Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[N:6]=1)=[O:4].S(Cl)(Cl)=O.[CH3:22]O>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([O:13][CH3:22])=[O:12])[CH:8]=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(C(=O)O)cc(C(=O)NC)n1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cc(C(=O)OC)cc(C(=O)NC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Bis(N-methylcarbamoyl)pyridine-4-carboxylic acid (1 g) was mixed with methanol (50 ml), and to the mixture was added thionyl chloride (2 ml). After addition of thionyl chloride, the mixture was stirred at room temperature overnight. The mixture was then evaporated under reduced pressure, and water was added to the residue followed by extraction with chloroform. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, and evaporated to dryness. The residual crystals were recrystallized from toluene to give 0.4 g of methyl 2,6-bis(N-methylcarbamoyl)pyridine-4-carboxylate. m.p. 202°-203° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([O:15][CH:16]([CH3:18])[CH3:17])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([CH3:36])[C:27]=1[O:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH:23]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.Cl>CN(C)C(=O)C.CCOCC>[CH3:36][C:26]1[CH:25]=[C:22]([C:23]2[NH:6][C:4](=[O:5])[C:3]3[C:7]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:8][C:9]([O:11][CH:12]([CH3:13])[CH3:14])=[N:10][C:2]=3[N:1]=2)[CH:21]=[C:20]([CH3:19])[C:27]=1[O:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)Oc1cc(OC(C)C)c(C(N)=O)c(N)n1
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=S([O-])O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3nc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-4,6-diisopropoxy-nicotinamide (450 mg, 1.78 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (440 mg, 1.78 mmol) in N,N-dimethyl acetamide (10 mL) were added NaHSO3 (790 mg, 4.44 mmol) and p-TSA (845 mg, 4.44 mmol). The reaction mixture was heated at 120° C. for 16 hours, then cooled to room temperature. The solvent was removed under reduced pressure. Then, water (100 mL) was added and stirred for 30 min at room temperature. The separated solids were filtered and dried to give crude product, which was purified by the Simpliflash system, using 2% methanol in dichloromethane, to give a yellow oil, which dissolved in ether. 2N HCl in ether was added, and the separated solids were filtered and dried to give the hydrochloride salt of the title compound as a yellow solid. Yield: 59 mg (6%). 1H NMR (400 MHz, DMSO-d6): δ 10.7 (br s, 1H), 7.88 (s, 2H), 6.31 (s, 1H), 5.41 (m, 1H), 4.80 (m, 1H), 4.14 (t, J=4.8 Hz, 2H), 3.61 (m, 2H), 3.16 (m, 4H), 2.34 (s, 6H), 2.03 (m, 2H), 1.91 (m, 2H), 1.32 (s, 6H), 1.30 (s, 6H). MS (ES) m/z: 481.18 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]2[C:29]([O:31][C:32](=O)[C:22]=2[CH:21]=1)=[O:30]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:29](=[O:30])[C:23]2[C:22](=[CH:21][CH:20]=[C:25]([C:26]([OH:28])=[O:27])[CH:24]=2)[C:32]1=[O:31]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3ccc(C)cc3o2)cc1N
Product: COc1ccc(-c2nc3ccc(C)cc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-6-methylbenzoxazole (58 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the title compound was obtained, 54 mg (55%). 1H NMR (DMSO) δ 8.31(dd, 1H) 8.16(m, 3H), 7.97(d, 1H), 7.50(d, 1H), 7.43(s, 1H), 7.32(d, 1H), 7.08(d, 1H), 3.73(s, 3H), 2.33(s, 3H). MS 427 m/z (M−H)−.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Br[C:32]1[N:33]=[C:34]2[CH:40]=[CH:39][N:38]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:35]2=[N:36][CH:37]=1.[C:51](=[O:58])([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[NH2:52].CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[S:41]([N:38]1[C:35]2=[N:36][CH:37]=[C:32]([NH:52][C:51](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[N:33]=[C:34]2[CH:40]=[CH:39]1)([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Temperature: 80 °C
Yield: 18.4 %

