Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)[N:10]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)[N:10]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 50 °C

Procedure:
A solution of the product from Example 104 Step F (0.280 g; 0.541 mmol) in methanol (4 mL) and THF (1 mL) in a round bottom flask was treated with 3N aq. NaOH (1.08 mL; 3.24 mmol) and heated to 50° C. for 2 hours. The volatiles were removed in vacuo, and the reaction was quenched with saturated aq. NaHSO4 solution and extracted with methylene chloride (5×). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford the crude product. NMR and LCMS indicated good purity and the crude product was used without further purification: m/e=504 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>CC#N>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:15](=[O:16])[CH2:14][C:13](=[O:17])[CH3:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc2[nH]nc(Br)c2c1
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1ccc2[nH]nc(Br)c2c1
Temperature: 50 °C
Yield: 26 %

Procedure:
The product of Step (b) (4.00 g, 18.86 mmol, 1 equiv) was suspended In CH3CN (20 mL). In a separate flask, diketene (1.45 mL, 18.89 mmol, 1 equiv) was dissolved in CH3CN (10 mL) The diketene solution was added to the initial suspension, and the mixture was heated to 50° C. for 18 hours. The reaction mixture was cooled and concentrated en vacuo. The resulting residue was purified by flash chromatography to afford 1.47 g (26%) of the product as a pink solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[OH:23]/[N:24]=[C:25](/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)\[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].[H-].[Na+].Cl>CN(C)C=O.O>[CH3:12][C:11]1[O:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH2:6][O:5][C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[CH2:2][O:23]/[N:24]=[C:25](/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)\[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC/C(=N\OCc1ccccc1OCc1nc(-c2ccccc2)oc1C)c1ccccc1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a stirred solution of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.50 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (990 mg) in N,N-dimethylformamide (40 ml) was added sodium hydride (60% in oil, 200 mg) at 0° C. After stirring for 2 hours, the reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:4, v/v) gave methyl E-4-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (1.65 g, yield 71%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]Br)[C:5]([I:8])=[N:6][CH:7]=1.C([O-])([O-])=[O:12].[Ca+2]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:12])[C:5]([I:8])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1cc(Br)cnc1I
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cc(Br)cnc1I
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a stirred solution of 5-bromo-3-bromomethyl-2-iodo-pyridine (25.0 g, crude, 66.313 mmol, 1 eq) in 1,4-dioxane (200 mL) was added suspension of CaCO3 (34.5 mL, 345 mmol, 5.2 eq) in water (200 mL) at room temperature. Resulting reaction mixture was refluxed for 10 hours. After complete consumption of starting material, reaction mixture was cooled to room temperature and filtered through celite bed over Buchner funnel, celite bed was washed with DCM (2×300 mL). Combined filtrate was washed with water (300 mL) and aqueous sodium bicarbonate (120 mL), dried over sodium sulfate and concentrated under reduced pressure to afford off white solid (15.3 g, crude). Crude compound was purified by washing with n-pentane (2×150 mL) to get desired compound as white solid (9.5 g, impure). Impure title compound was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ: 2.14 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.8, 2H), 7.86 (d, J=1.32 Hz, 1H), 8.33 (d, J=3.32, 1H). LC-MS (m/z): 313.9 (M+H).
Reaction SMILES: C12N([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][NH:31]2)[CH2:28]1)=[O:26].ClC1C=NC2C(=CC=CC=2)N=1>>[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][N:31]2[C:9]2[CH:18]=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:28]1)=[O:26]
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Agent: Clc1cnc2ccccc2n1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3cnc4ccccc4n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 19 and 2-chloro-quinoxaline. MS (ESI) mass calcd. for C26H22N4O, 406.49; m/z found, 407.2 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[CH:11]=1.[I:20]I>C1COCC1>[I:20][C:11]1[C:12]([O:16][CH2:17][O:18][CH3:19])=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][O:7][CH3:6]
Reactant: II
Reactant: COCOc1cccc(OCOC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(OCOC)c1I
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 0.22 mL, 0.56 mmol) was added to a solution of 12 (100 mg, 0.50 mmol) in anhydrous THF (790 μL) at 0° C. After 5 minutes, iodine (141 mg, 0.56 mmol) in anhydrous THF (320 mL) was added. After two hours at room temperature, the reaction was quenched via dropwise addition of MeOH and the solvent was concentrated. Water (5 mL) was added and the solution was extracted with EtOAc (3×10 mL). Combined organics were washed with saturated aqueous Na2S2O3, saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 15 as a brown oil (129 mg, 79%): 1H NMR (CDCl3, 100 MHz) 7.25-7.18 (m, 1H), 6.79-6.71 (m, 2H), 5.27 (s, 2H), 5.18 (s, 2H), 3.54 (s, 3H), 3.50 (s, 3H); IR (film) νmax 2953, 2924, 2853, 1458, 1377 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH3:24])[C:8]([F:11])=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH3:24])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN(C)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 23, Step 1, using the following starting materials: (6-fluoro-2′-methylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH2:5](N(CC)CC)C.Cl[C:13](=[CH2:17])[C:14]([O-:16])=O.O>C(OCC)C>[Cl:1][CH2:2][CH2:3][O:4][C:14](=[O:16])[C:13]([CH3:17])=[CH2:5]
Reactant: OCCCl
Reactant: C=C(Cl)C(=O)[O-]
Reactant: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: C=C(C)C(=O)OCCCl
Reaction time: 4 h

