Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:14][Si:15]([CH3:17])([CH3:16])[CH2:18][CH2:19][CH:7]1[C:6]([CH3:13])([CH3:12])[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:8]1=[O:11]
Reactant: CC1(C)CC(=O)c2cc(Br)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)c2ccccc2C(=O)C1CC[Si](C)(C)C
Temperature: 70 °C

Procedure:
To a solution of 815.0 mg (3.41 mmol) 6-bromo-2,3-dihydro-3,3-dimethyl-1H-inden-1-one (See Smith et al. Org. Prep. Proced. Int. 1978 123-131) in 100 ml of degassed Et3N (sparged with argon for 20 min) was added 259.6 mg (1.363 mmol) of copper(I) iodide, 956.9 mg (1.363 mmol) of bis(triphenylphosphine)palladium(II)chloride, and 3.14 g (34.08 mmol) of (trimethylsilyl)acetylene. This mixture was heated at 70° C. for 42 hours, cooled to room temperature, and filtered through a pad of silica gel and washed with ether. The filtrate was washed with water, 1M HCl, water, and finally with saturated aqueous NaCl before being dried over MgSO4. Concentration of the solution under reduced pressure, followed by column chromatography (silica gel; 10% Et2O -hexanes) afforded the title compound as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.79(1H, d, J=1.4 Hz), 7.69 (1H, dd, J=1.6, 8.3 Hz), 7.42 (1H, d, J=8.5 Hz), 2.60 (2H, s), 1.41 (6H, s), 0.26 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Cl)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.93 (s, 1H), 7.72–6.68 (m, 12H), 5.06–4.98 (m, 1H), 3.66–3.50 (m, br, 2H), 3.02–2.82 (m, br, 2H), 2.80–2.57 (m, br, 4H), 2.57–2.38 (m, br, 2H), 2.02–1.76 (m, br, 6H), 1.64–1.48 (m, br, 1H), 1.48–1.36 (m, br, 3H), 1.25 (d, 6H, J=6.8 Hz); Anal. Calc. for C33H41Cl2FN2O2.0.5EtOAc: C, 66.55; H, 7.18; N, 4.43; Found: C, 66.35; H, 6.86; N, 4.46. ESMS m/e: 550.8 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[O:11][C:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=3[C:9]=2[CH:8]=[C:7]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:6]=1)=[O:4].[ClH:34]>O1CCCC1>[ClH:34].[CH3:1][NH:2][C:3]([C:5]1[C:10]2[O:11][C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:9]=2[CH:8]=[C:7]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:27])[CH:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCNC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step B (41 mg, 0.08 mmol) in tetrahydrofuran (2.5 mL) was added concentrated HCl (0.5 mL) at 0° C. The reaction mixture was slowly allowed to reach to ambient temperature. After stirring overnight at ambient temperature the precipitate was filtered, washed with tetrahydrofuran, and dried overnight in vacuo at 45° C. to give N-methyl-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine-6-carboxamide hydrochloride (21 mg, 59%, AUC HPLC>99%) as a white solid: mp <<MP data>>; 1H NMR (DMSO-d6, 400 MHz) δ 9.35 (br s, 2H), 8.56-8.47 (m, 2H), 8.14 (d, J=2.0 Hz, 1H), 8.03-7.95 (m, 2H), 7.72-7.58 (m, 3H), 4.41 (s, 2H), 3.54 (t, J=6.0 Hz, 2H), 3.14 (t, J=6.0 Hz, 2H), 2.86 (d, J=4.8 Hz, 3H); APCI MS m/z 371 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:20]([C:34]([NH2:36])=[O:35])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@H:27]6[NH:31][CH2:32][CH2:33][C@@H:26]56)[N:24]=4)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:46][N:47]([CH3:51])[C:48]([Cl:50])=[O:49]>CN1C(=O)CCC1>[C:34]([C:20]1[N:21]=[CH:22][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]3[N:31]([C:48]([N:47]([CH3:51])[CH3:46])=[O:49])[CH2:32][CH2:33][C@@H:26]23)=[N:24][C:19]=1[NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)(=[O:35])[NH2:36].[ClH:50]
Reactant: CN(C)C(=O)Cl
Reactant: NC(=O)c1ncc(N2CCC[C@H]3NCC[C@H]32)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)N1CC[C@@H]2[C@H]1CCCN2c1cnc(C(N)=O)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 1045.6 %

