Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].P(Br)(Br)[Br:18]>C(OCC)C>[CH3:5]/[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH2:2][Br:18]
Reactant: BrP(Br)Br
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Yield: 215.5 %

Procedure:
A solution of 1.00 g (4.5 mmol) of (E,E)-farnesol (Aldrich, further purified by flash chromatography) in 10 ml of distilled diethyl ether at 0° C. under argon in the dark was treated dropwise with a solution of 195 μL (2.05 mmol, 0.45 eq.) of PBr3 in 2 ml of diethyl ether. The resultant mixture was stirred at 0° C. for one hour, then quenched with water and separated. The organic phase was washed with 5 ml of H2O, 5 ml of saturated NaHCO3, and 5 ml of brine, dried over Na2SO4 and evaporated to give 1.26 g (98%) of crude bromide as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12]Cl)[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:7]2=[O:21].[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:12][C:9]1[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7](=[O:21])[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1c2cccc(Cl)c2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2c(Cl)cccc2c(=O)n1-c1ccccc1Cl
Yield: 38.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2h (100 mg, 0.294 mmol), adenine (44 mg, 0.324 mmol), K2CO3 (45 mg, 0.324 mmol), and DMF (1 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 50 mg of a pale yellow solid (39%), mp 273.3-273.5° C. (discolors). 1H NMR (DMSOd6) δ: 8.11 (dd, J=1.3, 8.0 Hz, 1H); 8.08 (s, 1H); 8.05 (s, 1H); 8.00 (dd, J=1.3, 7.8 Hz, 1H); 7.79-7.83 (m, 2H); 7.63-7.66 (m, 2H); 7.56 (t, J=7.9 Hz, 1H); 7.21 (br s, 2H); 5.17 (d, J=17 Hz, 1H); 4.97 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 156.1, 152.8, 152.2, 150.2, 143.3, 142.0, 135.6, 133.1, 132.3, 131.9, 131.1, 131.0, 130.9, 129.4, 128.4, 126.0, 122.5, 118.4, 45.0. MS (ES): m/z 438.0 (M+). Anal. calcd. for C20H13Cl2N7O0.1CH4O0.6H2O(0.15KCl: C, 52.09; H, 3.18; N, 21.15. Found: C, 51.85; H, 2.93; N, 21.01.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]3[N:50]([CH:51]=2)[CH:49]=[CH:48][C:47]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:46]3)O1>O1CCOCC1.C([O-])(O)=O.[Na+].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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:43]3[CH:44]=[C:45]4[N:50]([CH:51]=3)[CH:49]=[CH:48][C:47]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:46]4)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCOC(=O)c1ccn2cc(B3OC(C)(C)C(C)(C)O3)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccn2cc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc2c1
Temperature: 100 °C

Procedure:
A mixture of bis(triphenylphosphine)palladium chloride (13.09 mg, 0.019 mmol), tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (187 mg, 0.373 mmol), and ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolizine-7-carboxylate (118 mg, 0.373 mmol) in dioxane (4 mL) and saturated aqueous NaHCO3 (1 mL) were heated to 100° C. in a Biotage Initiator microwave for 1 hour. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(7-(ethoxycarbonyl)indolizin-2-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 20 minutes, concentrated, and purified by preparatory HPLC, eluting with a gradient of 10-40% ACN (0.035% TFA) and water (0.05% TFA). The collected fractions were combined and dried to give a TFA salt of the title compound as a tan solid (31 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (t, J=6.80 Hz, 3H), 1.78-1.81 (m, 1H), 2.11-2.12 (m, 1H), 3.62-3.65 (m, 1H), 3.89-3.91 (m, 1H), 3.94-4.28 (m, 3H), 4.31 (q, J=6.83 Hz, 2H), 4.43 (d, J=8.3 Hz, 2H), 4.53-4.54 (m, 1H), 6.96 (dd, J=1.46, 7.32 Hz, 1H), 7.15 (d, J=4.88 Hz, 1H), 7.71 (s, 1H), 7.92-7.93 (m, 2H), 8.21 (s, 1H), 8.36 (d, J=7.32 Hz, 1H), 8.48 (s, 1H), 9.03 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C23H24FN5O4, 454. found, 454.
Reaction SMILES: Cl.[C:2]1(=O)[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].[OH-].[Na+]>>[NH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1[S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: O=C1CCCCCN1
Reactant: Nc1ccccc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCCCCc1nc2ccccc2s1
Temperature: 0 °C