Procedure:
A solution was prepared by dissolving 25 g of 2-chloroethanol (310 mmol) and 37.7 g of triethylamine (372.6 mmol) in 70 g of diethylether. Next, 33.72 g of chioroacrylate (272.6 mmol) dissolved in 70 g of diethylether was added drop wise to the solution at ambient temperatures with agitation being carried out for four hours. During the reaction, the reaction flask was cooled with water. The resulting solution was then washed with 300 g of water, 300 g of KHCO3 (aq), and 300 g of NaCl (aq). The organic phase was dried with Na2SO4, and the diethylether was removed by distillation. The yield of the chloroethylacrylate was 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN1CCCCC1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.4 g, 0.0188 mole), 1,1'-carbonyldiimidazole (3.0 g, 0.0188 mole) in anhydrous tetrahydrofuran (150 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 21/2 hours. The nitrogen flow was stopped and a solution of 1-(2-aminoethyl)piperidine (2.4 g, 0.0188 mole) in dry tetrahydrofuran (50 ml) was added. the solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between methylene chloride (75 ml) and water (75 ml). The layers were separated and the aqueous portion washed with methylene chloride (25 ml). The organic layers were combined and washed with potassium bicarbonate solution (2×50 ml), water (25 ml), dried over sodium sulfate, and concentrated in vacuo. The residue (6.6 g) was recrystallized from isopropyl alcohol-isopropyl ether to give 3.5 g (47%). Recrystallization from isopropyl alcohol-isopropyl ether gave 2.5 g of cream colored solid, mp 114°-115° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[N:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([N:20]3[CH:28]([OH:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[N:17]2)=[CH:12][CH:11]=1.[CH3:31][CH:32]([CH3:38])[CH2:33][CH2:34][C:35](Cl)=[O:36].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:31][CH:32]([CH3:38])[CH2:33][CH2:34][C:35]([O:30][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28](=[O:29])[N:20]1[C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[N:19][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[N:17]=1)=[O:36]
Reactant: CC(C)CCC(=O)Cl
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)CCC(C)C)nc2n1
Yield: 30.2 %