Procedure:
3-(4-(1-Cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide (420) (82 mg, 0.16 mmol) was dissolved in 3 mL NMP. To it were added DIEA (290 μL, 1.68 mmol) and then dimethylcarbamoyl chloride (62 μL, 0.67 mmol). The mixture was stirred at RT for 2 hours, quenched with 0.5 mL TFA, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (3aR,7aR)-4-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-N,N-dimethyloctahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide (421) as HCl salt (61 mg, 64%). LC-MS (ESI): m/z (M+1) 561.9. UV: λ=267, 275, 304, 334, 372 nm. Proton NMR (CD3OD): δ 7.64 (1H, m), 7.59 (2H, d, J=7.5 Hz), 7.20 (2H, d, J=8.0 Hz), 4.18 (2H, m), 3.71 (3H, m), 3.61-3.56 (2H, m), 3.44 (1H, m), 3.13 (3H, m), 2.90 (7H, s), 2.21 (3H, m), 2.15 (2H, m), 2.07 (1H, m), 1.95 (3H, m), 1.87 (3H, m), 1.73 (4H, m), 1.61 (2H, m) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13](Cl)=[O:14].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>ClCCl>[CH:16]1([NH:19][C:13](=[O:14])/[CH:12]=[C:6]2\[CH2:5][CH2:4][C:3]3[C:7]\2=[CH:8][C:9]([F:11])=[CH:10][C:2]=3[F:1])[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: O=C(Cl)/C=C1\CCc2c(F)cc(F)cc21
Solvent: ClCCl
Product: O=C(/C=C1\CCc2c(F)cc(F)cc21)NC1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
An ice cold solution of (E)-2-(4,6-difluoro-1-indanylidene)acetyl chloride (2.97 g, 0.013 mol) in dichloromethane (30 mL) was treated with cyclopropylamine (1.48 g, 0.026 mol, Aldrich) and the mixture was stirred for 4 h. The mixture was concentrated in vacuo and the residue was taken up in a mixture of ethyl acetate and 5% aqueous sodium bicarbonate. The ethyl acetate phase was washed with 5% aqueous sodium bicarbonate, saturated aqueous NaCl and dried (Na2SO4). Chromatography on silica gel with ethyl acetate:hexanes (1:1) as eluent and trituration of the resulting solid with pentane gave 1.92 g (59%) of (E)-N-cyclopropyl-2-(4,6-difluoro-1-indanylidene)acetamide as a white solid: m.p., 156-158° C.;
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4]1)[CH3:2].Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[N:15]=1>>[Br:16][C:14]1[N:15]=[C:10]([NH:8][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: CCn1cc(N)cn1
Reactant: Cn1cc(Br)nc(Br)c1=O
Product: CCn1cc(Nc2nc(Br)cn(C)c2=O)cn1
Yield: 75.3 %

