Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH:61]([C@@H:63]1[CH2:67][CH2:66][CH2:65][N:64]1[C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:61]/[C@@H:63]4[CH2:67][CH2:66][CH2:65][N:64]4[C:68]([O:70][C:71]([CH3:72])([CH3:74])[CH3:73])=[O:69])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.2 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (156 mg, 0.25 mmol) was dissolved in 3 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (375 μL, 0.38 mmol). After the reaction mixture was stirred for 45 minutes, a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate 2c (100 mg, 0.50 mmol) in 2 mL of tetrahydrofuran was added. The reaction mixture was stirred for another 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound tert-butyl (2S)-2-[(E)-3-[[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]amino]-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate 2d (161 mg, yield 96.2%) as a light yellow solid.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)=O.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:20]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1
Reactant: CS(=O)(=O)OCCCCCCCOc1ccccc1
Reactant: O=C(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCCCCCCCOc1ccccc1)c1cccnc1
Temperature: 52.5 °C
Yield: 80.3 %

Procedure:
A solution of 7-(phenyloxy)-1-heptyl methanesulfonate (0.2 g, 0.699 mmol) and nicotinic acid (0.173 g, 1.41 mmol) in anhydrous dimethyl formamide (15 mL) was placed in a 25 mL round bottomed flask. Potassium carbonate (0.097 g, 0.702 mmol) was added to this solution and the reaction mixture was heated at 50-55° C. using an oil bath for a period of 16 hours. It was then allowed to attain room temperature diluted with ethyl acetate (40 mL) and quenched with saturated NH4Cl containing ice (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated NAHCO3 (3×10 mL), water (2×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4. Removal of solvent from the dried extract under reduced pressure afforded the product 7-(phenyloxy)-1-heptyl nicotinate (0.176 g, 80.4%). The product ester from step C was analyzed yielding the following confirmatory data: 1H-NMR (CDCl3) δ 1.38-1.62 (m, 6H), 1.76-1.92 (m, 4H), 3.95 (t, 2H, J=6.45 Hz), 4.35 (t, 2H, J=6.64 Hz), 6.85-6.98 (m, 3H), 7.22-7.38 (m, 2H), 7.38 (dd, 1H, J1=7.93 Hz, J2=4.93 Hz), 8.29 (dt, 1H, J1=7.91 Hz, J2=1.92 Hz), 8.77 (dd, 1H, J1=4.83 Hz, J2=1.70 Hz) and 9.23 (d, 1H, J=2.00 Hz), 13C-NMR (CDCl3) δ 25.8, 25.9, 28.5, 28.9, 29.1, 65.4, 67.6, 114.3, 120.4, 123.2, 126.2, 129.3, 136.9, 150.8, 153.2, 158.9 and 165.2; IR (neat): 1712 cm−1; MS (ES+): 314 (M+1); Anal. Calcd. for C19H23NO3: C, 72.80; H, 7.40 and N, 4.47. Found: C, 72.94; H, 7.54 and N, 4.51.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[CH2:45]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:25]2[N:24]=[CH:23][C:22]3[CH2:21][CH2:20][C:19]4[C:15]([C:13]([NH:12][C:5]5[C:4]([CH2:2][CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=5[CH2:10][CH3:11])=[O:14])=[N:16][N:17]([CH3:35])[C:18]=4[C:27]=3[N:26]=2)[CH2:34][CH2:33]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(Cc4ccccc4)CC3)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (40 mg, 0.075 mmol) in dichloromethane (1 mL), DIPEA (0.2 mL, 1.1 mmol) and benzylbromide (0.011 mL, 0.090 mmol) were added. The mixture was stirred at room temperature for 2 h. Dichloromethane was added and the solution was washed water. The organic layer was then dried over Na2SO4 and the solvent evaporated to dryness. The crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 95/5) to 31 mg of the title compound. (75% yield)
Reaction SMILES: O[NH:2][C:3](=N)[NH:4][CH2:5][CH2:6][CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9].N[C@H](C(O)=[O:24])CCCNC(=N)N.CC(O)=O.C(CN=C(NO)N)C[C@H](N)C(O)=O.[N]=O>>[NH2:9][C@H:8]([C:10]([OH:12])=[O:11])[CH2:7][CH2:6][CH2:5][NH:4][C:3]([NH2:2])=[O:24]
Reactant: N=C(NO)NCCC[C@H](N)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NC(=NCCC[C@H](N)C(=O)O)NO
Agent: [N]=O
Solvent: CC(=O)O
Product: NC(=O)NCCC[C@H](N)C(=O)O