Procedure:
36.5 g of hydrogen chloride gas are introduced over a period of 30 minutes into a mixture of 113 g (1 mol) of caprolactam and 125 g (1 mol) of o-aminothiophenol, followed by the introduction of another 20 g of hydrogen chloride gas over a period of 3 hours at 160°C. The melt is then stirred into a mixture of 200 g of 45 % by weight sodium hydroxide and 200 g of ice, the supernatant oil separated off and the aqueous phase extracted by shaking with 200 ml of CH2Cl2. The combined organic phases are concentrated in vacuo and subsequently subjected to fractional distillation, giving 194 g (88 % of the theoretical) of 2-(5'-aminopentyl)-benzthiazole in the form of a yellowish oil with a boiling point of 131° to 133°C at 0.05 Torr.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:22](C1NC=CN=1)(C1NC=CN=1)=[O:23].C(OC(C)C)(=O)C>C(#N)C>[O:23]=[C:22]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Solvent: CC#N
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A 100 mL round bottom flask was charged with acetonitrile (20 mL, HPLC grade) and tert-butyl 4[(2-aminopyridin-3-yl)amino]piperidine-1-carboxylate (11, 1.89 g, 6.47 mmol) was added. Upon completion of addition, acetonitrile (5 mL) was added and the resulting suspension was stirred at room temperature for 30 minutes. Carbonyl diimidazole (1.57 g, 97.1 mmol) was then added over period of 10 minutes. The reaction mixture was heated to 50° C. and stirred overnight. The resulting solution was cooled to room temperature and concentrated under reduced pressure to give a brown solid. This solid was then mixed with 20 mL of isopropyl acetate and 20 mL of ice cold water. The resulting thick slurry was stirred overnight at room temperature. The brown solids were collected by vacuum filtration, washed with cold water (3×25 mL) and isopropyl acetate (3×25 mL) to give a light gray solid, which was dried to constant weight to give 1.73 g (84% yield) of tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate. This material was submitted to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 11.56 (broad s, 1H), 7.89 (d, 1H), 7.54 (d, 1H), 6.98 (dd, 1H), 4.34 (m, 1H), 4.08 (broad m, 2H), 2.85 (broad m, 2H), 2.13 (m, 2H), 1.72 9 (d, 2H), 1.43 (s, 9H). MS (EI) for C16H22N4O3: 319 (MH+)
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cl:9][C:10]1=[C:11]([Cl:17])[C:12]([O:14][C:15]1=O)=[O:13].C(O)(=O)C>CCOCC>[CH:1]1([N:8]2[C:15](=[O:14])[C:10]([Cl:9])=[C:11]([Cl:17])[C:12]2=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: NC1C=CCCCC1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1C(Cl)=C(Cl)C(=O)N1C1C=CCCCC1
Yield: 70.7 %

Procedure:
A mixture of 2-cycloheptenylamine (1.01 g), dichloromaleic anhydride (1.67 g) and acetic acid (10 ml) was heated under reflux for 3 hours. After cooling, ether (20 ml) was added to the reaction mixture which was then washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The deposited crystal was purified by recrystallization from hexane to obtain 1.67 g of N-(2-cycloheptenyl)dichloromaleinimide [Compound (217)].
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[CH2:6][C:7]1[CH:8]=[C:9]([B:13]2[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][O:14]2)[CH:10]=[CH:11][CH:12]=1>ClCCl>[CH3:19][C:16]1([CH3:20])[CH2:15][O:14][B:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[CH2:6][NH:4][CH:1]([CH3:3])[CH3:2])[O:18][CH2:17]1
Reactant: CC1(C)COB(c2cccc(CBr)c2)OC1
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NCc1cccc(B2OCC(C)(C)CO2)c1
Temperature: 23 °C
Yield: 89.3 %

Procedure:
To a solution of isopropylamine (15 mL, 10 g, 180 mmol, 10 eq) in dichloromethane (100 mL) was added dropwise a suspension of 2-[3-(bromomethyl)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane (5.0 g, 18 mmol, 1.0 eq) in dichloromethane (75 mL) over 1 hour. After the addition was complete the reaction was stirred for an additional hour at 23° C. and then the reaction solution was washed with brine, dried over sodium sulfate and concentrated to yield N-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzyl]propan-2-amine (4.2 g, 91%) as a clear oil. LRMS m/z (M+H) 516.2 found, 262.2 required.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1>>[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: CC1Cc2ccccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: CC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 59 %

