Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[S:21][CH3:22].I([O-])(=O)(=O)=[O:24].[Na+].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO>[CH3:22][S:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]=1)=[O:24]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1c(-c2ccncc2S(C)=O)nc2cc(C(F)(F)F)ccc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a mixture of 0.49 g of 1-methyl-2-(3-methylthiopyridine-4-yl)-5-trifluoromethyl-1H-benzimidazole, 5 ml of methanol and 10 ml of water was added 0.65 g of sodium periodate under ice cool, then, the mixture was stirred for 1 hour at 40° C. After cooling down to room temperature, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium thiosulfate aqueous solution were poured, and the mixture was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.48 g of 2-(3-methanesulfinylpyridin-4-yl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 18).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH:15]=[CH:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:28]=1)[CH3:2]>[Pd].CO>[CH2:1]([C:3]1[N:4]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH2:15][CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:28]=1)[CH3:2]
Reactant: CCc1nc2cnc3cc(C=CN4C(=O)c5ccccc5C4=O)ccc3c2n1CC(C)(C)O
Agent: [Pd]
Solvent: CO
Product: CCc1nc2cnc3cc(CCN4C(=O)c5ccccc5C4=O)ccc3c2n1CC(C)(C)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (0.4 g), methanol (75 mL) and 2-{2-[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]ethenyl}-1H-isoindole-1,3(2H)-dione (1.9 g, 4.3 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The reaction was shaken at 50° C. for approximately 18 hours and then cooled to ambient temperature. The reaction mixture was filtered followed by concentration under reduced pressure to provide 1.9 g of 2-{2-[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]ethyl}-1H-isoindole-1,3(2H)-dione as a bright yellow solid. MS (APCI) m/z 443 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:28]=[C:29]([NH:33][C:34](=[O:41])[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH:30]=[CH:31][CH:32]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH2:42](Cl)Cl.CO.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:42][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:28]=[C:29]([NH:33][C:34](=[O:41])[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[CH:30]=[CH:31][CH:32]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:1]1
Reactant: ClCCl
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6ccccc6)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-{3-[2-(1,2,3,4-tetrahydro-7-isoquinolinylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)benzamide (107 mg, 0.199 mmol) in 2:1 DCM/MeOH (1.5 mL) was added 37% aq. formaldehyde (50 μL, 0.67 mmol), glacial acetic acid (13 μL) and sodium triacetoxyborohydride (64 mg, 0.30 mmol). The mixture was stirred at rt for 1 h. The mixture was worked up by removal of solvent with a totary evaporator and partitioning the residue between saturated aq. NaHCO3 and 5:1 CHCl3/isopropanol. The organic layer was separated, dried and concentrated to give 67 mg of crude material. Purification by silica gel chromatography (0 to 30% methanol in DCM) afforded 60.4 mg of the title compound as a cream-colored solid. LCMS (ES)+ 552.3. 1H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 3H), 2.57 (bs, 2H), 2.72 (m, 2H), 3.39 (s, 2H), 6.49 (d, 1H, J=5.6), 6.95 (d, 1H, J=8.0, 7.10 (t, 1H, J=6.8), 7.28 (d, 1H, J=8.0), 7.37 (d, 1H, J=8.0), 7.42-7.56 (m, 5H), 7.93 (d, 2H, J=7.2), 8.11 (s, 1H), 8.22 (d, 1H, J=5.6), 8.45 (d, 1H, J=8.8), 8.81 (d, 1H, J=7.2, 9.41 (s, 1H), 10.37 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([CH2:7]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([CH2:7][C@H:5]1[NH:6][C:2](=[O:1])[CH2:3][CH2:4]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)N2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CCC(=O)N1
