Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][CH:28]([CH3:30])[CH3:29])C.CC(C)CC#C.ClC(OCC)=O>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CCC(C)C
Agent: C#CCC(C)C
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 5-methyl-hex-2-ynoic acid ethyl ester (prepared from 4-methyl-pent-1-yne and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, 5697-5708) employing the procedure described in Example 99. [α]D25 −13.93 (c 0.546, CHCl3)
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:29][CH2:30][CH2:31][OH:32].Cl>>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][CH2:29][CH2:30][CH2:31][OH:32])[CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: OCCCCl
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(N)C4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(NCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS301 starting from 73 mg (0.20 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-3-ylamine and 33 μl of 3-chloro-1-propanol. The product is the hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:15][CH2:16][C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][OH:12])[CH:9]=1)([O-:3])=[O:2].[CH3:25][C:26]([CH3:28])=O>>[CH3:25][C:26]1([CH3:28])[O:14][C:10]([CH3:13])([C:8]2[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([O:15][CH2:16][C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:7]=2)[CH2:11][O:12]1
Reactant: CC(O)(CO)c1cc(OCC#Cc2ccccc2)cc([N+](=O)[O-])c1
Reactant: CC(C)=O
Product: CC1(C)OCC(C)(c2cc(OCC#Cc3ccccc3)cc([N+](=O)[O-])c2)O1
Yield: 95 %

Procedure:
Using the procedure described in Example 1, 2-[5-nitro-3-(3-phenylprop-2-ynyloxy)phenyl]propane-1,2-diol was reacted with acetone to give 2,2,4-trimethyl-4-[5-nitro-3-(3-phenylprop-2-ynyloxy)phenyl]-1,3-dioxolane in 95% yield, as an oil.
Reaction SMILES: N1CCC([O:6][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)C1.[OH-].[Na+].C1O[C@H]1C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[C:7]([OH:14])(=[O:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OC1CCNC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc([C@H]2CO2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Yield: 234.6 %

Procedure:
To a biphasic mixture of 25.0 gm of the compound of Example 2 (69 mmol, 1.0 equiv.) in 125 mL of toluene was added 2.75 gm of sodium hydroxide (69 mmol, 1.0 equiv.) dissolved in 20 mL of water followed by 8.27 gm (69 mmol, 1.0 equiv.) of (S)-styrene oxide. The reaction mixture was heated to reflux overnight, at which time HPLC analysis showed that only trace starting material remained. Upon cooling to room temperature the layers were separated. The organic layer was washed with an additional 1.4 gm (35 mmol, 0.5 equiv.) of sodium hydroxide dissolved in 20 mL of water followed by another wash with 20 mL of water. The toluene solvent was removed under vacuum to provide 19.77 gm (92%) of a thick oil which solidified on standing. The crude product contained an ~1.2:1.0 mixture of regioisomers and was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]([CH3:21])[CH2:19][OH:20])[CH2:11][CH2:10]2.[H-].[Na+].[CH3:27]I.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]([CH3:21])[CH2:19][O:20][CH3:27])[CH2:11][CH2:10]2
Reactant: CC(CO)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(C)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Yield: 45.4 %

Procedure:
To a mixture of 6-(3-Fluoro-benzyloxy)-2-(2-hydroxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinolin-1-one (0.020 g, 0.061 mmol) and sodium hydride (55%, 2.2 mg, 0.067 mmol) in N,N′-dimethylformamide (0.2 mL), methyl iodide (0.009 mL, 0.152 mmol) was added. Water was added and the reaction was extracted with ethyl acetate. After drying of the organic layer with MgSO4, filtration and evaporation, the residue was purified by chromatography (SiO2, hexane/ethyl acetate 9:1 v:v) to give the title compound as a white solid (0.0095 g, 43%). MS: m/e=344.4 (M+H+).
Reaction SMILES: [Na].O=[C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH:5]=O.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[NH:21][C:22]([NH2:24])=[NH:23].[OH-].[K+]>C(O)CCC.C(O)(=O)C>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[NH:21][C:22]1[N:24]=[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:23]=1
Reactant: O=CCC(=O)c1cccnc1
Reactant: Cc1ccc(N)cc1NC(=N)N
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCCO
Product: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C