Procedure:
Using the same general procedure as Example 102k, reaction of 111b (500 mg, 4.50 mmol) and 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.33 g, 4.95 mmol) afforded a 75% yield (1.01 g) of 111c as an off-white solid: mp 237-239° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.02 (s, 1H), 7.73 (s, 1H), 7.20 (s, 1H), 4.11 (q, 2H, J=7.5 Hz), 3.41 (s, 3H), 1.34 (t, 3H, J=7.3 Hz); MS (ESI+) m/z 298.0 (M+H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][N:18]2[C@H:23]([CH3:24])[CH2:22][CH2:21][C@@H:20]([CH2:25][OH:26])[CH2:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][N:18]2[C@H:23]([CH3:24])[CH2:22][CH2:21][C@@H:20]([CH:25]=[O:26])[CH2:19]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CN2C[C@H](CO)CC[C@H]2C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(CN2C[C@H](C=O)CC[C@H]2C)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of DMSO (1.75 mL, 24.7 mmol) in CH2Cl2 was cooled at −78° C. and treated with oxalyl chloride (2.16 mL, 24.7 mmol) dropwise. The solution was stirred at −78° C. for 20 mins and then treated with a solution of [(3R,6R)-1-(4-methoxybenzyl)-6-methylpiperidin-3-yl]methanol (4.10 g, 16.4 mmol) in CH2Cl2 (15 mL) dropwise. After stirring at −78° C. for 1 h, the reaction was allowed to warm to ambient temperature and triethylamine (11.5 mL, 82.0 mmol) was added. After stirring overnight, the reaction was diluted with CH2Cl2 and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-10% MeOH in CH2Cl2 to provide (3R,6R)-1-(4-methoxybenzyl)-6-methylpiperidine-3-carbaldehyde as an orange oil, which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 266.4 for M+H3O+.
Reaction SMILES: [CH2:1]([C@H:3]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:5](=[O:17])[CH2:4]1)[CH3:2].[C:18](=[O:22])([O:20][CH3:21])[NH2:19].CC(C)([O-])C.[Li+].O1CCCC1.O>O1CCCC1.C1(C)C=CC=CC=1>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([NH:6][C@H:3]([CH2:1][CH3:2])[CH2:4][C:5]([NH:19][C:18](=[O:22])[O:20][CH3:21])=[O:17])=[CH:8][CH:9]=1
Reactant: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Reactant: COC(N)=O
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](CC(=O)NC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 79 %

Procedure:
866 mg (3.57 mmol) of (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone produced in Example 6 and 402 mg (5.4 mmol) of methyl carbamate were dissolved in tetrahydrofuran (15 mL) and further mixed with a lithium tert-butoxide/tetrahydrofuran solution (1 mol/L, 5.4 mL, 5.4 mmol) at room temperature. After stirring at the same temperature for 2 hours, water (5.0 mL) was further added to the reaction solution and extraction with toluene (10 mL) was repeated twice. The residue obtained by concentration of the separated organic layer after washing with water was purified on silica gel column chromatography to obtain methyl (R)-{3-[4-(trifluoromethyl)phenylamino]-pentanoyl}carbamate as a white solid (897 mg, isolated yield: 79%). 1H-NMR (CDCl3, 400 MHz/ppm): 5 0.98 (3H, t), 1.5-1.8 (2H, m), 2.9-3.2 (2H, m), 3.77 (3H, s), 3.8-3.9 (1H, m), 4.2-4.3 (1H, br), 6.60 (2H, d), 7.37 (2H, d), 7.9-8.1 (1H, br)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=3)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (77) (100 mg, 0.28 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[CH:10]=[CH:11][C:12](=[O:14])[O:13][C:8]=2[CH:7]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]1[CH:27]=[CH:26][NH:25][CH2:24][CH2:23]1>CN(C=O)C>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]3[CH:10]=[CH:11][C:12](=[O:14])[O:13][C:8]=3[CH:7]=2)[CH2:24][CH:23]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: C1=CC(c2cccs2)CCN1
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCN3CC=C(c4cccs4)CC3)cc2o1

