Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]([CH2:13][C:14]1[CH:15]=[C:16]([NH:27][C:28]([O:30][CH2:31][C@@H:32]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=2[CH3:43])[CH3:33])=[O:29])[CH:17]=[C:18]([F:26])[C:19]=1[O:20][C@H:21]1[CH2:25][CH2:24][O:23][CH2:22]1)[CH3:12])=O)C1C=CC=CC=1.[NH2:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[C:51]([N:55]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:50][CH:49]=[CH:48]2.O.[C:71]([OH:75])(=[O:74])[CH:72]=O>CC#N.CN(C=O)C>[C:66]([O:65][C:63]([N:55]([C:56]([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:57])[C:51]1[C:52]2[C:47](=[CH:46][C:45]([NH:44][CH:72]([C:37]3[CH:38]=[CH:39][C:34]([C@@H:32]([CH3:33])[CH2:31][O:30][C:28](=[O:29])[NH:27][C:16]4[CH:15]=[C:14]([CH2:13][NH:11][CH3:12])[C:19]([O:20][C@H:21]5[CH2:25][CH2:24][O:23][CH2:22]5)=[C:18]([F:26])[CH:17]=4)=[C:35]([CH3:43])[CH:36]=3)[C:71]([OH:75])=[O:74])=[CH:54][CH:53]=2)[CH:48]=[CH:49][N:50]=1)=[O:64])([CH3:69])([CH3:68])[CH3:67]
Reactant: O=CC(=O)O
Reactant: Cc1cc(B(O)O)ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O[C@H]2CCOC2)c(CN(C)C(=O)OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNCc1cc(NC(=O)OC[C@H](C)c2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc(F)c1O[C@H]1CCOC1
Temperature: 85 °C
Reaction time: 20 h
Yield: 52.6 %

Procedure:
39D (405 mg, 0.681 mmol), Intermediate 1 (245 mg, 0.681 mmol) and glyoxylic acid monohydrate (50.4 mg, 0.681 mmol) were dissolved in CH3CN (3 ml) and DMF (0.5 ml). The mixture was stirred at 85° C. for 20 h, quenched with water, and extracted with EtOAc (3×20 ml). The combined organic layer was washed with 1N HCl, brine, dried (Na2SO4) and concentrated. The crude was purified by flash chromatography (0-10% MeOH in CH2Cl2). The desired fractions were combined and concentrated. The residue was dissolved in MeOH (8 mL). Pd/C was added and the mixture was hydrogenated at 40 psi for 6 h. The mixture was filtered and concentrated gives 39E (298 mg, 0.358 mmol, 52.6% yield). MS (ESI) m/z: 832.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH2:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(O)=[O:2].C(O)(=O)C.CO>O1CCCC1>[OH:2][CH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(CCc2cccc3cncn23)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: OCc1ccc(CCc2cccc3cncn23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(p-carboxyphenethyl)-imidazo[1,5-a]pyridine (2.66 g) is dissolved in 100 ml of dry tetrahydrofuran at 0° and 20 ml of 1M borane tetrahydrofuran complex in tetrahydrofuran (20 ml) is added dropwise. The reaction mixture is stirred at room temperature for two hours, and 20 ml of acetic acid and 20 ml of methanol are added carefully. The mixture is refluxed for 1 hour, cooled and evaporated, the resulting oil is partitioned between ether and 1N sulfuric acid. The aqueous phase is separated, adjusted to pH=8 and extracted with ethyl acetate the extract is dried over sodium sulfate and evaporated to yield 5-[p-(hydroxymethyl)phenethyl]imidazo[1,5-a]pyridine.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[NH2:14][C:15]([CH3:36])([CH3:35])[CH2:16][N:17]1[C:29]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:30])[C:20]=2[N:19]=[C:18]1[CH2:31][O:32][CH2:33][CH3:34]>ClCCl>[NH2:30][C:21]1[C:20]2[N:19]=[C:18]([CH2:31][O:32][CH2:33][CH3:34])[N:17]([CH2:16][C:15]([NH:14][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])([CH3:35])[CH3:36])[C:29]=2[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)NC(=O)C(C)C
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Triethylamine (556 μL, 4.00 mmol) and isobutyryl chloride (230 μL, 2.20 mmol) were added sequentially to a chilled (0° C.) solution of 1-(2-amino-2-methylpropyl)-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (628 mg, 2.00 mmol) in dichloromethane (20 mL). The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and diluted with dichloromethane (50 mL) The organic layer was separated, washed sequentially with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to an amber foam. This material was dissolved in hot propyl acetate (10 mL) and then allowed to cool overnight. Hexanes were added and the now cloudy solution was heated until clear and then allowed stand until crystals formed. The solvent was removed by pipette. The crystals were rinsed with cold propyl acetate/hexanes and then dried under high vacuum at 70° C. to provide 464 mg of N-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]-2-methylpropionamide as an off white crystalline solid, mp 154.5-155.5° C. Anal. calcd for C20H28N6O2: % C, 62.48; % H, 7.34; % N, 21.86. Found: % C, 62.14; % H, 7.62; % N, 21.71.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([OH:12])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:14](OCC)=[O:15].O>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:10])[NH:11][C:14](=[O:15])[O:12]2)=[CH:6][CH:7]=1
