Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:47](=[O:48])[C:46]2[C:41](=[C:42]([O:51][CH3:52])[C:43]([O:49][CH3:50])=[CH:44][CH:45]=2)[O:40][C:39]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:47](=[O:48])[C:46]4[C:41](=[C:42]([O:51][CH3:52])[C:43]([O:49][CH3:50])=[CH:44][CH:45]=4)[O:40][C:39]=3[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1OC
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1OC
Yield: 41 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7,8-dimethoxy-2-phenyl-chromen-4-one (82 mg, 0.20 mmol) was reacted to give the title compound (41 mg, 41%). 1H NMR (400 MHz, CDCl3): δ 7.56-7.52 (d, 1H), 6.99-6.68 (m, 9H), 6.61-6.56 (d, 1H), 4.61-4.54 (m, 1H), 3.57-3.53 (m, 6H), 2.12-2.00 (m, 4H), 1.65-1.28 (m, 2H), 1.00-0.72 (m, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[S:17][CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH3:21][C:20]1[CH:19]=[CH:18][S:17][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Cc1ccsc1Br
Product: COC(=O)CCc1ccc(C#Cc2sccc2C)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 2-bromo-3-methylthiophene (70 μL, 0.62 mmol) according to the general procedure IF to give 75 mg (53%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:5): Rf=0.57 (EtOAc:PE, 1:2); 1H NMR (CDCl3) δ 7.47-7.40 (m, 2H), 7.17 (dd, J=8.4, 6.7 Hz, 3H), 6.85 (d, J=5.1 Hz, 1H), 3.67 (s, 3H), 2.96 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 2.37 (s, 3H); 13C NMR (CDCl3) δ 173.1, 142.4, 140.8, 131.5, 129.2, 128.3, 125.7, 121.2, 118.7, 95.2, 82.0, 51.6, 35.4, 30.8, 15.0; ESI-MS m/z 307.1 (M+Na+).
Reaction SMILES: [OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[CH3:15]I>O1CCCC1.[Ag]=O>[CH3:15][O:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)CC1CCC(O)c2sccc21
Reactant: CI
Agent: O=[Ag]
Solvent: C1CCOC1
Product: COC1CCC(CC(N)=O)c2ccsc21
Reaction time: 8 h
Yield: 95 %

Procedure:
Eight g (37.86 mm) of 4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylacetamide and methyl iodide (28 ml, 0.45 M) are stirred in tetrahydrofuran (160 ml). The suspension is treated with silver oxide (60 g, 0.259 M) added in portions over a period of 5 hours. The reaction mixture is stirred overnight, filtered through celite, the cake is washed with tetrahydrofuran (2 × 100 ml) and dichloromethane (100 ml) and the filtrate evaporated to afford the crude title compound as a yellow-orange solid (8.1 g, 95% Y) m.p. 108° C-113° C dec. Two recrystallizations from acetone/hexane afford the analytical specimen, m.p. 124° C-126° C dec.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.Cl[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([O:27][CH3:28])[CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:28][O:27][C:25]1[CH:26]=[C:21]([C:9]2[CH2:18][CH2:17][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:11][CH:10]=2)[CH:22]=[CH:23][C:24]=1[N+:29]([O-:31])=[O:30]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C2=CCC3(CC2)OCCO3)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (1.09 g, 4.13 mmol) in dioxane (17 mL) was added 5-chloro-2-nitroanisole (0.64 g, 3.44 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol) and 1.0 M Na2CO3 in H2O (10.32 mL, 10.32 mmol). The mixture was degassed by purging the reaction flask with vacuum/then N2 back-fill (5×). Under N2 the reaction was then heated to 80° C. and stirred overnight (approximately 16 h). The reaction was cooled to rt and diluted with EtOAc, then filtered through Celite, washing with EtOAc. The filtrate was concentrated under vacuum. The residue was taken up in EtOAc and H2O. The H2O layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step C (911 mg, 3.13 mmol, 91%) as an amber oil. MS (ESI): 292 [M+H]+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:29][C:30]1[C:31]([Cl:42])=[CH:32][C:33]2[S:34][CH2:35][C:36](=[O:41])[N:37]([CH3:40])[C:38]=2[N:39]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Cl:42][C:31]1[C:30]([CH2:29][NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]=[CH:18][C:17]3=[O:28])[CH2:10][CH2:9]2)=[N:39][C:38]2[N:37]([CH3:40])[C:36](=[O:41])[CH2:35][S:34][C:33]=2[CH:32]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4nc5c(cc4Cl)SCC(=O)N5C)C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4nc5c(cc4Cl)SCC(=O)N5C)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To 