Procedure:
Under inert atmosphere, 16 g sodium salt of β-oxo-3-pyridinepropanal, with HPLC purity of 99% (A %) and 25% salt content (residue by calcination), and 11.7 g (2-methyl-5-aminophenyl)guanidine in 115 mL n-butanol is suspended. 9 mL acetic acid is added, and the mixture is stirred at room temperature for an hour. 6 g potassium hydroxide is added portionwise, and the mixture is refluxed for 18 hours, removing the water with a Dean Stark apparatus. Once completed the conversion, the suspension is cooled and the organic layer is washed with water. The organic layer is concentrated to a small volume, and toluene is added. The precipitate is filtrated, yielding, upon drying, 15.5 g of product with HPLC purity of 99.2% (A %), identified through LC-MS and 1H-NMR.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.B(OC(C)C)(OC(C)C)[O:22]C(C)C.[OH-].[Na+].OO>C1COCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([F:20])[C:17]([OH:22])=[CH:18][CH:19]=1
Reactant: Fc1cccc(Cl)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: OO
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Oc1ccc(Cl)nc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of i-Pr2NH (828 mL, 5.85 mol) in anhydrous THF (1.3 L) was cooled to −10° C. n-BuLi (1.6 M in hexanes, 3660 mL, 5.85 mol) was added and the solution was stirred for 10 min at 0° C. The reaction mixture was cooled to −78° C. and a solution of 2-chloro-6-fluoropyridine (700 g, 5.32 mol) in anhydrous THF (1.3 L) was slowly added keeping the internal temperature below −60° C. After the addition was complete, the reaction mixture was stirred for an additional hour and then a solution of triisopropyl borate (1221 mL, 5.32 mol) in anhydrous THF (620 mL) was added drop wise keeping the internal temperature below −60° C. After the addition, the reaction mixture was warmed to RT and stirred over night. Water (3 L) was added and the mixture was stirred vigorously. The reaction mixture was concentrated under reduced pressure. The residue was treated with a cold aqueous solution of NaOH (10 M, 1610 mL, 16.0 mol) and 50% H2O2 (392 mL, 6.92 mol) and stirred over night (Note: the internal temperature increased slowly from 5 to 60° C.). The reaction mixture was quenched with ice and 4N HCl until pH of the mixture was ˜5. EtOAc (5 L) was added and stirred well. After phase separation, the aqueous layer was extracted with EtOAc (1.5 L×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide 6-chloro-2-fluoropyridin-3-ol as an off white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21][C:22]4[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=4[F:32])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:33])[NH:10][N:9]=2)[CH:7]=1>[Pd]>[CH3:35][O:34][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([O:21][C:22]3[C:23]([F:32])=[C:24]([F:31])[C:25]([F:30])=[C:26]([F:29])[C:27]=3[F:28])(=[O:19])=[O:20])=[CH:15][CH:16]=2)[C:11](=[O:33])[NH:10][N:9]=1
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: [Pd]
Product: COc1ccccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 75 °C
Reaction time: 48 h
Yield: 52.3 %