Reactant: NC(=O)N(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(-c2ccc(Cl)cc2)o1
Reaction time: 0.5 h

Procedure:
1-(4-Chlorophenyl)-1-hydroxyurea (34 grams; 0.18 mole) dissolved in aqueous sodium hydroxide (200 ml; 2 N) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of 10° to 15°C and ethyl chloroformate (17 ml) is slowly added with stirring. After the addition is completed stirring is continued for a period of about 1/2 hour. Water (200 ml) is then added to the reaction mixture with stirring and the resulting mixture is poured into 3 liters of water. The resulting aqueous solution is then filtered and the filtrate is cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate is recovered by filtration and is dried. The resulting product is then dissolved in a 100:5 mixture of methylene chloride and tetrahydrofuran and the solution is dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure to yield the desired product 2-(4-chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=O)[CH3:9])(C)(C)C.Cl>C(Cl)(Cl)Cl>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:27])[CH:8]([CH3:9])[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:13]=2[CH:14]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)cc1C(=O)c1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1N=C(c2ccccn2)c2cc(Br)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
To a stirred solution of ester 124 (16 g, 35.69 mmol) in CHCl3 (300 mL) at rt, hydrogen chloride gas was added in slowly. After 20 min, the addition was stopped and the solution was allowed to stir overnight at rt. The reaction mixture was washed with a saturated solution of sodium bicarbonate (2×50 mL) and water (2×50 mL). The organic layer was concentrated under reduced pressure. The residual oil was dissolved in methanol-water (3:1, 300 mL) and the pH was adjusted to 8.5 by the addition of aq sodium hydroxide (1 N). The reaction mixture was stirred for 10 h at rt. The solution was concentrated under reduced pressure and water (80 mL) was added. The solution was extracted with CH2Cl2 (3×70) and concentrated under reduced pressure. The crude solid 125 was purified by recrystallization from methanol/water to provide pure 125 (9.42 g, 80%). mp 227-229° C.; IR (KBr, cm−1) 2928, 1684, 1611, 1476; 1H NMR (CDCl3) δ 9.47 (bs, 1 H), 8.62 (d, J=4.7 Hz, 1 H), 8.0 (d, J=7.90 Hz, 1 H), 7.81 (td, J=7.7, 1.6 Hz, 1 H), 7.56 (dd, J=8.6, 2.2 Hz 1 H), 7.50 (dd, J=2.1 Hz, 1 H), 7.36 (dd, J=7.4 Hz, 1 H), 7.06 (d, J=8.6 Hz, 1 H), 3.85 (q, J=6.5 Hz, 1 H), 1.76 (d, J=6.5 Hz, 3 H); MS (EI) m/e (relative intensity) 330 (M+, 50), 329 (50), 314 (52), 288 (100), 250 (30), 208 (32), 179(50), 88(72); [α]26D=403.2 (c 0.50, EtOAc).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[C:14](=[O:20])[N:13]([CH3:21])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:30]([NH:33][CH2:34][CH2:35][CH3:36])[CH2:31][CH3:32]>C(O)(=O)C>[CH2:30]([N:33]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][S:19][C:15]=4[C:14](=[O:20])[N:13]([CH3:21])[CH2:12][C:11]=23)=[N:4][CH:1]=1)[CH2:34][CH2:35][CH3:36])[CH2:31][CH3:32]
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)o1
Temperature: 25 °C
Reaction time: 45 h
Yield: 28.5 %

Procedure:
A solution of 3.0 g (0.010 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid prop-2-ynylamide in 180 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 45 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The black-brown solid residue was suspended in 200 ml of THF, treated with 13.7 ml (0.10 mol) of dipropylamine and stirred at room temperature for 17 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There were obtained 1.14 g (29%) of 3-(5-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]-diazepin-6-one as yellowish crystals; m.p. 142°-144°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[CH3:14][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5]2
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc2cc(O)ccc2[nH]1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