20 mL of a chloroform solution containing 0.23 g of tert-butyl(7-chloro-4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 20 mL of trifluoroacetic acid was added and stirred at room temperature for 12 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.16 g of 1-(2-(4-((7-chloro-4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[C:15]2[CH2:18][N:17]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]2[CH2:18][N:17]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cc(F)cc(Br)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(c1cc(F)cc(Br)c1)C1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared from ethyl (3-bromo-5-fluorophenyl)[1-(diphenylmethyl) azetidin-3-ylidene]acetate according to the procedure described in Preparation 6 except that THF was used as the co-solvent; Mass Spectrum: m/e=482 (M+1, 79Br), 484 (M+1, 81Br).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:15][NH:14][CH2:13]1)=[O:11].[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:14]3[CH2:15][CH:12]([C:10](=[O:11])[NH:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:16])[F:17])[CH2:13]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CNC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CC(C(=O)Nc3ccccc3C(F)(F)F)C2)nn1
Yield: 11 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use azetidine-3-carboxylic acid (2-trifluoromethylphenyl)amide in place of piperidin-4-yl-(2-trifluoromethylphenyl)amine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 11% yield. 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J=8.2 Hz, 1H), 8.02 (d, J=9.2 Hz, 1H), 8.0 (m, 1H), 7.65-7.55 (m, 3H), 7.27 (m, 1H), 6.65 (d, J=9.2 Hz, 1H), 4.4-4.5 (m, 4H), 3.75-3.65 (m, 1H), 3.6-3.5 (m, 2H), 1.5 (q, J=7.5 Hz, 2H), 0.75-0.70 (m, 1H), 0.5-0.4 (m, 2H), 0.10-0.06 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 169.9, 163.2, 160.5, 145.1, 134.5, 133.0, 126.6, 126.3, 125.2, 111.2, 55.0, 39.6, 36.0, 34.5, 8.6, 4.2. MS (ES+) m/z 434 (M+1).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][N:40](C(OC(C)(C)C)=O)[CH:41]=2)O1>C(O)C.C1(C)C=CC=CC=1.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>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:37]3[CH:38]=[N:39][NH:40][CH:41]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C
Reaction time: 60 h

Procedure:
1-Methylethyl((cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol) was dissolved in ethanol (1 mL) and Toluene (1 mL), mixed with potassium carbonate (74.9 mg, 0.542 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (96 mg, 0.325 mmol, available from Aldrich) and tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) and refluxed under nitrogen at 90° C. for 22 hours reaction time. The reaction was left to stand at room temperature for 2.5 days. It was refluxed again at 90° C. for 24 hours. A second sample of 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (96 mg, 0.325 mmol) was added to the reaction mixture after this time and heating continued. A third sample of 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (96 mg, 0.325 mmol) was added to the reaction mixture after 102.5 hours reaction time and the mixture was allowed to stir overnight under nitrogen at the same temperature. Another sample of 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (96 mg, 0.325 mmol) was added after 199 hours total reaction time. After 248 hours reaction time the mixture was cooled to room temperature and partitioned between distilled water (40 mL) and EtOAc (40 mL). The organic and aqueous layers were run off and the latter was extracted 3 more times using EtOAc (3×40 mL). Organic fractions were combined, washed (brine (50 mL), dried (sodium sulfate), filtered and evaporated to dryness to give an orange/brown oil (248 mg). The residue was purified by SP4 on a 25+S silica cartridge using a gradient of 0 to 2.5% 2M methanloic ammonia in ethyl acetate. Product-containing fractions were evaporated to dryness and purified again using MDAP. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (18 mg). LCMS (Method C): Rt=0.73, MH+=357
