissolved in 5 ml of water and admixed slowly with 640 mg of 114.1, dissolved in 10 ml of tetrahydrofuran, with ice bath cooling. The mixture was stirred at room temperature overnight. Another 210 mg of sodium periodate were added and the mixture was stirred for a further 8 h. Thereafter, the reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The chromatographic purification (silica gel; 96/4 dichloromethane/methanol) afforded 3-(4-methanesulfinyl-3-trifluoromethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (114.1a). Molecular weight 334.05 (C13H13F3N2O3S); retention time Rt=1.69 min. [B]; MS (ES−): 335.19 (M−H+).
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:19]1([CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[NH:1]1[C:5]2=[C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:29]([NH:28][C:26](=[O:27])[CH2:25][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[S:30])=[CH:13][C:12]=3[F:18])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
A mixture of 261 (44 mg, 0.18 mmol) and 2-phenylacetyl isothiocyanate (36 □L, 0.19 mmol) in THF (2 mL) was stirred at room temperature for 2 hours, and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to afford the title compound 262a (30 mg, 40%) as an off-white solid. 1HNMR (DMSO-d6) δ (ppm): 12.41(s, 1H), 12.07(s, 1H), 11.77(s, 1H), 7.84(dd, 1H, J1=10.95 Hz, J2=2.0 Hz), 7.58(t, 1H, J1=J2=2.7 Hz), 7.51(d, 1H, J=5.7 Hz), 7.43-7.39(m, 2H), 7.37-7.33(m, 4H), 7.31-7.26(m, 2H), 6.55(dd, 1H, J1=1.76 Hz, J2=2.9 Hz), 3.84(s, 2H), MS (m/z): 421.1(M+H) (found).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Cl)nc21
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To 6-chloro-1H-pyrrolo[2,3-b]pyridine (1.00 g, 6.55 mmol) in THF (1 mL) was added NaH (60%, 0.315 g, 7.86 mmoL) at 0° C. in several portions. The resulting mixture was stirred for 1 hr, followed by addition of triisopropylsilyl chloride (1.67 mL, 7.86 mmol) in neat at 0° C. The mixture was continued stirring at 0° C. under N2 for 2 hr, quenched with H2O (40 mL), and extracted with Et2O (100 mL). After separation, the organic phase was washed with brine (30 mL), dried (MgSO4), concentrated on rotary vacuo, and purified on Biotage Flash Collector eluting with 15˜30% EtOAc/Hexanes (600 mL) to afford the expected product, 6-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.51 g, 75%). 1H-NMR (400 MHz, CHLOROFORM-D) δ ppm 1.09-1.13 (m, 18 H) 1.80 (dt, J=14.92, 7.52 Hz, 3 H) 6.52 (d, J=3.53 Hz, 1 H) 7.02 (d, J=8.06 Hz, 1 H) 7.25 (d, J=3.53 Hz, 1 H) 7.77 (d, J=8.31 Hz, 1 H); Mass spec 309.19 Calc for C16H25ClN2Si 308.15.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=410.2 [M+H]+.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8].[CH3:19][NH:20][CH:21]1[CH2:29][CH2:28][C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH2:22]1>>[CH3:19][N:20]([CH:21]1[CH2:29][CH2:28][C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH2:22]1)[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8]
Reactant: O=CCCCNC(=O)c1ccc2ccccc2c1
Reactant: CNC1CCc2ncsc2C1
Product: CN(CCCCNC(=O)c1ccc2ccccc2c1)C1CCc2ncsc2C1
Yield: 25 %

Procedure:
Compound 3 is prepared from 2E and 3C as described for 1. The resulting oil is crystallized as salt of oxalic acid from ethanol/diethylether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)=[C:4]([F:17])[CH:3]=1.CC(C)([O-])C.[Na+].Cl[C:25]1[N:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)=[CH:27][N:26]=1.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:25]3[N:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[N:36]4)=[CH:27][N:26]=3)[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: Clc1ncc(CCCCn2ccnn2)cn1
Reactant: OCc1coc(C=Cc2ccc(Cl)cc2F)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc(Cl)ccc1C=Cc1nc(COc2ncc(CCCCn3ccnn3)cn2)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(4-Chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.100 g, 0.39 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) followed by addition of sodium tert-butoxide (NaOtBu) (0.046 g, 0.47 mmol). After stirring for 15 min at r.t. 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine (0.085 g, 0.36 mmol) is added slowly and stirred for further 3 h at r.t. Ethyl acetate (20 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 98:2) 2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine is obtained as a colorless solid. Yield 0.125 g (77%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39]([CH3:42])(=[O:41])=[O:40]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[C:10]([F:11])[C:5]3=[N:4][CH:3]=2)=[CH:19][C:18]=1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39]([CH3:42])(=[O:41])=[O:40]
Reactant: Fc1c(C(F)(F)F)ccn2c(Br)cnc12
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccc(F)cc3S(C)(=O)=O)c2)OC1(C)C
Product: CS(=O)(=O)c1cc(F)ccc1-c1cc(-c2cnc3c(F)c(C(F)(F)F)ccn23)ccc1F
Yield: 42 %