Procedure:
Nω-hydroxy-L-arginine is the physiologically occurring intermediate of the NO synthase catalysed oxidation L-arginine. NOHA is oxidised in a further step of NO synthase, nitrogen monoxide being released and L-citrulline being formed.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([OH:12])(=[O:11])[CH:9]=[CH2:10]>N1(C2CCCCC=2)CCCC1.O>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:10][CH2:9][C:8]([OH:12])=[O:11]
Reactant: O=C1CCCCC1
Reactant: C=CC(=O)O
Agent: C1=C(N2CCCC2)CCCC1
Solvent: O
Product: O=C(O)CCC1CCCCC1=O
Temperature: 25 °C
Yield: 59.9 %

Procedure:
29.4 Grams (0.300 mol; 31.1 mL) cyclohexanone, 14.4 grams (0.200 mol; 13.7 mL) of acrylic acid, 1.6 mL (9.6×10-3 mol) of 1-pyrrolidino-1-cyclohexene and 0.09 grams (5×10-3 mol) of water were added to a 250 mL round bottomed flask equipped with a reflux condenser, thermometer, and magnetic stirrer. The mixture was stirred and heated under reflux for four hours. The mixture was then cooled to room temperature resulting in a slushy mixture. Next, the reaction product was subjected to fractional distillation using a 1×20 cm Vigreux column and 0.3 mm Hg vacuum. The fraction taken at 145-151° C. yielded 20.4 g of 91 percent 3-(2-oxocyclohexyl)-propanoic acid (54 percent yield). This fraction was recrystallized in 40 mL CHCl3 /200 mL petroleum ether to give 15.4 grams of 3-(2-oxocyclohexyl)propanoic acid at 99 percent purity.
Reaction SMILES: [C:1]([C:3]([CH3:18])([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH3:4])#[N:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]([CH3:18])([O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH3:4])#[N:2]
Reactant: COC(=O)c1ccc(OC(C)(C)C#N)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC(C)(C)C#N)ccc1C(=O)O
Temperature: 65 °C
Yield: 78 %

Procedure:
Methyl 4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoate (340 mg, 1.36 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide (98 mg, 4.1 mmol) was added and reaction mixture was heated at 65° C. for 1 hour. The crude material was diluted with 10 mL of water and was extracted two times with ether. The ether extracts were discarded and the aqueous layer was made acidic with 4M HCl. The product was then extracted into ethyl acetate, dried over sodium sulfate, filtered, and evaporated to dryness to yield 4-(1-cyano-1-methyl-ethoxy)-2-methoxy-benzoic acid (78%) as a pale yellow solid. ESI-MS m/z calc 235.1, found 236.1 (M+1)+. Retention time: 1.29 minutes (3 min run).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[O:11][CH2:12][CH:13]1[CH2:16][N:15](C(C2C=CC=CC=2)C)[CH2:14]1.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>C(O)C.[Pd]>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[CH3:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[O:11][CH2:12][CH:13]1[CH2:16][NH:15][CH2:14]1
Reactant: Cc1cccc(C)c1OCC1CN(C(C)c2ccccc2)C1
Agent: [Pd]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1OCC1CNC1
Yield: 95.8 %