Procedure:
A 2.9 g (0.012 mole) sample of 7-(3-chloropropoxy)-2H-1-benzopyran-2-one as prepared in Example 1 above, 2 g (0.012 mole) 4-(2-thienyl)tetrahydropyridine, and 5 g NaHCo3 in 80 ml DMF is stirred at 80°-90° C. for seven hours at room temperature overnight then filtered and evaporated in vacuo. The residue in methylene dichloride is washed with NaHCO3, dried (MgSO4) and evaporated in vacuo. 7-[3-[3,6-Dihydro-4-(2-thienyl)-1(2H)-pyridinyl]propoxy]-2H-1-benzopyran-2-one as 4.3 g of dark oil was obtained. The oil was dissolved in 20 ml of 2-propanol and treated with 3 ml of 20% 2-propanolic hydrogen chloride solution to give 2.4 g of the monhydrochloride salt, mp 235-7° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1
Reactant: O=C1COc2ccc(O)cc2N1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Product: COc1cc2c(Oc3ccc4c(c3)NC(=O)CO4)ncnc2cc1OCCCN1CCCC1
Yield: 0.1 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mol), (prepared as described for the starting material in Example 9), was reacted with 6-hydroxy-2H-4H-1,4-benzoxazin-3-one (83 mg, 0.5 mol), (J. Chem. Soc. C, 1971, 2696), to give 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline (170 mg, 94%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:17])([F:16])[CH2:5][N:6]([CH2:14][CH3:15])[C:7](=[O:13])[CH2:8][O:9]C(=O)C>CO>[F:3][C:4]([F:16])([F:17])[CH2:5][N:6]([CH2:14][CH3:15])[C:7](=[O:13])[CH2:8][OH:9]
Reactant: CCN(CC(F)(F)F)C(=O)COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC(F)(F)F)C(=O)CO
Temperature: 20 °C
Reaction time: 15 h

Procedure:
8 ml of saturated sodium hydroxide solution were added to a solution of 20 g (0.088 mol) of N-(2,2,2-trifluoroethyl)-N-ethyl-acetoxyacetamide in 100 ml of methanol. The mixture was stirred at 20° C. for 15 hours and concentrated and the concentrate was neutralized with acetic acid and extracted with methylene chloride. The organic phase was dried and filtered. After the solvent had been distilled off, N-(2,2,2-trifluoroethyl)-N-ethylhydroxyacetic acid amide was obtained as a yellow oil. ##STR14##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=O)=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:28][NH2:29]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH:29][CH3:28])=[O:24])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CN
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Solvent: CCO
Product: CNC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 18 h

Procedure:
A suspension of the product of Example 1 (100 mg) in a 33% w/v solution of methylamine in ethanol (3 ml) was stirred for 18 hours. The solid formed, after filtration and washing with a little ethyl acetate, gave the title compound, 65 mg: m.p. 169°-171° C.; NMR (d6DMSO) δ8.14 (2H, d), 8.06 (1H, bq), 8.00 (2H, d), 7.05 (2H, d), 6.80 (2H, d), 4.56 (2H, s), 3.82 (2H, s), 3.30 (4H, t), 2.66 (3H, d), 2.61 (4H t); m/e 369 (M+H)+ ; calculated for C20H24N4O3 : C, 65.2; H, 6.6; N, 15.2. found: C, 65.0; H, 6.8; N, 15.1%.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:17]3[CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][C:9]=1[F:30])=[O:6])[CH3:3].CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:52]([N:55]1[CH2:60][CH2:59][CH:58]([C:61](O)=[O:62])[CH2:57][CH2:56]1)(=[O:54])[CH3:53]>CN(C=O)C>[C:52]([N:55]1[CH2:56][CH2:57][CH:58]([C:61]([N:21]2[CH2:22][C:17]3[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:15][C:14]([C:11]4[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[C:9]([F:30])[CH:10]=4)=[N:19][C:18]=3[CH2:20]2)=[O:62])[CH2:59][CH2:60]1)(=[O:54])[CH3:53]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)C2CCN(C(C)=O)CC2)C3)cc1F
Temperature: 25 °C
Yield: 6.8 %