Procedure:
3-Bromo-8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridine was coupled to 2-(2,4′-difluoro-2′-methanesulfonylbiphenyl-5-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 1 to give 3-(2,4′-difluoro-2′-methanesulfonylbiphenyl-5-yl)-8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridine as a white solid (147 mg, 42%): δH (400 MHz, CDCl3) 2.91 (3H, s), 6.99 (1H, dd, J 7 and 6), 7.35-7.47 (3H, m), 7.61-7.65 (2H, m), 7.85 (1H, s), 7.98-8.01 (1H, m), 8.48 (11H, d, J 7); m/z (ES+) 471 [MH+].
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]([N:8]1[CH:12]=[C:11]([OH:13])[CH:10]=[N:9]1)([CH3:7])[CH3:6]>CC(C)=O.C(N(CC)CC)C>[CH:5]([N:8]1[CH:12]=[C:11]([O:13][C:3](=[O:4])[NH:2][CH3:1])[CH:10]=[N:9]1)([CH3:7])[CH3:6]
Reactant: CN=C=O
Reactant: CC(C)n1cc(O)cn1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1cnn(C(C)C)c1
Temperature: 45 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
6 g (0.105 mol) of methyl isocyanate were added to a solution of 12.6 g (0.1 mol) of 1-isopropyl-4-hydroxy-pyrazole in 100 ml of acetone and 2 drops of triethylamine. The mixture was stirred at 45° C. for 12 hours and the solvent was then distilled off in vacuo. 17.4 g (95% of theory) of N-methyl-carbamic acid O-(1-iso-propylpyrazol-4-yl) ester were thus obtained in the form of beige crystals with a melting point of 40° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O>[N+:8]([C:5]1[CH:4]=[CH:3][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cn1
Yield: 26.7 %

Procedure:
To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL) was added 1-(4-piperidyl)piperidine (1.0 g, 5.9 mmole) and triethyl amine (0.99 mL, 7.1 mmole). The contents were heated to 120 degrees in a CEM Discovery microwave system for 3 hours. The crude reaction was then loaded over a silica gel column and eluted with DCM/methanol (0-20%) to afford 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine as an oil (457 mg). 1H NMR (600 MHz, DMSO-d6) δ ppm 1.26-1.36 (m, 2H) 1.43 (m, 6H) 1.76 (m, 2H) 2.37 (m, 5H) 2.94 (t, J=12.74 Hz, 2H) 4.06 (d, J=13.47 Hz, 2H) 7.41 (dd, J=9.37, 2.64 Hz, 1H) 8.08 (d, J=9.37 Hz, 1H) 8.20 (d, J=2.64 Hz, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Yield: 93.9 %