Procedure:
Triethylamine (2 mL) was added to a solution of 3-[(2,6-dimethylphenoxy)methyl]-1-(1-phenylethyl)azetidine (6.01 g, 21.3 mmol) in absolute ethanol (100 mL). The solution was hydrogenated on a Parr apparatus with approximately 1 g of 10% Pd on carbon as a catalyst at 55° C. and 60 psi (initial pressure) overnight. The mixture was cooled, filtered, and concentrated in vacuo. The residue was dissolved in 2-propanol and added to a solution of maleic acid (2.1 g, 18 mmol). The solid which formed was collected by filtration and recrystallized from 2-propanol to give 5.3 g (81%) of white solid; mp 150°-151.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>[OH-].[Na+]>[Cl:12][C:11]1[CH:10]=[C:9]2[C:4](=[CH:3][C:2]=1[NH:1][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:5]=[C:6]([OH:14])[C:7]([OH:13])=[N:8]2
Reactant: CCOC(=O)Cl
Reactant: Nc1cc2nc(O)c(O)nc2cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Nc1cc2nc(O)c(O)nc2cc1Cl
Reaction time: 1 h
Yield: 9792.4 %

Procedure:
A solution of 10 g (47,3 mmol) 6-amino-7-chloro-2,3-dihydroxyquinoxaline in 200 ml 0,5N sodium hydroxide was ice-cooled, and then 30 ml (0,36 mmol) ethyl chloroformate was added. Stirring was continued at 0° C. for 1 h and at 25° C. for 1 h. To the reaction mixture was added 1N hydrochloric acid to pH 2-3, and the precipitated product was filtered off and washed with water to give 12 g of a crude product. Recrystallization (dimethylsulfoxide-0,5N hydrochloric acid) gave 10 g (75%) 6-chloro-7-ethoxycarbonylamino-2,3-dihydroxyquinoxaline, m.p.>300° C. NMR (DMSO-d6) 11.9 (2H, broad s), 8.9 (1H, broad s), 7.37 (1H,s), 7.17 (1H,s), 4.1 (2H,q), 1.28 (3H,t).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4cc(C)ccc4nc3OC)CC2)cc(OC)c1OC
Yield: 94 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 94%). 1H NMR (300 MHz, CDCl3): δ 2.44-2.49 (m, 3H), 3.18-3.25 (m, 4H), 3.80-3.86 (m, 12H), 4.04-4.13 (m, 4H), 6.20 (s, 2H), 7.02-7.20 (m, 1H), 7.31-7.40 (m, 1H), 7.46-7.63 (m, 2H).
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([C:7]1[C:8](N)=[N:9][C:10]([O:26][CH3:27])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[O:24][CH3:25])[N:12]=1)[CH3:6].[BrH:29]>O.[Cu](Br)Br>[Br:29][C:8]1[N:9]=[C:10]([O:26][CH3:27])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[O:24][CH3:25])=[N:12][C:7]=1[CH2:5][CH3:6]
Reactant: Br
Reactant: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1N
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1Br
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (21 mg, 0.3 mmol) in water (1 mL) is added to a stirred solution of 3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2ylamine (86 mg, 0.25 mmol) in 48% hydrogen bromide (0.3 mL) at 0 C. After 1.5 hours copper bromide (43 mg, 0.3 mmol) is added and the mixture heated to 70 C for 1 hour. The mixture is cooled to room temperature and extracted with ether. The extracts are dried (sodium sulfate), filtered and concentrated to give [4-(5-bromo-6-ethyl-3-methoxypyrazin-2yl)-3-methoxyphenoxy]trifluoromethane (76 mg).
Reaction SMILES: O[CH:2]([CH3:24])/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:23])[CH:14]=2)[CH2:9][CH2:8]1)=[O:6].C(N(S(F)(F)[F:31])CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:31][CH:2]([CH3:24])/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:23])[CH:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1cc(N2CCN(C(=O)/C=C/C(C)O)CC2)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N2CCN(C(=O)/C=C/C(C)F)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(E)-4-Hydroxy-1-[4-(2-methyl-4-quinolyl)piperazin-1-yl]pent-2-en-1-one (32.5 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (200 μl) and added to a solution of (diethylamino)sulphur trifluoride (DAST; 19 μl, 0.12 mmol) in 200 μl dichloromethane. The mixture was stirred for 30 minutes at room temperature, additional DAST was added (10 μl, 0.063 mmol) and stirring was continued for additional 30 minutes. Solid sodium carbonate (25 mg) was added, the mixture was filtered, the filtrate evaporated to dryness and the residue purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 4 mg (0.012 mmol, 12%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[N:11][CH:10]=2)=[CH:5][CH:4]=1.Cl[CH:17]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH:18]=O>C(O)(CC)(C)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][C:12]3[N:13]([C:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[CH:18][N:15]=3)[N:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(Cl)C=O)cc1
Reactant: Nc1ncc(-c2ccc(F)cc2)nn1
Agent: Cl
Solvent: CCC(C)(C)O
Product: COc1ccc(Cc2cnc3ncc(-c4ccc(F)cc4)nn23)cc1
Temperature: 130 °C