Procedure:
A stirred solution of (S)-1-ethyl-3-(2-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (intermediate 18) (133 mg, 0.25 mmol) and N-methylmorpholine (55 μL, 0.5 mmol) in DMF (5 mL, anhydrous) was added EDC (53 mg, 0.275 mmol), HOBT (37 mg, 0.275 mmol), and 1-acetylpiperidine-4-carboxylic acid (43 mg, 0.25 mmol). The reaction mixture was stirred at room temperature until analysis by LCMS deemed reaction complete. Solvent was then removed in vacuo. Purified by prep. HPLC (low pH) Then further purified using a TsOH cartridge to remove residual formic acid from HPLC (loaded in MeOH eluted with 2M methanolic ammonia). Yielding a light pink solid (9.6 mg, 0.017 mmol, 7%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].O[C:8]1[C:13](I)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=1.Cl.CN(C)[C:21](=O)[CH3:22]>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.O1CCOCC1>[OH:4][C:1]1[C:13]([CH:8]2[CH2:22][CH2:21]2)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(C2CC2)c1
Reaction time: 10 h

Procedure:
Cesium carbonate (3.6 g), cyclopropylboronic acid•monohydrate (1.0 g), tetrakis(triphenylphosphine)palladium (0.87 g), and water (0.2 ml) were added to a 1,4-dioxane (20 ml) solution containing 2-hydroxy-3-iodo-5-nitropyridine (2.00 g) in a nitrogen atmosphere, followed by stirring for 10 hours. Then, N,N-dimethylacetamide (10 ml) was added to the reaction solution, followed by stirring at 120° C. for 7.5 hours. The reaction solution was adjusted to room temperature and the pH was adjusted to pH 2 with the addition of water and 6M hydrochloric acid, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1 to 0:1), and a white solid of 2-hydroxy-5-nitro-3-cyclopropylpyridine (0.41 g) was thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][C@H:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])=[CH:18][C:17]=1[F:23]
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(F)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (27 mg, yield 59%).
Reaction SMILES: N=C=N.[CH2:4]([CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([OH:14])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:22][CH:23]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:24]([OH:41])[CH:25]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:37]([O:36][C:34]([NH:33][CH:25]([CH:24]([OH:41])[CH:23]([NH:22][C:12](=[O:14])[CH:11]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Agent: N=C=N
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)C(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the carbodiimide coupling procedure of Example 55, dibenzylacetic acid was coupled to the resultant compound of Example 11 to give the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>>[NH:10]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: Cc1ccnc(Cl)c1
Solvent: O
Product: Cc1ccnc(NN)c1
Temperature: 150 °C
Yield: 50.1 %

Procedure:
2-Chloro-4-methylpyridine (3.43 mL, 39.19 mmol) and hydrazine hydrate (19.07 mL, 391.9 mmol) were suspended together in a flask and heated to 150° C. for 72 hours. The mixture was concentrated in vacuo to an oil. The oil was taken up in EtOAc and the resulting solid was removed by vacuum filtration. The organic filtrate was washed with 40% aqueous NaOH (2×50 mL) and dried over Na2SO4, filtered and concentrated to provide the desired product (2.42 g, 54%) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=[CH:22][CH:21]=1.[C:30]1([Se:36]Cl)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[Cl:19][C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH:25]([Se:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]=2[N:23]=[CH:22][CH:21]=1
Reactant: Cl[Se]c1ccccc1
Reactant: Clc1ccnc2c1CCCC2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1ccnc2c1CCCC2[Se]c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
A solution of diisopropylamine (18.5 ml, 132 mmol) in tetrahydrofuran (100 ml) at 0° was treated with 1.5M butyllithium solution in hexane (88 ml, 132 mmol) under an atmosphere of nitrogen, stirred for 10 min, cooled to -78°, treated dropwise with the product of Step 2 (7.35 g, 44 mmol) in tetrahydrofuran (50 ml) at <-65°, stirred at -78° for 20 min, treated with phenylselenyl chloride (8.5 g, 44 mmol) in tetrahydrofuran (50 ml), warmed to room temperature, and quenched with saturated aqueous ammonium chloride (250 ml). The reaction was worked-up in a similar way to that described in Example 25, Step 1 and the product (9 g) isolated by chromatography [silica; hexane-ether (2:1)] as an oil.