Procedure:
To a flask was added Pd2(dba)3 (1.3 g, 1.4 mmol), di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (1.21 g, 2.84 mmol), and 1,4-dioxane (75 mL). The catalyst-ligand mixture was degassed via vacuum/nitrogen purge (3 times) and heated at about 80° C. for about 10 min. 2-Bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (5.0 g, 14 mmol, Preparation #7), tert-butyl carbamate (2.5 g, 21 mmol), and NaOt-Bu (2.05 g, 21.3 mmol) were added. After an additional vacuum/nitrogen purge, the reaction was heated at about 80° C. for about 16 h. The reaction was cooled to ambient temperature and diluted with EtOAc (70 mL). The reaction mixture was filtered and the filtrate was washed with water (3×20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and solvent removed under reduced pressure to give a reddish-brown solid. The crude material was purified by silica gel chromatography eluting with a gradient of 10-50% EtOAc in heptane to yield tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate as a yellow amorphous solid (1.0 g, 18%): LC/MS (Table 2, Method a) Rt=2.63 min; MS m/z: 389 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:14]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:16])([CH3:17])[CH2:6][CH2:5]2
Reactant: C1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCCCC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.005 g, 4.00 mmol) in 22 mL THF was treated with 722.8 mg CDI (4.4 mmol) and stirred for 2 h at room temperature. The pale yellow solution was then treated with 450 μL (381 mg, 4.47 mmol) piperidine in 22 mL THF in 1-2 mL portions over 2 h. The reaction was stirred overnight at room temperature. The reaction was concentrated and the residue dissolved in 100 mL CH2Cl2 and sequentially washed with 50 mL 0.25 M HCl, 50 mL 1.0 M NaHCO3, 50 mL saturated NaCl and dried over Na2SO4. The organic phase was concentrated. Flash chromatography yielded 992 mg of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperidin-1-yl)methanone as an off-white solid.
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].[CH:20]([C:22]1[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:24][CH:23]=1)=O.CO>COCCOC>[C:11]([CH2:20][C:22]1[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:24][CH:23]=1)#[N:12]
Reactant: CS(=O)(=O)Nc1ccc(C=O)c2ccoc12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CC#N)c2ccoc12
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
A solution of tosylmethyl isocyanide (1.8 g, 9.22 mmole) in anhydrous ethylene glycol dimethyl ether (60 mL) was added drop-wise into a stirred suspension of potassium tert-butoxide (2.81 g, 25.0 mmole) in anhydrous ethylene glycol dimethyl ether (60 mL) under nitrogen at −65° C. After stirring at −65° C. for 15 min., N-(4-formyl-benzofuran-7-yl)-methanesulfonamide (2.0 g, 8.36 mmole) in anhydrous ethylene glycol dimethyl ether (60 mL) was added drop-wise and the reaction temperature was maintained below −60° C. After stirring for another hour before methanol (30 mL) was added. The reaction mixture was heated to reflux for 20 minutes then stirred at room temperature for 16 hrs. The resulting solution was partitioned between ethyl acetate and aqueous 2% acetic acid. The organic extract was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 40 to and 50% ethyl acetate in hexane to give N-(4-cyanomethyl-benzofuran-7-yl)-methanesulfonamide as a solid (1.31 g, 62%). 1H NMR (DMSO-d6) δ: 3.11 (s, 3H), 4.28 (s, 2H), 7.17 (d, 1H, J=2.2 Hz), 7.24-7.30 (m, 2H) 8.15 (d, 1H, J=2.2 Hz), 9.23 (s, 1H). M−H 249.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12]C(Cl)C>>[Cl:12][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][CH:10]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: CC(Cl)Cl
Product: Clc1c[nH]nc1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-phenyl-1H-pyrazole (3 g, 20.81 mmol) in dichloroethane (60 ml) N-chlorosuccinimide (2.92 g, 21.85 mmol) was added and the mixture was stirred over night at room temperature. The mixture was then concentrated under reduced pressure and the remainder was purified via chromatography on silica gel (eluent: cyclohexane/ethyl acetate 0-30% (v/v)). Concentration of the combined fractions gave 3.54 g of a slightly yellow amorphous solid; ESI-MS [M+H]+: 179.0
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11]N=C[CH:8]=2)[O:5][CH:6]=1.BrC1OC([Si](C)(C)C)=C(Br)C=1.[N:24]1C=CC=C(B(O)O)[CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[N:24][CH:25]=[CH:11][CH:12]=2)[O:5][CH:6]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1coc(-c2ccncc2)c1
Agent: C[Si](C)(C)c1oc(Br)cc1Br
Product: Brc1coc(-c2cccnc2)c1

Procedure:
The sub-title compound was prepared by a method analogous to that described for the preparation of 4-bromo-2-(4-pyridyl)-furan from 2,4-dibromo-5-(trimethylsilyl)furan and pyridine-3-boronic acid. The sub-title compound (725 mg) was obtained as a beige solid, m/z 224,226 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]O)[O:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][Cl:19])[O:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1OC(CO)CN1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(CCl)CN1Cc1ccccc1
Yield: 80.6 %

Procedure:
A solution of 20 g (0.1 mole) of 3-benzyl-5-hydroxymethyl-2-oxazolidinone and 24 g (0.2 mole) of sulfonyl chloride in chloroform was refluxed for 3 hr. The reaction mixture was dried over anhydrous sodium sulfate, concentrated and subjected to distillation to give 18.2 g (81%) liquid, b.p. 176°-178° C. at 0.1 mm.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:11](C)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:13](Cl)Cl>>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][N:10]([CH3:13])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cn1nccc1-c1ccc(Br)s1
Reactant: ClCCl
Product: Cn1ccc(-c2ccc(Br)s2)n1