5-Hydroxy-1H-indole-2-carboxylic acid (0.50 g, 2.82 mmol) was dissolved in MeOH:CH2Cl2 (1:1, 15 mL), trimethylsilyl diazomethane (2.0 M in hexanes, ˜5.0 mL) was added dropwise until a persistent yellow color formed and the reaction mixture was stirred for 0.5 h. To the solution was added acetic acid (0.5 mL) and the solvent was evaporated. Purification was accomplished by column chromatography (CH2Cl2: MeOH) to afford the title compound (0.55 g, 99%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.59 (br. s., 1H), 8.88 (dd, 1H), 7.23 (d, 1H), 6.85-6.96 (m, 2 H), 6.77 (dd, 1H), 3.81 (d, 3H). MS: m/z 192.2 (M+1).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:36]=[C:35]([C:37]([O:39]C)=[O:38])[CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>CO.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>[N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:31]5[N:36]=[C:35]([C:37]([OH:39])=[O:38])[CH:34]=[CH:33][CH:32]=5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(Br)n1
Reactant: CC1(C)OB(c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cccc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)n1
Temperature: 80 °C

Procedure:
A vial containing (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (Example 64A, 23 mg, 0.056 mmol), methyl 6-bromo-2-pyridinecarboxylate (12 mg, 0.056 mmol), bis(triphenylphosphine)palladium(II) chloride (5 mg, 7 μmol), and K2CO3 (23 mg, 0.17 mmol) in methanol (0.5 mL) was heated to 80° C. for 2 hours and cooled. The mixture was filtered and concentrated. The residue was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). A custom purification system was used, consisting of the following modules: Waters LC4000 preparative pump; Waters 996 diode-array detector; Waters 717+ autosampler; Waters SAT/IN module, Alltech Varex III evaporative light-scattering detector; Gilson 506C interface box; and two Gilson FC204 fraction collectors. The system was controlled using Waters Millennium32 software. Fractions were collected based upon UV signal threshold and selected fractions subsequently analyzed by flow injection analysis mass spectrometry using positive APCI ionization on a Finnigan LCQ using 70:30 methanol: 10 mM NH4OH(aqueous) at a flow rate of 0.8 mL/minute. Loop-injection mass spectra were acquired using a Finnigan LCQ running LCQ Navigator 1.2 software and a Gilson 215 liquid handler for fraction injection. The title compound was obtained as the bis trifluoroacetate salt. 1H NMR (300 MHz, CD3OD) δ ppm 1.52-1.68 (m, 1H), 1.74-1.93 (m, 3H), 1.95-2.09 (m, 2H), 2.32-2.47 (m, 1H), 2.64-2.75 (m, 1H), 3.02-3.23 (m, 2H), 3.51-3.76 (m, 3H), 3.79-3.95 (m, 2H), 4.08-4.22 (m, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.99-8.09 (m, 2H), 8.10-8.17 (m, 2H), 8.62 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 409 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:15][NH:16]C(OC(C)(C)C)=O)([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:24])[C:4]([NH:15][NH2:16])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:8]([OH:13])[CH:7]=1
Reactant: COC(=O)C(C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OC)cc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold reaction mixture containing compound 108 (0.17 g, 0.5 mmol) and TEA (0.07 mL, 0.5 mmol) in dichloromethane (5 mL) was added ethyl chloroformate (0.025 mL, 0.5 mmol). The resulting mixture was stirred at 0° C. for 30 min and then at room temperature for 1. After concentration, the residue was partitioned with 10% citric acid and ethyl acetate. The organic phase was separated and dried over MgSO4. After removing the solvent under reduced pressure, the resulting residue was treated with 50% trifluoroacetic acid in dichloromethane at room temperature for 30 min. Removal of the solvent and purification by reverse phase preparative HPLC afford 73 mg of a 1:1 mixture of the title compounds 123 and 124. 1H NMR (CD3OD, 400 MHz): 1.35 (q, 3H), 1.46 (d, 3H), 2.98 (dd, 2H), 3.80 (d, 3H), 4.28 (q, 4H), 6.60–6.98 (m, 3H). MS (ESI) m/z 313.25 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)(O)[O-].[Na+].C[C:19]([CH2:21][CH:22]([CH3:24])C)=O.O.Cl[CH2:27][C:28](Cl)=[O:29]>C(Cl)(Cl)Cl>[CH2:24]([N:1]1[C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=2[O:12][CH2:27][C:28]1=[O:29])[CH2:22][CH2:21][CH3:19]
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: O=C(Cl)CCl