Procedure:
2-[2-(2-Methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one is prepared by following the procedure described in example 1e (step 4e) using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 510 mg of 2-methyl-2,3-dihydro-1H-indole. 400 mg of 2-[2-(2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH2:5]([OH:16])[C@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14]O)[OH:13])[OH:11])[OH:9])[OH:7].I>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:4])[O:13][CH:12]([CH:10]2[O:11][C:6]([CH3:8])([CH3:5])[O:9][CH:8]2[CH:6]2[O:7][C:12]([CH3:14])([CH3:10])[O:16][CH2:5]2)[CH2:14][O:3]1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Agent: I
Solvent: c1ccncc1
Product: CC1(C)OCC(C2OC(C)(C)OC2C2COC(C)(C)O2)O1
Temperature: 60 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-mannitol and 175 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 60° C. for 5 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. After completion of the reaction, a small amount of pyridine was added. The acetone was then distilled off under reduced pressure and the residue was dissolved in chloroform. The solution was washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure to give 15.0 g (90%) of 1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol. After recrystallization from 70% ethanol, it melted at 68.5°-70.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[NH:13][C:12]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][N:44]1[C:48]([CH2:49]O)=[N:47][CH:46]=[N:45]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([O:23][CH2:49][C:48]3[N:44]([CH3:43])[N:45]=[CH:46][N:47]=3)=[N:13][C:12]=12
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Reactant: Cn1ncnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncnc1COc1nc2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 37.7 %

Procedure:
3-(2-Fluorophenyl)-6-phenyl-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (10 mg, 0.033 mmol), triphenylphosphine (21 mg, 0.08 mmol) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (11 mg, 0.087 mmol) were suspended at room temperature in dry tetrahydrofuran (0.5 ml). Diethyl azodicarboxylate (15 μl, 0.095 mmol) was added at which point a clear yellow solution resulted. The reaction was stirred at room temperature for 64 hours before purification by preparative thin layer chromatography to afford 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-phenyl-1,2,3-triazolo[1,5-α]pyrimidine (5 mg, 39%) as a white solid. δH (400 MHz, CDCl3) 3.79 (3H, s, NMe, 5.69 (2H, s, OCH2), 7.24 (1H, td, J=9.2 and 1.2 Hz, ArH), 7.31 (1H, td, J=8.4 and 1.3 Hz, ArH), 7.39-7.43 (1H, m, ArH), 7.48-7.51 (3H, m, ArH), 7.54-7.58 (2H, m, ArH), 7.86 (1H, s, CH-triazole), 8.00 (1H, td, J=8.3 and 2.0 Hz, ArH), 8.80 (1H, s, PhC═CH);m/z (ES+) 402 (M+H+).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH3:28])=[N:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C[Si]([N:42]=[C:43]=[O:44])(C)C>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:43]([NH2:42])=[O:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1nn(C2CCCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C2CCCC2)c2cc(N3CCN(C(N)=O)[C@@H](Cc4ccccc4)C3)ccc12
Reaction time: 16 h
Yield: 35.9 %

Procedure:
A solution of 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclopentyl-3-methyl-1H-indazole (44 mg, 0.12 mmol) in CH2Cl2 (1 mL) was treated with diisopropylethylamine (21 μL, 0.12 mmol) followed by trimethylsilyl isocyanate (31 μL, 0.24 mmol). The reaction mixture was stirred for 16 h after which time an additional equivalent of TMS-isocyanate was added and the reaction mixture was stirred an additional 16 h. The reaction mixture was evaporated and purified by reverse phase HPLC. Product was obtained as a colorless solid (18 mg, 36%). LC/MS (Method B) 3.64 min, [M+1]+ 418.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.CO[C:22](OC)([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:23][C:22]1([CH3:24])[N:8]([C:9]2[S:10][C:11]3[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)[C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[O:1]1
Reactant: N#Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(C#N)cc2s1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To a stirred mixture of 2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazole-6-carbonitrile (1.2 g, 4.5 mmol) from Step 2 of this Example and 2,2-dimethoxypropane (4.7 g, 45 mmol) in 1,4-dioxane (30 mL) were added para-toluenesulfonic acid (89 mg, 0.5 mmol) and molecular sieves (4 Å) and the mixture was heated at reflux for 15 h. The mixture was cooled to rt, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel flash chromatography to afford 2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazole-6-carbonitrile (700 mg, 50%) as a white solid. LCMS (ESI) m/z 314 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[O:18]=[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:19])[N:9]1[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][N+:5]=1[O-:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc(N2C(=O)c3ccccc3C2=O)cc1C
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3ccccc3C2=O)[n+]([O-])cc1C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a solution of 2-(4,5-dimethylpyridin-2-yl)-isoindoline-1,3-dione (1.7 g, 0.01 mol) in CH2Cl2 (50 mL) was added m-CPBA (3.5 g, 0.02 mol) at the room temperature. The mixture was stirred overnight, then quenched by addition of a saturated solution of Na2S2O3 (100 mL). The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 2-(1,3-dioxoisoindolin-2-yl)-4,5-dimethylpyridine 1-oxide (1.5 g, 83%), which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[N+:26]([C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)([O-])=O>C(Cl)Cl.CO>[N:32]1[CH:33]=[C:29]([NH:26][C:23]([C:20]2[CH:21]=[CH:22][C:13]([C:3]3[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[Cl:1])=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)=[O:24])[NH:30][CH:31]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3cnc[nH]3)c3ncccc23)c1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), stirring the reaction mixture for 3 h at 70° C., and using 4-nitro-imidazole instead of 2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 442.9 [M+H]+; tR=3.93 min (System 1); TLC: Rf=0.17 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[C:5](N)=[N:6][C:7]=1[CH3:8].N([O-])=[O:15].[Na+]>FC(F)(F)C(O)=O.O>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([OH:15])=[N:6][C:7]=1[CH3:8]
Reactant: O=N[O-]
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1Br
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(O)c([N+](=O)[O-])c(C)c1Br
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4,6-dimethyl-3-nitro-2-pyridinylamine (Heitsch, H.; et al. Bioorg. Med. Chem. 1997, 5, 673, 2.0 g, 8.1 mmol) in trifluoroacetic acid/water (v/v, 2:1, 30 mL) was added sodium nitrite (1.1 g, 16 mmol) in small portions at room temperature, and then the reaction mixture was stirred overnight. The resulting precipitates were collected by filtration, washed with water, and dried under reduced pressure to give 2.2 g (quant.) of the title compound: 1H-NMR (CDCl3) δ 2.53 (3H, s), 2.38 (3H, s).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)#[N:3].[CH2:17]([O:19]CC)[CH3:18]>C(O)C>[ClH:1].[CH2:13]([O:12][C:10]([CH2:9][O:8][C:7]1[CH:15]=[CH:16][C:4]([C:2](=[NH:3])[O:19][CH2:17][CH3:18])=[CH:5][CH:6]=1)=[O:11])[CH3:14]
Reactant: CCOCC
Reactant: CCOC(=O)COc1ccc(C#N)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=N)c1ccc(OCC(=O)OCC)cc1
Reaction time: 72 h