Procedure:
A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3-amine hydrochloride (50 mg, 0.2 mmol) and 2-chloro-3-(4-methoxyphenyl)propanal (48 mg, 0.24 mmol) in tert-amyl alcohol (1 mL) was heated at 130° C. for 4 h. After cooling, the mixture was purified by preparative HPLC to afford the desired product. (7.1 mg) LCMS: (M+H)=335.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].Cl[P:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(N(CC)CC)C.C1C=CC=CC=1>[C:18]1([P:17]([O:15][C:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:10][C:5]=2[C:1]([CH3:4])([CH3:3])[CH3:2])[O:15][C:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=2[C:1]([CH3:4])([CH3:3])[CH3:2])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClP(Cl)c1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c2ccccc2)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 42.4 grams of 2,4-di-tert-butylphenol in 101 grams of triethylamine was added dropwise over a 15-minute period 17.9 grams of dichlorophenylphosphine. The reaction mixwas then heated for 6 hours at 65°-70° C. After cooling to room temperature, the reaction mixture was diluted with 50 ml of benzene and poured onto a rapidly stirred mixture of 70 grams of concentrated hydrochloric acid and 200 grams of chopped ice. The product was then isolated as in Example 17 with the product crystallized from acetonitrile as white crystals melting at 90°-93° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](Cl)=[O:16])[O:7][CH2:6]1)[CH2:2][CH3:3].[CH2:21](N(CCC)C1CC2C(=CC=CC=2C(OC)=O)OC1)CC.[Li]C.O>O1CCCC1.[Cu]I>[CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](=[O:16])[CH3:21])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2cccc(C(=O)Cl)c2C1
Reactant: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Agent: [Cu]I
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C1COc2cccc(C(C)=O)c2C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Dipropylamino-5-chloroformylchroman*HCl (4.42 g, 13.4 mmol), prepared from 3-dipropylamino-5-methyloxycarbonylchroman (Example 2) analogous to the procedure used in Example 3, in dry tetrahydrofuran (20 ml), was added to a pre-formed solution of lithium dimethylcuprate; prepared from MeLi and CuI, in 200 mL tetrahydrofuran at -78° C. The solution was stirred for 15 minutes at -78° C. and was then allowed to reach room temperature during 10 minutes. Then, 30 mL H2O was slowly added. The organic phase was decanted, dried with Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:8. The title compound was crystallized as salt from ethyl acetate. Mp 106°-108° C. (oxalate).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:24].[NH:25]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:26]1>>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:24])=[C:2]([N:25]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=4)[CH2:26]3)[N:11]=2)[C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cc(C2CCNC2)ccn1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 56 %