Reactant: CC(=O)CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCN1C(=O)COc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold, stirred solution of methyl 3-amino-4-hydroxybenzoate (3.0 g) and sodium bicarbonate (3.3 g) in 1:1 isobutyl methyl ketone/water (40 mL) was added chloroacetyl chloride (1.7 mL), and the mixture was stirred for 1 h. The mixture was warmed to room temperature and refluxed for 14 h, cooled to room temperature, diluted with chloroform, and separated. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) afforded a phenoxazine 3.2 g as a white solid, which was used without further purification or characterization. To a solution of phenoxazine from step 1 (700 mg) and potassium carbonate (934 mg) in methanol (8 mL) was added bromobutane (1.8 mL), and the mixture was refluxed for 6 d. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afforded 800 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.72-7.68, 7.02-6.99, 4.66, 4.00-3.92, 1.69-1.64, 1.46-1.38, 1.01-0.95.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]=[C:20]([NH2:26])[C:19]=2[N:27]=1)[CH3:13]>>[NH2:26][C:20]1[C:19]2[N:27]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:3]([N:2]([CH3:1])[C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:4])[CH2:32][CH2:31]3)[C:18]=2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)N(C)c2ccccc2)CC1

Procedure:
Using the method of Examples 54-65, N-methyl-N-phenylcarbamoyl chloride was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 465.3006.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)[CH2:18][N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a 50 mL round-bottomed flask was added 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (226 mg, 0.93 mmol) [prepared according to the procedure of Example 95], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (519 mg, 1.349 mmol) [prepared according to Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (515 mg, 1.1 mmol) in chloroform (10 mL). DIEA (820 μL, 4.70 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (379 mg, 69%): LC-MS (ES) m/z=573 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][C:12]=1[C:13](O)=[O:14].CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl.O>[NH2:10][C:11]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][C:12]=1[C:13]([NH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncc(Br)cc1C(=O)NCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
To a degassed solution of (4-fluorophenyl)methanamine (500 mg, 4.0 mmol), 2-amino-5-bromonicotinic acid (867 mg, 4.0 mmol) and Et3N (1.21 g, 12.0 mmol) in dry DCM (10 mL) was added T3P (2.54 g, 8.0 mmol) at 0° C. under N2 protection. The mixture was stirred at 0° C. for 20 minutes. The mixture was diluted with water, and then it was extracted with EtOAc, dried over Na2SO4, filtrated and concentrated to give the crude product of 2-amino-5-bromo-N-(4-fluorobenzyl)nicotinamide (1.05 g, yield: 81%). 1H-NMR (CDCl3, 400 MHz) δ 8.18 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.31 (t, J=8.0 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.38 (d, J=4.0 Hz, 2H), 6.17 (d, J=5.2 Hz, 1H), 5.12 (d, J=6.4 Hz, 2H). MS (M+H)+: 324/326.
Reaction SMILES: [CH3:1][C:2]1[CH:3]2[CH2:9][C:6]([CH3:10])([CH2:7][CH:8]=1)[CH2:5][CH2:4]2.C(OO)(=[O:13])C.C([O-])(=O)C.[Na+]>>[CH3:1][C:2]12[O:13][CH:8]1[CH2:7][C:6]1([CH3:10])[CH2:9][CH:3]2[CH2:4][CH2:5]1
Reactant: CC(=O)OO
Reactant: CC1=CCC2(C)CCC1C2
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC12CCC(C1)C1(C)OC1C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
2,5-Dimethyl-bicyclo[3.2.1]oct-2-ene (800 g, 5.88 mol, obtained as above in EXAMPLE I) was fed into a solution of peracetic acid (CH3CO3H, 32%, 1.466 Kg, 6.18 mol) and sodium acetate (CH3CO2Na, 72 g, 0.882 mol), and cooled to 0° C. The reaction mixture was aged for 6 hours, and subsequently quenched with water and toluene. The reaction mixture was shaken and split. The organic layer was first washed with a solution of sodium carbonate (Na2CO3), and then with a solution of sodium sulfite (Na2SO3). Fractional distillation of the organic layer provided 2,6-dimethyl-3-oxa-tricyclo[4.2.1.0*2,4*]nonane (734 g) having a boiling point of 31° C. at a pressure of 18 mmHg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(N(CC)CC)C.[Cu]I.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>[CH2:12]([N:11]([CH2:15][CH2:16][CH3:17])[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)[CH2:13][CH3:14]
Reactant: CCCN(CCC)C1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C

Procedure:
Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-dipropylamine (Intermediate 121, 150.0 mg, 0.50 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5 d. The title compound was isolated by chromatography (0-3% EtOAc-hexanes).