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.CO.[CH3:17][Si](C=[N+]=[N-])(C)C>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)cc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
4-Amino-2-(trifluoromethyl)benzoic acid (10 g, 48.8 mmol) was suspended in THF (100 mL) and methanol (30 mL) and was cooled in an ice bath. (Trimethylsilyl)diazomethane (2 M solution in hexanes; 32 mL) was added drop-wise. The mixture was stirred for 5 minutes and then concentrated to afford methyl 4-amino-2-(trifluoromethyl)benzoate (quantitative yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 1H), 6.99 (d, 1H), 6.77 (d, 1H), 4.18 (br s, 2H), 3.88 (s, 3H); GCMS for C9H8F3NO2: 219 (M+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21](Cl)=[C:16]3[CH:15]=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30](=[O:39])[NH:31][CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C>C1COCC1>[C:25]([O:29][C:30](=[O:39])[NH:31][CH:32]1[CH2:33][CH2:34][CH:35]([NH:38][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[N:13]([C:5]4[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[N:14]=[CH:15][C:16]=23)[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1cc(-n2ncc3c(Cl)ncnc32)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3c2cnn3-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
1-(3,5-Bis-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (147 mg, 0.4 mmol), (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.44 mmole, 1.1 eq) and diisopropylethyl amine (0.44 mmol, 1.1 eq) were dissolved in THF (3 mL) and then stirred at room temperature over night. THF was removed in vacuo and the solid residue was re-dissolved in 30/70 mixture of water and ACN gave yellow solid. The solid was washed with water and dried in vacuo provided compound A44 as creamy green solid (179 mg, 82%). 1H NMR (CDCl3, 400 MHz) δ 1.43 (s, 9H), 1.75 (m, 2H), 1.98–1.97 (m, 2H), 2.04 (m, 2H), 2.95 (sb, 2H), 4.12 (q, 1H), 4.62 (m, 1H), 7.80 (s, 1H), 8.09 (s, 1H), 8.50 (s, 1H), 8.94 (m, 2H). Exact mass calculated for C24H26F6N6O2 544.2, Found 545.5 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[C:8]=2[CH:13]([CH3:15])[CH3:14])[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:8]([CH:13]([CH3:14])[CH3:15])=[C:7]([O:16][CH3:17])[C:6]([O:18][CH3:19])=[CH:5]2)=[CH:10][C:11]=1[CH3:12]
Reactant: COc1cc2c(c(C(C)C)c1OC)CC(C)C(Br)=C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1cc2cc(Br)c(C)cc2c(C(C)C)c1OC
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Compound 13 (3.50 g, 10.8 mmol) was dissolved in 25 mL of benzene and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.45 g, 10.8 mmol) was added slowly with stirring and stirring was continued for 2 h. The reaction mixture was filtered through a short column of silica and eluted with dichloromethane. The solvent was evaporated and the product was crystallized from petroleum ether to give 3.21 g (9.93 mmol, 92%) of 14 as colorless crystals: mp 62°-63° C.; 1H NMR δ 1.51 (d, J-7.2 Hz, 6 H), 2.56 (s, 3 H), 3.90 (s, 3 H), 3.96 (s, 3H), 3.97 (m, 1 H), 6.94 (s, 1 H), 7.92 (s, 1 H), 7.96 (s, 1 H). Anal. (C16H19 BrO2) C,H.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[CH2:14]1[O:16][CH2:15]1>C(O)C>[OH:16][CH2:15][CH2:14][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: C1CO1
Reactant: CC1CC(C)(C)NC2CCCCC12
Solvent: CCO
Product: CC1CC(C)(C)N(CCO)C2CCCCC12

Procedure:
1-(2'-hydroxyethyl)-2,2,4-trimethyl decahydroquinoline was prepared. 150 milliliters of ethanol and 84.0 grams (0.3 mole) of 2,2,4-trimethyl decahydroquinoline of about 96% cis structure were placed in a reactor vessel equipped for heating and agitation. 15.4 grams (0.35 mole) of ethylene oxide was added dropwise to the reactor vessel and the mix then heated to reflux for 21 hours. The ethanol was then evaporated off and the reaction mixture distilled to yield 10.2 grams of a liquid product boiling at 103°-105° C. at 0.3 mm Hg. The NMR and mass spectrometer spectra were consistent with the desired product. Calculated contents for the formula C14H27NO are 74.61% carbon, 12.08% hydrogen, and 6.22% nitrogen and the measured contents were 74.62% carbon, 12.11% hydrogen, and 6.13% nitrogen.