Procedure:
Triethylamine (27 cc) is added to a solution, maintained at a temperature in the region of 20° C., of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (12.3 g) in methylene chloride (200 cc). 4-Methylpentanoyl chloride (10.8 g) and 4-dimethylaminopyridine (50 mg) are then introduced dropwise in the course of 20 minutes, and the reaction mixture is then heated for 19 hours under reflux. The suspension obtained in poured into water (800 cc) and the solid obtained is separated by filtration and removed. The organic phase is separated after settling has occurred, washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is purified by chromatography on silica gel (0.063-0.2 mm; 150 g) contained in a column 2.7 cm in diameter (eluant: methylene chloride), eluting 50-cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After the solid obtained has been recrystallized in acetonitrile, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-methylpentanoate (4.9 g), m.p. 133° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23]O)[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7].[CH3:37][NH:38][CH3:39]>>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][N:38]([CH3:39])[CH3:37])[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7]
Reactant: CNC
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCO)CN2c1ccccc1
Product: CN(C)CCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=543.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and dimethylamine.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C@@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH2:1]([NH:17][C@H:10]([CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: C[C@@H](NCc1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a stirred solution of benzaldehyde (1.58 mL, 15.5 mmol) in 10 mL of absolute ethanol at room temperature under nitrogen was added (R)-α-methylbenzylamine (2.0 mL, 15.51 mmol, 99% ee.). The reaction mixture was stirred for 3 hours. The reaction solution was then dried over magnesium sulfate and diluted to a 60 mL volume with EtOH. Ethanol washed Raney nickel Ni (~1.5 g) was added and the resulting suspension was treated with 58 psi of hydrogen in a Parr Type Shaker. After 1 day, additional Raney nickel (~1 g) and 30 mL of ethanol were added and the hydrogenolysis continued for 3 days. The reaction mixture was filtered through Celite to remove the catalyst and concentrated to afford 3.11 g (95%) of N-benzyl (R)-α-methylbenzylamine as a pale yellow oil contaminated with~5% of benzyl alcohol and (R)-α-methylbenzylamine; 1H NMR (DMSO-6, 250 MHz) δ7.1-7.5 (m, 10H, Ar), 3.68 (q, 1H, J=6.6 Hz), 3.48 (dd, 2H, J1 =13.6 Hz, J2 =20.5 Hz), 1.26 (d, 3H, J=6.6 Hz, CH3); 13C NMR (DMSO-d6) δ146.1, 141.0, 128.2, 128.0, 127.8, 126.5, 126.4, 56.7, 50.6, 24.5. This mixture was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:13][C:14](=[O:23])[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22].[SH:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[S:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:13][C:14](=[O:23])[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]
Reactant: O=C(Nc1cccc2c(Cl)c(Br)cnc12)c1c(Cl)cccc1Cl
Reactant: Sc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc2c(Sc3ncc[nH]3)c(Br)cnc12)c1c(Cl)cccc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a solution of 3-bromo-4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (120 mg) in N-methylpyrrolidone were added 2-mercaptoimidazole (33.5 mg) and potassium carbonate (50.1 mg), and the mixture was stirred for 40 minutes at ambient temperature, for 1 hour at 40° C., for 1 hour at 80° C. and for 1 hour at 90° C. To the mixture was added water, and the resulting precipitate was collected by filtration and washed with water and ethanol to give 3-bromo-8-(2,6-dichlorobenzoylamino)-4-(imidazol-2-ylthio)quinoline (88.0 mg).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[CH2:12]([NH2:15])[CH:13]=[CH2:14].[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:12]([NH:15][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:20][CH:21]=1)[CH:13]=[CH2:14]
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: C=CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 2.5 h
Yield: 96 %

Procedure:
To a solution of 1-hydroxybenzotriazole hydrate (5.4 g, 40 mmol), allyl amine (60 mmol), and 4-(trifluoromethoxy)benzoic acid (8.3 g, 40 mmol) in DMF (110 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (11.5 g, 60 mmol) at R.T. After the reaction mixture was stirred for 2.5 hrs, the solution was partitioned between 10% citric acid and ether. The organic layer was washed with sat. aqueous sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated. The residue was purified by silica gel chromatography (20% ether/hexanes) to yield the title compound (colorless solid 96%). 1H NMR (400 MHz, CDCl3) δ7.85 (d, J=7.1 Hz, 2 H, Ar), 7.28 (d, J=5.9 Hz, 2 H, Ar), 6.31 (s, 1 H, NH), 5.94 (m, 1 H, CH2CHCH2), 5.25 (dd,J=8.6, 7.1 Hz, 2 H, NHCH2CH), 4.10 (m, 2 H, CHCH2);
Reaction SMILES: OC1C(=O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N2CCN(C)C(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([N:51]3[C:55]4=[N:56][CH:57]=[CH:58][CH:59]=[C:54]4[CH:53]=[CH:52]3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:60][CH2:61][N:62]([CH:65]3[CH2:67][CH2:66]3)[C:63](=[O:64])[C:39]=12)C1C=CC=CC=1>>[CH:65]1([N:62]2[CH2:61][CH2:60][N:40]3[C:41]([CH2:45][C:46]4([N:51]5[C:55]6=[N:56][CH:57]=[CH:58][CH:59]=[C:54]6[CH:53]=[CH:52]5)[CH2:47][CH2:48][CH2:49][CH2:50]4)=[N:42][C:43](=[O:44])[C:38]([OH:37])=[C:39]3[C:63]2=[O:64])[CH2:66][CH2:67]1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1C1CC1
Agent: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(O)c2C1=O
Product: O=C1c2c(O)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1C1CC1