Temperature: 55 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A round bottom flask was charged with (S)-(5-oxopyrrolidin-2-yl)methyl-4-methylbenzenesulfonate (18.4 g, 68.5 mmol), DMF (400 mL), and NaN3 (17.8 g, 274 mmol). The resulting mixture was stirred at 55° C. for overnight. Removal of solvent under reduced pressure followed by flash chromatography purification (7% MeOH in CHCl3 as the eluent) provided the (S)-5-(azidomethyl) pyrrolidin-2-one (8.45 g, 60.36 mmol, 88%) as a yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][CH2:6][C@@H:5]([CH3:8])[NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH:17][CH3:18])[N:11]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:9][C:10]1[CH:15]=[C:14]([N:4]2[C@H:5]([CH3:8])[CH2:6][O:7][C@H:2]([CH3:1])[CH2:3]2)[N:13]=[C:12]([NH:17][CH3:18])[N:11]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CO[C@H](C)CN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)cc(N2C[C@@H](C)OC[C@H]2C)n1

Procedure:
To a solution of (2R,5R)-2,5-dimethylmorpholine (400 mg, 3.47 mmol) and 4,6-dichloro-N-methyl-2-pyrimidinamine (742 mg, 4.17 mmol) in CH3CN (5 mL) stirred at room temperature was added Hunig's base (1.213 mL, 6.95 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 1 hour. After cooling the reaction, the mixture was concentrated under reduced pressure and the residue was added to a silica gel column and was eluted with Hex/EtOAc (10:1 to 3:1). Collected fractions:the first fraction was the starting material 4,6-dichloro-N-methyl-2-pyrimidinamine (300 mg), and the second fraction was the title compound (460 mg) as a light yellow solid. LC-MS (ES) m/z=257 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([CH:28]([CH3:30])[CH3:29])[CH2:4][CH2:5][CH:6]([CH:8]1[C:12]2([CH3:27])[CH2:13][CH2:14][CH:15]3[C:20]4([CH3:26])[CH2:21][CH2:22][CH:23]([OH:25])[CH2:24][CH:19]4[CH2:18][CH2:17][CH:16]3[CH:11]2[CH2:10][CH2:9]1)[CH3:7].CC[C@@H](C(C)C)CC[C@H]([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@@H]4CC[C@H]3[C@@H]2CC1)C>>[CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:29])[CH3:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7]
Reactant: CCC(CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C)C(C)C
Agent: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Product: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C

Procedure:
Pure sitostanol or stigmastanol is a commercial product obtained by catalytic hydrogenation of sitosterol. Its synthesis from beta-sitosterol was described in 1937: Bernstein, Wallis, J. Org. Chem Soc., 2, 341.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:8][CH:7]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc2c[nH]c3ccccc23)cc1
Yield: 70.5 %

Procedure:
A solution of 3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester (12.6 g, 37.7 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (12.8 g, 53.6 mmol), (i-Pr)2NEt, (7.42 g, 57.4 mmol) in DMSO (100 mL) is heated to 50° C. After 8 hours the mixture is partitioned with CH2Cl2/H2O. The organic layer is dried (Na2SO4) and evaporated. The residue is chromatographed on silica gel to produce 3-[4-({[2-(tert-butyidimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (13.1 g). Following the procedure described for the preparation of the hydroxamate compound in Example P1, 3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoic acid methyl ester (5.4 g, 11 mmol) is converted to N-hydroxy-3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenamide (5.1 g,) and used without further purification. The hydroxamic acid (5.0 g, 13.3 mmol) is then dissolved in 95% TFA/H2O (59 mL) and heated to 40-50° C. for 4 hours. The mixture is evaporated and the residue purified by reverse phase HPLC to produce N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide as the trifluoroacetate salt (m/z 380 [MH+]).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>O1CCOCC1>[N:14]1([C:2]2[C:11]3[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:13])[CH:3]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Solvent: C1COCCO1
Product: Cc1cc(-n2ccnc2)c2cccc(O)c2n1

Procedure:
A mixture of 4-chloro-2-methyl-quinolin-8-ol (2.0 g, 10 mmol) and imidazole (3.53 g, 51.8 mmol) in dioxane (20 mL) was heated to reflux for 28 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with DCM/methanol 10:1) to give the title compound. MS (m/z): 226.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[O:18]=[C:16]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([F:14])[CH:7]=2)[NH:1]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1cc(F)c([N+](=O)[O-])cc1N
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2cc(F)c([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
3.1 g (15.6 mmol) of 2-amino-5-fluoro-4-nitro-benzamide were dissolved in 130 ml of tetrahydrofuran and treated at 0° C. with 3.1 g (10.4 mmol) of triphosgene. The mixture was left to warm to room temperature and stirred for a further 1.5 hrs. Then, the solution was concentrated and triturated with water. The precipitate was filtered off under suction and dried. 2.09 g (60%) of 2,4-dioxo-6-fluoro-7-nitro-1,2,3,4-tetrahydroquinazoline were obtained as yellowish crystals;
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.C(=O)([O-])[O-].[K+].[K+].C(OP([CH2:27][C:28]#[N:29])(=O)OCC)C.O>O1CCCC1>[C:28]([CH:27]=[CH:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:29]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C=CC#N)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-formylbenzoate (2.00 g, 12.2 mmol) in tetrahydrofuran (20 mL) were added potassium carbonate (2.02 g, 14.6 mmol), diethyl(cyanomethyl)phosphonate (2.29 mL, 14.6 mmol) and water (0.4 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give methyl 3-(2-cyanoethenyl)benzoate as a white solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[CH2:13]([O:15][C:16](=[O:44])[C:17]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])([CH3:35])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]2[CH2:32][NH:31][C:30](=[O:33])[N:29]2[CH3:34])=[CH:21][CH:20]=1)[CH3:14].[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:44])[C:17]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])([CH3:35])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]2[CH2:32][N:31]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)[C:30](=[O:33])[N:29]2[CH3:34])=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1F
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3cccc(C(F)(F)F)c3)C(=O)N2C)cc1)Oc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Trifluoromethylbenzyl bromide (0.03 mL, 0.175 mmol, d=1.565) and tetrabutyl ammonium iodide (catalytic amount) are added to a 0° C. suspension of 2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.052 g, 0.117 mmol) and sodium hydride (0.012 g, 0.292 mmol, 60% suspension on mineral oil), and pre-stirred for 1 h at ambient temperature. The reaction mixture is stirred at ambient temperature for 18 h, diluted with ethyl acetate, and washed with 1N HCl, water, and brine. The organic layer is dried, concentrated, and carried into the next step. MS [EI+] 603 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10]O.[C:12]1(=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[NH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][N:13]1[C:14](=[O:21])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]1=[O:22]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCC#Cc1ccccn1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1ccccn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
4-(Pyridin-2-yl)but-3-yn-1-ol (96 mg, 0.65 mmol), isoindoline-1,3-dione (140 mg, 0.97 mmol) and triphenylphosphine polymer bound 3 mmol/g (340 mg, 1.02 mmol) were dissolved in DCM (2 mL) and cooled to 0° C. Di-tert-butylazodicarboxylate (226 mg, 0.96 mmol) dissolved in DCM (0.5 mL) was added dropwise over 30 min. to the reaction mixture followed by THF (0.5 mL) and the reaction mixture was stirred for 16 h at room temperature. After filtration through celite, the organic phase was washed with a solution of NH4OH, brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:7) to yield 130 mg (0.47 mmol, 73%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as an orange solid.