Procedure:
A solution of 1-acetyl-4-(4-nitrophenyl)piperazine (28.8 g) in ethanol (400 ml) was hydrogenated at 4 bar in the presence of 10% palladium/carbon (0.5 g) until no further hydrogen was taken up. The catalyst was filtered off and the filtrate was evaporated. The residue was triturated with diethyl ether, filtered and dried to give the title compound (23.8 g), m.p. 142°-144° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([CH:27]([CH3:31])[C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[CH:27]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(Oc1ccccc1)C(=O)Cl
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: CC(Oc1ccccc1)C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-phenoxypropionyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-phenoxypropanamide as a white powder, m.p. 85.0-87.5° C. 1H NMR (300 MHz, DMSO-d6) δ8.15 (s, 1H), 8.07 (t, J=6.0 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.62 (dd, J=8.4, 1.2 Hz, 1H), 7.43 (dt, J=7.5, 1.2 Hz, 1H), 7.28-7.16 (m, 3H), 6.91-6.81 (m, 3H), 6.57 (s, 2H), 4.62-4.53 (m, 3H), 3.10 (q, J=6.9 Hz, 2H), 1.76 (quintet, J=7.1 Hz, 2H), 1.43 (quintet, J=7.1 Hz, 2H), 1.33 (d, J=6.6 Hz, 3H); MS (EI) m/e 403.2005 (403.2008 calcd for C23H25N5O2).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[S:16]1[C:20]2[CH:21]=[C:22]([C:25]([N:27]3[CH2:34][CH2:33][C:32]4([CH3:36])[CH2:35][CH:28]3[CH2:29][C:30]3[CH:40]=[CH:39][C:38](O)=[CH:37][C:31]=34)=[O:26])[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1.C(N(CC)CC)C.N>CN(C)C1C=CN=CC=1.ClCCl>[S:16]1[C:20]2[CH:21]=[C:22]([C:25]([N:27]3[CH2:34][CH2:33][C:32]4([CH3:36])[CH2:35][CH:28]3[CH2:29][C:30]3[CH:40]=[CH:39][C:38]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[CH:37][C:31]=34)=[O:26])[CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1
Reactant: CC12CCN(C(=O)c3ccc4ncsc4c3)C(Cc3ccc(O)cc31)C2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC12CCN(C(=O)c3ccc4ncsc4c3)C(Cc3ccc(OS(=O)(=O)C(F)(F)F)cc31)C2
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic anhydride (0.77 mL) is added to a solution of benzothiazol-6-yl-(8-hydroxy-6-methyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone (1.24 g; for synthesis see Example 92), triethylamine (3.4 mL), and 4-dimethylaminopyridine (10 mg) in dichloromethane (12 mL) chilled to −10° C. under argon atmosphere. The solution is stirred at ca. −5° C. for 30 min and then at room temperature overnight. The reaction solution is added to ice-cold water and then concentrated aqueous ammonia solution is added. The resulting mixture is extracted with dichloromethane, the combined organic extracts are washed with water and dried (MgSO4). The solvent is removed under reduced pressure to give the crude product that is used without further purification.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([CH:17]=[O:18])=[C:12]([Cl:16])[C:13]=1[C:14]#[N:15].C(#N)C>CN(C)C=O>[CH:17]([C:11]1[S:10][CH:9]=[C:13]([C:14]#[N:15])[C:12]=1[Cl:16])=[O:18]
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#Cc1csc(C=O)c1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.6 %

Procedure:
35 g (325 mmol) of tert-butyl nitrite were added dropwise at room temperature to a solution of 53.0 g (250 mmol) of 2-amino-4-chloro-5-formylthiophene-3-carbonitrile (the synthesis of this compound is described in Patent DB 3738910) in 600 ml of a 1:1 mixture of acetonitrile and dimethylformamide, during which process the temperature of the reaction mixture rose from 20° C. to 37° C. and vigorous evolution of gas began. The mixture was cooled to 25° C. and stirred for 7 hours at room temperature, the black solution was concentrated on a rotary evaporator under a high vacuum, the residue was purified by column chromatography (eluant dichloromethane), and 29 g (68%) of the desired compound were obtained as yellow oil. 1H NMR (270 MHz, DMSO-d6): δ=9.1 (s, 1H), 10.0 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[S:19](Cl)(=[O:21])=[O:20]>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[S:19]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:20])=[O:21]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: Cc1noc(N)c1Br
Product: COc1ccc(OC)c(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 58 %

Procedure:
2,5-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,5-dimethoxybenzenesulfonyl chloride according to the procedures described in Example 8 (see, also Example 30), below. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 118-120°, yield 58%.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:20]=2)=[C:8]([O:21]C)[CH:7]=1)([OH:3])=[O:2].Cl>>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:20]=2)=[C:8]([OH:21])[CH:7]=1)([OH:3])=[O:2]
Reactant: COc1cc(OCC(=O)O)ccc1-c1nc2cnccc2[nH]1
Agent: Cl
Product: O=C(O)COc1ccc(-c2nc3cnccc3[nH]2)c(O)c1

Procedure:
2-(4-Carboxymethoxy-2-methoxyphenyl)imidazo(4,5-c)-pyridine, m.p. 235°, hydrochloride, m.p. 252°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[N:16]=[C:15]([Cl:20])[N:14]=1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:12][C:13]1[N:14]=[C:15]([Cl:20])[N:16]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[N:18]=1
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 0 °C

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) in 15 mL of N,N-Dimethylformamide and 3.6 mL of Diisopropylethylamine is cooled to 0° C. 2,4,6-trichloro-1,3,5-triazine (2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is warmed up to room temperature and stirred until formation of the desired compound. The reaction mixture is filtered and purified by prep-HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1>C(O)(=O)C.[Pt]=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:7])=[CH:16][CH:17]=1
Reactant: O=C(NCc1cccnc1)c1ccc(O)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(NCC1CCCNC1)c1ccc(O)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-hydroxy-N-pyridin-3-ylmethyl-benzamide (2.0 g, 0.0088 mol) in acetic acid (135 mL) was added platinum oxide (200 mg) and the mixture stirred under hydrogen for 3 h. The reaction was filtered and concentrated in vacuo to give an oil.