Procedure:
A RBF was charged with perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (1.25 g, 2.35 mmol). The reaction was purged with N2. Then ethyl acetate (23.5 mL) was added followed by palladium, 10 wt % on activated carbon (0.749 g, 0.704 mmol). The flask was evacuated and back filled with N2 (3×). The flask was evacuated again and then pressurized with hydrogen to 42 PSI. The reaction was heated to 75° C. After 2 d, LCMS showed 92:8 ratio of product:SM. The reaction was cooled to rt and filtered through a pad of Celite with the aid of EtOAc. The filtrate was concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 30% EtOAc in heptane, to provide perfluorophenyl 1-(2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (613 mg, 52.4% yield) as off-white solid. m/z (ESI) 499.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:20]1([C:26]([C:28]2[NH:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:33][C:31]4[NH:32][C:28]([C:26]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[O:27])=[CH:29][CH:30]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: O=Cc1ccc(C(=O)N2CCOCC2)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1ccc(C(=O)N2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (62.5 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 69 mg (59%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.41 (br s, 1H, NH), 11.65 (br s, 1H, NH), 8.81 (br s, 1H, NH), 8.28 (s, 1H), 7.76 (s, 1H), 7.75 (m, 1H), 7.53 (m, 1H), 7.38 (t, J=9.05 Hz, 1H), 6.91 (d, J=3.6 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 3.71 (m, 4H, 2×CH2), 3.65 (m, 4H, 2×CH2). MS 469 [M++1].
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([OH:33])(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[CH2:34]([O:41][CH2:42][C@H:43](O)[CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:34]([O:41][CH2:42][C@H:43]([O:32][C:16](=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCOC[C@@H](O)COCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCCOC[C@H](COCc1ccccc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 4 mL solution of DCC (111 mg, 0.54 mmol), DMAP (3 mg, 0.02 mmol) and palmitic acid (86 mg, 0.34 mmol) in CH2Cl2 was cooled to 0° C. A solution of 3-O-benzyl-1-O-oleyl-sn-glycerol (100 mg, 0.228 mmol) in CH2Cl2 (2 mL) was added to it in a drop-wise manner and stirred for 12 h at rt. The mixture was filtered over Celite, washed with saturated aqueous sodium bicarbonate solution and brine, dried on anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using silica gel (hexane:EtOAc=15:1, Rf=0.35) to get the product (154 mg, quantitative) as colorless oil. [α]D28+5° (c=2.0, CHCl3); IR (CHCl3) cm−1 2924, 2854, 1742, 1651, 1460, 1369, 1241, 1164, 1109, 1028, 733, 698 cm−1; 1H NMR (600 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 6H, CH3), 1.22-1.38 (m, 44H, CH2), 1.52 (dt, J=7.2, 14.4 Hz, 4H, CH2), 1.94 (dd, J=6.6, 12.6 Hz, 4H, CH2), 2.20 (t, J=7.8 Hz, 2H, CH2), 2.24 (t, J=7.8 Hz, 2H, CH2), 3.51 (ddd, J=5.0, 10.2, 15.6 Hz, 2H, CH2OBn), 4.11 (dd, J=5.4, 12.0 Hz, 1H, CH2OAcyl), 4.27 (dd, J=3.6, 12.0 Hz, 1H, CH2OAcyl), 4.44, 4.48 (AB q, J=12.0 Hz, 2H, PhCH2), 4.06 (dt, J=4.2, 9.0 Hz, 1H, CH), 5.35 (ddd, J=6.0, 11.4, 15.6 Hz, 2H, CH═CH 7.20-7.32 (m, 5H, ArH); 13C NMR (150 MHz, CDCl3) δ 14.1, 22.65, 22.66, 24.8, 24.9, 27.1, 27.2, 29.06, 29.09, 29.16, 29.27, 29.29, 29.33, 29.46, 29.50, 29.61, 29.63, 29.67, 29.74, 31.88, 31.90, 34.1, 34.3, 62.6, 68.2, 70.0, 73.3, 127.6, 127.7, 128.4, 129.7, 130.0, 137.7, 173.0, 173.3; EMSI calc'd for C44H76NaO5 [M+Na]+ 707.56. found: 707.50.
Reaction SMILES: [O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:47])[NH:9][C@@H:10]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:11]([OH:39])[CH2:12][N:13]([CH2:31][C:32]([CH3:38])([CH3:37])[CH2:33][CH2:34][C:35]#[N:36])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:4][O:3][CH2:2]1>CO>[O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:47])[NH:9][C@@H:10]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:11]([OH:39])[CH2:12][N:13]([CH2:31][C:32]([CH3:38])([CH3:37])[CH2:33][CH2:34][C:35]#[N:36])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:4][O:3][CH2:2]1
Reactant: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CO
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)S(=O)(=O)c1ccc(O)cc1
Reaction time: 0.5 h
Yield: 115.8 %

Procedure:
{(1S,2R)-1-Benzyl-3-[(4-cyano-2,2-dimethyl-butyl)-(4-benzyloxybenzenesulfonyl)-amino]-2-hydroxy-propyl]-carbamic acid[1,3]dioxan-5-yl ester (2.2 mg, 0.003 mmol) was dissolved in methanol (1 mL). Solution was degassed with nitrogen for 5 minutes the 10% Pd/C (2 mg) was added. Reaction was pressurized with H2 (1 ATM) and stirred for 30 minutes. Catalyst removed by filtration and solvent was removed in vacuo leaving 2.0 mg (95%) of product as a colorless residue. MS(ES): 576.2 (M+1), HPLC; tR=10.39 min. (84%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4]>[C].[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (200 mg) obtained in Example 94, 10% palladium carbon (20 mg) and methanol (4 ml) was stirred under a hydrogen atmosphere for 1 hr. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (127 mg) as a colorless powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[C:12]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][C:15]=2[CH3:20])[C:11]([Cl:21])=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][C:9]2=[O:22].[CH2:23]([O:30][C:31]1[C:36]([CH2:37]Cl)=[C:35]([CH3:39])[CH:34]=[C:33]([CH3:40])[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:30][C:31]1[C:36]([CH2:37][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[C:11]([Cl:21])[C:12]([C:14]4[N:18]([CH3:19])[N:17]=[N:16][C:15]=4[CH3:20])=[CH:13][C:4]=3[Br:3])[C:9]2=[O:22])=[C:35]([CH3:39])[CH:34]=[C:33]([CH3:40])[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nnn(C)c1-c1cc(Br)c2c(c1Cl)C(=O)NCC2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCc3c(Br)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 18 mg, 0.45 mmol) was added to an icebath chilled solution of 5-bromo-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293h, 80 mg, 0.225 mmol) in anhydrous N,N-dimethylformamide (15 mL), and the resulting mixture stirred at 0° C. for 30 minutes. Solid 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (compound Z, 59 mg, 0.225 mmol) was added and stirring continued at 0° C. for one hour. While still cold, the reaction was quenched with water (20 mL). The resulting solution was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (5×50 mL), dried over sodium sulfate, concentrated, and purified by silica gel chromatography (eluting with 1:1 petroleum ether/ethyl acetate) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293i, 76 mg, 58% yield) as a light yellow oil.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C#C)[CH2:2]CC.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:26][CH:27]=2)=[CH:19][CH:18]=1.[Li+].[Cl-]>O1CCOCC1.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>[C:1]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:24][C:25]([C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N:26][CH:27]=2)=[CH:19][CH:18]=1)#[CH:2]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C#Cc1ccc(-c2cnc([C@@H]3CCCN3C(=O)OC(C)(C)C)[nH]2)cc1
Temperature: 80 °C