Procedure:
2-Cyclopropyl-9-hydroxy-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (420) was prepared following the same method as described for 9-hydroxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (408) from 9-Benzyloxy-2-cyclopropyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (419) (45 mg, 0.09 mmol) and was obtained as an off-white solid (35 mg, 94%).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:40][CH:33]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NC1CCCCCC1
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCCCC4)ncnc32)[C@]1(C)F
Yield: 67.4 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.55 g, 1.10 mmol) in ethanol (about 5 ml) was added cycloheptylamine (about 1.80 ml, 14.2 mmol) and refluxed for about 30 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.4 g) as a colorless solid. Yield: 62%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.38 (s, 1H), 8.04 (d, 2H), 7.97 (s, 1H), 7.60-7.55 (m, 1H), 7.47-7.42 (m, 2H), 6.52 (d, 1H, J=22.2 Hz), 5.81 (bs, 1H), 4.83-4.77 (m, 2H), 4.48-4.41 (m, 1H), 2.15 (s, 3H), 1.89-1.88 (s, 3H), 1.62-1.11 (m, 16H); ES Mass: [M+1]+ 540 (60%), [M+Na] 562 (100%); IR cm−: 3430, 2924, 2853, 2348, 1753, 1725, 1617, 1451, 1274, 1060, 950, 711. HPLC: 92%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH:48]([C:52](O)=[O:53])[CH2:47]3)=[O:45])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([NH:28][C:52]([CH:48]2[O:49][CH2:50][CH2:51][N:46]([C:44]([O:43][CH2:42][CH:40]3[C:39]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:33]4[C:41]3=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:45])[CH2:47]2)=[O:53])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=C(O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCO1
Reaction time: 2 h

Procedure:
HATU (1.17 g, 3.0 mmol) and cyclopropylamine (0.17 g, 3.0 mmol) were added to a solution of 4-[(9H-fluoren-9-ylmethoxy)carbonyl]morpholine-2-carboxylic acid (1.0 g, 2.9 mmol) and DIPEA (0.56 mL, 3.2 mmol) in DMF (50 mL). The reaction mixture was stirred for 2 hrs. at ambient temperature and the solvent was concentrated. The product was recovered in EtOAc and washed with water, saturated NaHCO3 solution, water and brine. The organic layer was dried over anhydrous MgSO4 and the solvent was concentrated to provide the title compound that was used for the next step without further purification. MS (ESI) (M+H)+=393.0.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([NH2:12])[C:3]=12.[CH3:13][O:14][C@H:15]([CH3:19])[C:16](O)=[O:17].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.C(OCC)(=O)C.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([NH:12][C:16](=[O:17])[C@H:15]([O:14][CH3:13])[CH3:19])[C:3]=12
Reactant: Nc1c[nH]c2ncc(F)c(F)c12
Reactant: CO[C@H](C)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(F)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
TEA (0.82 mL, 5.91 mmol) was added to a mixture of 4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 1.18 mmol; Example 13, Step C), (R)-2-methoxypropanoic acid (0.25 g, 2.37 mmol) and BOP-Cl (0.60 g, 2.37 mmol) in DCM (5 mL) at room temperature. The reaction was stirred at room temperature for 1 hour, and then a 2N LiOH solution (3 mL) was added. The mixture was stirred at room temperature for 30 minutes, and water (10 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by chromatography on silica gel (hexane:ethyl acetate 1:2) to give (R)—N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.21 g, 70%) as a solid.