Reaction SMILES: [N:1]([C@H:4]1[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:8]=2[CH2:7][CH2:6][CH2:5]1)[CH2:15][N:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]3)=[N+]=[N-]>CCOC(C)=O.CO.[Pd]>[CH2:18]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][C:8]3[CH2:7][CH2:6][CH2:5][C@@H:4]([NH2:1])[C:9]=3[CH:10]=2)[CH2:15]1)[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CN1CCc2cc3c(cc2C1)CCC[C@H]3N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CN1CCc2cc3c(cc2C1)CCC[C@H]3N
Reaction time: 8 h

Procedure:
A suspension of 30 mg of Pd/C (10% w/w) in a solution of (R)-6-azido-2-isobutyl-1,2,3,4,6,7,8,9-octahydrobenzo[g]isoquinoline (296 mg, 1 mmol) in 30 mL of EtOAc was stirred under H2 atmosphere overnight. The reaction mixture was then directly submitted to flash chomatograph (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:15 to 100:25 to 100:35) to give (R)-2-isobutyl-1,2,3,4,6,7,8,9-octahydrobenzo[g]isoquinolin-6-amine as a colorless oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[C:19]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([I:1])=[N:3]2)[CH:18]=[CH:17][N:16]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1ccnc(Cl)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.12 g, 0.016 mol) in N,N-dimethylformamide (50 mL) was reacted with 60% sodium hydride in oil (0.75 g, 0.019 mol) at ambient temperature. The mixture was stirred for 15 minutes, and 2-chloro-4-nitropyridine (3.00 g, 0.019 mol) was added. The mixture was heated at 100° C. for 18 hours. The mixture was cooled to room temperature and the precipitate was filtered, washing with N,N-dimethylformamide (20 mL), and then slurried in ethyl acetate (50 mL) for four hours. The solid was filtered and dried in vacuo to give 1-(2-chloro-4-pyridyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.39 g, 0.009 mol) as a tan solid:
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].CO.[CH2:7]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][CH3:10]>O1CCOCC1>[CH2:15]([N:14]1[CH2:13][CH2:12][N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:1]1=[O:2])[CH2:16][CH2:17][CH3:18]
Reactant: O=CC=O
Reactant: CCCCNCCNCCCC
Solvent: C1COCCO1
Solvent: CO
Product: CCCCN1CCN(CCCC)C(=O)C1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To 10 g (69.0 mmoles) of 40 percent glyoxal and 200 ml of methanol is rapidly added 11.9 g (69.0 mmoles) of N,N'-di(n-butyl)ethylenediamine. The solution is rapidly brought to reflux and heating is maintained for 5 minutes. The dark brown solution is then allowed to cool to room temperature at which time fine white crystals precipitate from the brown oil. The oil is diluted with 100 ml of 1,4-dioxane and the solid is removed by filtration. The dioxane solution is concentrated under aspirator vacuum and distilled in a short path distillation apparatus to give 4.5 g of 1,4-di(n-butyl)piperazin-2-one in the form of a brown oil (31 percent yield).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[CH:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([CH3:16])[N:11]=[C:12]([C@@H:14]3[CH2:15][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)[N:3]=1
Reactant: C=Cc1cc(-n2nc(C)nc2C)cc(C)n1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)cc(C)n1
Temperature: 25 °C

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyridine (24-4, 620 mg, 2.69 mmol) in toluene (12 mL) was added at reflux a solution of ethyl diazoacetate (614 mg, 5.38 mmol) in toluene (2 mL) in three portions over 10 minutes. The reaction mixture was refluxed for 2 hours, cooled to room temperature, and concentrated. The residue was purified by silica gel column chromatography (0-90% ethyl acetate in hexanes) to afford ethyl trans-2-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-2-yl)cyclopropanecarboxylate (24-5) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.17 (d, 1H, J=1.7 Hz), 7.09 (d, 1H, J=1.7 Hz), 4.17 (q, 2H, J=7.2 Hz), 2.63-2.57 (m, 1H), 2.59 (s, 3H), 2.52 (s, 3H), 2.41 (s, 3H), 2.33-2.27 (m, 1H), 1.70-1.57 (m, 2H), 1.28 (d, 3H, J=7.2 Hz). LRMS m/z (M+H) 301 found, 301 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1.C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:36]3[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[N:10]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)O)c3)cc12
Yield: 66.8 %

Procedure:
To a mixture of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (500 mg, 1.04 mmol) and 3-bromophenylacetic acid (268 mg, 1.25 mmol) in a 20 mL microwave reaction flask was added THF (3 mL), acetonitrile (3 mL) and sodium carbonate (3 mL, 1 N aqueous solution, 3 mmol). The mixture was bubbled with N2 for 1 min. dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II) (73 mg, 10% mol) was added and the bubbling continued for another minute. The flask was sealed and irradiated with microwave in Emrys Optimizer at 120° C. for 20 min. The reaction mixture was partitioned between aqueous saturated sodium chloride and ethyl acetate (15 mL: 15 mL). The aqueous layer was extracted with ethyl acetate (10 mL×2). Normal work up of the combined organic layers and purification with flash chromatography on silica gel using a gradient of methanol in dichloromethane yielded {3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid as a yellow solid (340 mg, 67% yield). MS: m/z 490 (M+H+).