Procedure:
Pd(Ph3P)4 (0.115 g, 0.099 mmol) was added to a mixture of tributyl(ethynyl)stannane (1.539 g, 4.88 mmol), (S)-tert-butyl 2-(4-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.965 g, 2.46 mmol; for its preparation, see PCT Publication No. WO 2008/021927) and LiCl (0.277 g, 6.53 mmol) in dioxane (20 mL) in a sealed pressure tube. The mixture was purged with nitrogen, sealed and heated at 80° C. for 3 hr. After it was allowed to cool to ambient temperature, the volatile component was removed in vacuo and the residue was partitioned between CH3CN and hexanes (2:1 ratio in volume). The hexane layer was washed with an equal volume of CH3CN. The combined CH3CN phase was rotervaped, and the resultant crude material was purified with a BIOTAGE® (100 g silica gel; 40-50% EtOAc/hexanes) to afford Intermediate M1a as a dull orange solid (591 mg). 1H NMR (DMSO-d6, δ=2.50 ppm, 400 MHz): 12.21/11.95/11.88 (three ‘br s’, 1H), 7.74 (d, J=8.3, 1.6H), 7.66-7.47 (m, 1.66H), 7.41 (d, J=8.3, 1.6H), 7.32 (m, 0.14H), 4.84-4.75 (m, 1H), 4.19/4.12 (two ‘s’, 1H), 3.52 (m, 1H), 3.39-3.29 (m, 1H), 2.28-1.77 (m, 4H), 1.39/1.15 (two ‘s’, 9H). LC/MS: Anal. Calcd. for (M+H)+ C20H24N3O2: 338.18. Found, 338.28.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C(CO)=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>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Brc1cnn(-c2ccccc2)c1
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CO
Agent: O=C([O-])[O-]
Product: c1ccc(-n2cc(-c3ccco3)cn2)cc1
Temperature: 80 °C
Yield: 15.9 %

Procedure:
4-bromo-1-phenyl-1H-pyrazole (140 mg, 0.627 mmol), furan-2-ylboronic acid (88.2 mg, 0.941 mmol), Pd(PPh3)4 (70 mg, 0.062 mmol), and Cs2CO3 (400 mg, 1.254 mmol) were combined in toluene-methanol (1:1) (2 ml). The reaction mixture was heated under microwave at 80° C. for 60 minutes. The reaction mixture was then filtered and washed with toluene-ethanol (5 ml), and the filtrate was concentrated. The crude product was column purified using 15-20% ethyl acetate/hexanes, and was then further purified by preparative HPLC to yield the desired 4-(furan-2-yl)-1-phenyl-1H-pyrazole (22 mg, 0.10 mmol 16.7%). The HPLC purity of the final product was 99.72%. LC-MS [M+H] 211 (C13H10N2O+H expected 211.08). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13]Br)=[CH:5][CH:4]=1.[ClH:15]>C(Cl)Cl>[ClH:15].[Br:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][NH2:1])=[CH:5][CH:4]=1
Reactant: N
Reactant: BrCc1ccc(Br)c2ccccc12
Agent: Cl
Solvent: ClCCl
Product: NCc1ccc(Br)c2ccccc12
Temperature: -40 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of 1-bromo-4-methylnaphthaline (25 g, 0.113 mol), NBS (22.2 g, 0.123 mol) and benzoylperoxide (5 g) in CCl4 (750 mL) was refluxed for 5 h. The reaction mixture was cooled, filtered off the succinimide and concentrated to give crude bromide (34 g) and used for the next reaction without any purification. To a cold (−40° C.) solution of liquid ammonia (2 L) was added 1-bromo-4-bromomethyl naphthaline (crude 34 g) dissolved in 200 mL of CH2Cl2 over a period of 45 min. The reaction mixture was then stirred at −40° C. for 18 h. The reaction mixture was then allowed to stir at RT and concentrated under vacuum to give yellow residue. The residue was then treated with 3N HCl (250 mL), filtered off the solid obtained and washed with CH2Cl2 (2×250 mL). The solid was dried under vacuum to give (4-bromo-1-naphthyl)methylamine hydrochloride (25 g, 80%). HPLC purity: 96.6%