Procedure:
Dry hydrogen chloride was passed through a mixture of ethyl 2-p-cyanophenoxyacetate (30.75 g.), diethyl ether (500 ml.) and ethanol (10 ml.) at 0°-5° C. until the solution was saturated with hydrogen chloride, and the mixture was kept at 0° C. for 3 days and then filtered. There was thus obtained as solid residue ethyl p-(ethoxycarbonylmethoxy)benzimidate hydrochloride, m.p. 124°-126° C. A mixture of this compound (6.51 g.), diethyl ether (100 ml.) and a solution of potassium carbonate (3.6 g.) in water (15 ml.) was shaken, the ethereal phase was separated and to it was added a solution of ethyl glycinate hydrochloride (3.1 g.) in water (10 ml.). The mixture was stirred at laboratory temperature for 45 hours and the organic phase was separated, washed with water, dried and evaporated to dryness. The residual oil, which consisted of ethyl N-(ethoxycarbonylmethyl)-p-(ethoxycarbonylmethoxy)benzimidate (5.8 g.) was dissolved in ethanol (75 ml.) hydrazine hydrate (1 ml.) was added and the mixture was heated under reflux for 18 hours and then evaporated to dryness. The residue was purified by chromatography on silica gel using chloroform containing increasing amounts (up to 5% v/v) of ethanol as eluant. There was thus obtained ethyl p-(1,4,5,6-tetrahydro-6-oxo-1,2,4-triazin-3-yl)phenoxyacetate, m.p. 135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I.Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:31][O:15][C:14](=[O:16])[CH:13]([N:12]1[C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 1 g (2.47 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid in 10 ml N,N-dimethylformamide, 129 mg (2.964 mmol) sodium hydride (55% dispersion in mineral oil) and 368 mg (2.594 mmol) methyl iodide were added. The reaction was stirred at room temperature for 2 h and then poured on 100 ml ethyl acetate and 100 ml 1M aqueous hydrochloric acid. The phases were separated and the organic layer washed two times with 100 ml water and 100 ml brine. The combined water layers were extracted with 100 ml ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Colorless solid (92%). MS (Turbo Spray): m/z=419.1 [M+H].
Reaction SMILES: [CH3:1][NH2:2].O.CS[C:6]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[CH:7][N+:8]([O-:10])=[O:9]>C(O)C>[CH3:1][NH:2][C:6]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[CH:7][N+:8]([O-:10])=[O:9]
Reactant: CN
Reactant: COc1ccnc(CSCCNC(=C[N+](=O)[O-])SC)c1
Solvent: O
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSCc1cc(OC)ccn1
Reaction time: 0.33 h

Procedure:
Methylamine in ethanol (33% 20 cc) was added to 1-methylthio-1-[2-(4-methoxy-2-pyridylmethylthio)ethylamino]-2-nitroethylene monohydrate (2.01 g) and the mixture was stirred at 18° for 20 minutes and evaporated to an oil which was crystallised from propan-2-ol to give the title product (1.1 g) m.p. 107°-108.5°.