Procedure:
To a stirred solution of 1-(5-bromothiophen-2-yl)-3-dimethylaminopropenone (0.70 g, 2.7 mmol) in EtOH (15 mL) was added methylhydrazine (0.16 mL, 3.0 mmol) and then acetic acid (0.45 mL, 8.0 mmol). The resulting mixture was heated at reflux for 2 h, allowed to cool to ambient temperature and then concentrated under reduced pressure. The residue was diluted with DCM (50 mL), washed with H2O and brine, then dried (Na2SO4), concentrated and purified by chromatography (silica, DCM) to yield the title compound 10a (0.21 g) as a white solid and regioisomer, 5-(5-bromothiophen-2-yl)-1-methyl-1H-pyrazole, 11a (035 g) as a pale yellow solid. 10a: Rf 0.42 (DCM); 1H-NMR (CD2Cl2): δ 7.36 (1H, d), 7.01 (2H, m), 6.41 (1H, d), 3.87 (3H, s); 11a: Rf 0.19 (DCM); 1H-NMR (CD2Cl2): δ 7.42 (1H, d), 7.10 (1H, d), 6.94 (1H, m), 6.36 (1H, d), 3.92 (3H, s).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[N:5]=2)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])=[CH:13][CH:12]=1.C(N(CCCC)CCCC)CCC>[OH-].[Na+].O>[CH:1]1([C:4]2[N:5]=[C:6]3[N:9]=[C:23]([OH:24])[C:17]([C:14]4[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=4)=[C:18]([OH:19])[N:7]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)cc1
Reactant: Nc1n[nH]c(C2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Oc1nc2nc(C3CC3)nn2c(O)c1-c1ccc(F)cc1

Procedure:
10.2 g (81.9 mmol) 5-Cyclopropyl-1,2,4-triazole-3-ylamine, 25 g (98.3 mmol) diethyl (4-fluorophenyl)malonate and 32.2 mL (135.2 mmol) tributylamine are stirred at 180° C. for 18 hours. The solution is diluted with 120 mL 2N NaOH solution and 120 mL water and the resulting mixture is extracted three times with methyl-tert. butylether. These organic extracts are discarded. The aqueous phase is acidified to pH 1 with 2N HCl. The precipitate is collected by filtration, washed with plenty of water and dried. This material (13.5 g=57.6%) is used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][C@H:7]1[CH2:17][CH2:18][CH2:19][CH3:20])=[O:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:17]([C@@H:7]1[CH2:8][C@H:9]([NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:10][CH2:11][C@@H:6]1[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of 2-amino-N-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexyl)acetamide was combined with 3-Trifluoromethylbenzoic acid (1 equivalent), EDCI (1 equivalent), HOBT (1.1 equivalents), and triethylamine (1 equivalent) in 2 mL of CH2Cl2 was stirred at room temperature overnight. The reaction mixture was directly chromatographed on silica gel (eluting with 2-8% NH4OH/MeOH/CH2Cl2) to give N-(2-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide as a white solid. MS found: (M+H)+=456.47; 1H NMR (400 MHz, CDCl3) δ(TMS): 0.83-1.98 (m, 25H), 2.67-2.79 (m, 1H) 4.12-4.28 (m, 3H), 6.80-6.90 (m, 1H), 7.49-7.63 (m, 2H), 7.78-7.84 (m, 1H), 8.00-8.06 (m, 1H), 8.15 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH:12]2[N:19](C(OC(C)(C)C)=O)[CH:15]([CH2:16][C:17]=1[CH3:18])[CH2:14][CH2:13]2)(=[O:10])[CH3:9]>>[C:8]([C:11]1[CH:12]2[NH:19][CH:15]([CH2:16][C:17]=1[CH3:18])[CH2:14][CH2:13]2)(=[O:10])[CH3:9]
Reactant: CC(=O)C1=C(C)CC2CCC1N2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1=C(C)CC2CCC1N2