Reaction SMILES: [C:1]([C@@H:3]1[C@@H:10]2[C@@H:6]([O:7][C:8]([CH3:12])([CH3:11])[O:9]2)[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[O:4]1)#[CH:2].I[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36].C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:11][C:8]1([CH3:12])[O:7][C@@H:6]2[C@@H:10]([C@@H:3]([C:1]#[C:2][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:37])[F:36])[O:4][C@H:5]2[N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[O:9]1
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: FC(F)(F)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C#Cc1ccccc1C(F)(F)F)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of [9-((1R,2R,4R,5R)-4-ethynyl-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)purin-6-yl]cyclopentylamine (40 mg, 0.12 mmol), a compound of formula (5), in tetrahydrofuran (4 ml) under nitrogen was added catalytic amounts (3 mg) of dichlorobis(triphenylphosphine)palladium(II) and copper(II)iodide, followed by 1-iodo-2-trifluoromethylbenzene (0.25 ml, 0.3 mmol). Triethylamine (0.4 ml) was then added, and the mixture stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC, eluting with methanol:methylene chloride (6.5:1), to yield [9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-(trifluoromethyl)-phenyl]ethynyl}-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)purin-6-yl]cyclopentylamine, a compound of formula (6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:10]1.[SH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][CH3:38])=[O:31].C(N(C(C)C)C(C)C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13]([S:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][CH3:38])=[O:31])=[CH:12][C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:10]1
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)n(-c2cc(F)ccc2F)n1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OCC)nn1-c1cc(F)ccc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
A solution of ethyl 1-(2,5-difluorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-3-carboxylate (3.4 g), 2-ethylhexyl 3-mercaptopropionate (2.4 g) and N-ethyldiisopropylamine (1.9 g) in toluene (30 mL) was sufficiently deaerated, tris(dibenzylideneacetone)dipalladium (0) (342 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (432 mg) were added, and the mixture was further deaerated. Under an argon atmosphere, the reaction mixture was stirred at 110° C. for 2 hr, and allowed to cool to room temperature. Water and ethyl acetate were added, and the mixture was filtered through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→7:1) to give the title compound as a yellow oil (yield 1.8 g, yield 53%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=O)[CH:25]=[CH:26][CH:27]=1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccc(F)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 64.8 %

Procedure:
In a similar fashion to compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100.00 mg, 0.29568 mmol), 3-FC6H4CHO (40.4 mg, 0.325 mmol) and Ammonium acetate (45.6 mg, 0.591 mmol) were reacted to yield 84.7 mg (65%) of the title compound. (300 MHz, DMSO-d6) 13.33 (s, 1H), 8.18 (m, 2H), 8.04 (s, 1H), 7.75 (s, 1H), 7.41 (t, J=16.5 Hz, 8 Hz, 2H), 7.22 (s, 1H), 6.39 (d, J=15 Hz, 2H), 5.22 (t, J=17 Hz, 8.5 Hz, 1H), 2.89 (s, 1H), 2.78 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=444 (M+H), HPLC: 2.56 min. (G Method)
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40]([CH:52]2CCC[CH2:54][CH2:53]2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:54][CH2:53][CH2:52][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Agent: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCCCc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 4-phenylbutanal for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.58 (dd, J=9.0, 16.5, 1H), 7.66 (t, J=6.4, 2H), 7.34 (t, J=5.6, 4H), 7.29-7.22 (m, 4H), 4.39-4.29 (m, 1H), 3.24 (d, J=10.4, 1H), 2.91 (dd, J=2.4, 9.0, 0.5H), 2.66 (ddd, J=6.5, 10.6, 13.1, 1H), 2.57 (ddd, J=5.3, 12.3, 17.7, 3H), 2.51-2.45 (m, 1H), 2.43-2.29 (m, 3H), 2.26 (dd, J=3.0, 8.8, 0.5H), 2.24-2.08 (m, 2H), 1.91-1.83 (m, 1H), 1.81-1.72 (m, 1H), 1.71-1.58 (m, 2H), 1.49 (dt, J=7.8, 15.9, 1H), 1.41 (dt, J=6.9, 17.2, 2H), 1.31 (ddd, J=6.7, 13.2, 20.5, 1H), 1.23 (dd, J=6.5, 13.0, 3H), 0.71 (dd, J=2.6, 6.6, 3H); MS (ESI+) m/z 419 (M+H)+.