Procedure:
Starting from 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.51 g, 1.5 mmol) and 4-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1, provided the title compound (0.39 g, 56%) as an off-white solid, mp 253°-255° C. (dec).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19].CC1C=CN=C(N)C=1C>C(Cl)Cl>[CH3:21][S:18]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:20])=[O:19]
Reactant: CCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Agent: Cc1ccnc(N)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
500 mg (1.08 mmol) of (R)-9-(6-tert-butyl-dimethyl-silanyloxy)-2,5,7,8-tetramethylchroman-2-yl)nonanol was dissolved in dry DCM (10 ml) under argon atmosphere, followed by the addition of triethylamine (224 ul), MsCl (mesylchloride) (125 ul) and a catalytic amount of DMAP (dimethyl amino pyridine) at 0° C. After 15 minutes the cooling bath was removed and the reaction stirred at room temperature for 1.5 hours. TLC monitoring showed complete conversion in 100% DCM as mobile phase. Extraction with water and DCM afforded crude product that was obtained following evaporation of the solvent under reduced pressure. Column chromatography on silica (100% DCM) gave pure (R)-9-(6-tert-butyl-dimethyl-silanyloxy)-2,5,7,8-tetramethylchroman-2-yl)nonyl methanesulfonate in high yields (following high vacuum). (90%, 526 mg, 0.97 mmol)
Reaction SMILES: C[O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@@H:6]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[O:7][C@H:8]2[CH2:14][NH:15][CH:16]=[O:17].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:35]([O:34][C:32](=[O:33])[CH:31]([N:21]1[CH2:20][CH2:19][CH:18]([C@@H:6]2[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:13])[C:3]=3[OH:2])[C@H:8]([CH2:14][NH:15][CH:16]=[O:17])[O:7]2)[CH2:23][CH2:22]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=1)[CH3:36]
Reactant: CCOC(=O)Cc1ccccc1Br
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCC([C@@H]2Cc3c(ccc(C)c3O)[C@H](CNC=O)O2)CC1

Procedure:
Stir a solution of N-((1R,3S)-5-methoxy-6-methyl-3-(4-piperidinyl)-1-isochromanyl-methyl)formamide (200 mg, 0.58 mmole), ethyl 2-bromophenylacetate (229 mg, 0.94 mmole) and diisopropylethylamine (243 mg, 1.88 mmole) in acetonitrile overnight at room temperature. Add ethyl acetate and water (2 mL each), then separate the organic phase and dry over Na2SO4. Purify the crude product on a 4 g silica gel column (eluting with ethyl acetate:heptane 3:1). Collect the appropriate fractions and concentrate to obtain the title compound. It was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[OH-:17].[Na+]>O1CCOCC1>[NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccco2)nc(N)[nH]c1=O
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a stirred solution of 4.2 g (18.1 mmol) 2-amino-4-(2-furyl)-6-(methylthio)-pyrimidine-5-carbonitrile in 50 ml dioxane was added 50 ml (100 mmol) 2M sodium hydroxide solution and the mixture heated at reflux for 16 h. The reaction mixture was then concentrated in vacuo and the residue resuspended in 300 ml ethyl acetate and the mixture stirred for 30 minutes. The resulting crystals were collected by filtration and dried in vacuo. They were then dissolved in 150 ml water and the mixture neutralised with 1M hydrochloric acid. The resulting crystals were collected by filtration and washed with water to afford 3.3 g (90%) 2-amino-4-furan-2-yl-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile as an off-white crystalline solid. ES-MS m/e (%): 201 ([M—H]−, 100).
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=[S:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2c(c3cccnc3n1-c1ccccc1)OCC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=c1c2c(c3cccnc3n1-c1ccccc1)OCC2

Procedure:
A suspension of 3,5-dihydro-5-phenyl-furo[3,2-c][1, 8]naphthyridin-4(2H)-one (3 g.) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent; 5 g.) in dry toluene (100 ml.) was stirred in an atmosphere of nitrogen and heated to reflux for 6 hrs. After cooling, the organic layer was washed with water, dried and evaporated. The product was purified by chromatography over silica gel in CH2Cl2 containing increasing amounts of ethyl acetate (0-5%). The fractions containing pure product were combined, evaporated, suspended in ethanol, filtered and dried to yield the desired product, m.p. 242°-244.5° C.