Procedure:
A solution of trifluoroacetic acid (18.8 mmol, 2.13 mL) and 2-Acetyl-3-methyl-8-(tert-butyloxycarbonyl)-8-azabicyclo [3.2.1]oct-2-en (0.49 g, 1.88 mmol) was stirred at room temperature for about 0.5 hour. The solution was concentrated three times under reduced pressure after the addition of hexane to remove excess trifluoroacetic acid. A concentrated solution of sodium carbonate was added to the residue to form a basic solution. The solution was extracted with methylene chloride, dried using sodium sulfate and purified by bulb-to-bulb distillation (80° C. (1.0 mmHg)) to give 2-acetyl-3-methyl-8-azabicyclo [3.2.1]oct-2-ene.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[Se:8][C:7]=1[C:15]([O:17]CC)=[O:16])[CH3:3].[OH-].[Na+].Cl>CO.O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[Se:8][C:7]=1[C:15]([OH:17])=[O:16])[CH3:1]
Reactant: CCOC(=O)c1[se]c2ncccc2c1N=NN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)N=Nc1c(C(=O)O)[se]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-[(dimethylamino)diazenyl]selenopheno[2,3-b]pyridine-2-carboxylate (170 mg, 0.52 mmol), prepared as described in Example 6 step b) in methanol (10 mL) was added a solution of sodium hydroxide (83 mg, 2.08 mmol) in water (2 mL) and stirred at room temperature (rt) for 2 h. The mixture was diluted with ice cold water and acidified with dil. HCl. The mixture was stirred for 30 min and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product, which was recrystallized from chloroform-methanol-hexane as a light brown color solid (30 mg, 20%), mp 172-174° C. IR (KBr) νmax 3427, 3025, 2919, 1707, 1265, 1218, 1013, 863 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 13.09 (1H, br s, —COOH), 8.65-8.69 (2H, m, H-4,6), 7.53 (1H, dd, J=8.2, 4.6 Hz, H-5), 3.67 (3H, s, —NCH3), 3.29 (3H, s, —NCH3); LC-MS (positive ion mode): m/z 319, 321 (M+Na)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:22])[N:14]2[CH2:17][O:18][C:19](=[O:21])[CH3:20])=[CH:9][CH:8]=1.Cl.[S:24]1[CH:28]=[CH:27][C:26]2[C:29]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:30][CH:31]=[CH:32][C:25]1=2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[S:24]1[CH:28]=[CH:27][C:26]2[C:29]([N:33]3[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]4[CH:16]=[C:15]5[C:10]([CH:11]=[CH:12][C:13](=[O:22])[N:14]5[CH2:17][O:18][C:19](=[O:21])[CH3:20])=[CH:9][CH:8]=4)[CH2:35][CH2:34]3)=[CH:30][CH:31]=[CH:32][C:25]1=2
Reactant: c1cc(N2CCNCC2)c2ccsc2c1
Reactant: CC(=O)OCn1c(=O)ccc2ccc(OCCCCCl)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
Acetic acid 7-(4-chlorobutoxy)-2-oxo-2H-quinolin-1-ylmethyl ester (299 mg), 1-benzo[b]thiophen-4-ylpiperazine hydrochloride (235 mg), potassium carbonate (319 mg) and sodium iodide (152 mg) were suspended in DMF (5 ml), and this was stirred at 70° C. for 3 hr and further at 80° C. for 4 hr. After cooling to room temperature, to the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:9) and further by basic silica gel column chromatography, and concentrated under reduced pressure to give the title compound (132 mg) as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:41]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH:43]=[N:42]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2cn[nH]c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Yield: 42.9 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (24 mg, 0.048 mmols), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (28 mg, 0.144 mmols), potassium carbonate (40 mg), and Pd(PPh3)4 (3 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (10 mg, 43%)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: ClCc1ccccn1
Reactant: COc1cc(O)ccc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccn2)ccc1C=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
In 53 mL of N,N-dimethylformamide were dissolved 8.00 g (52.6 mmol) of 4-hydroxy-2-methoxybenzaldehyde, 14.5 g (105 mmol) of potassium carbonate, and 9.06 g (55.2 mmol) of 2-chloromethylpyridine hydrochloride and the solution was stirred at 50° C. for 4 hours. To the reaction mixture, 260 mL of water was added at room temperature and the precipitated crystal was separated by filtration. The crystal was washed with water and dried under reduced pressure to give 11.5 g (82% yield) of the title compound as a pale grey-brown powder with the following properties.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[CH2:13][C:14]#[N:15].[CH2:18](N)[CH2:19][NH2:20]>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:10])([F:11])[F:12])[C:4]=1[CH2:13][C:14]1[NH:20][CH2:19][CH2:18][N:15]=1
Reactant: N#CCc1c(C(F)(F)F)cccc1C(F)(F)F
Reactant: NCCN
Product: FC(F)(F)c1cccc(C(F)(F)F)c1CC1=NCCN1

Procedure:
2-(2,6-Bis-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2,6-bis-trifluoromethyl-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): colourless crystals; MS (EI): 296.2 (M+.), 275.1 ((M-F)+.), 267.1 ((M-C2H5)+.), 227.1 (((M-imidazoline)+.), 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:30](O)=[O:31])=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:21]3[C:20]([Cl:19])=[CH:25][C:24]([C:26]([F:28])([F:27])[F:29])=[CH:23][N:22]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a light yellow oil. MS (ISP): m/z=467.2 [M+H]+.