Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:25])[CH2:9][C:10]([NH:12][C@@H:13]([CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:14]([O:16]C)=O)=[O:11])[CH3:6].C(OCC)C.[Na]>C(O)C>[CH:19]1([CH2:18][C@@H:13]2[NH:12][C:10](=[O:11])[C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:25])=[C:14]2[OH:16])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)CC(=O)N[C@@H](CC1CCCCC1)C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1=C(O)[C@H](CC2CCCCC2)NC1=O
Yield: 99.8 %

Procedure:
Sodium ethoxide, 21 weight percent in ethanol, 204 g (0.63 mol) (5% less than theory to prevent racemization), is added to a solution of 200 g (0.67 mol) of (S)-α-[[3-ethoxy-1,3-dioxopropyl]amino]cyclohexanepropanoic acid, methyl ester in 650 ml of absolute ethanol. The solution is heated to reflux for 5 minutes, cooled and treated with about 1.5 liters of diethyl ether to precipitate the sodium salt of the product. The mixture is filtered, washed with 500 ml of diethyl ether and then with 100 ml of petroleum ether. The cake is dried on the funnel using a rubber-dam to prevent moisture from condensing to afford 178.8 g of (S)-5-(cyclohexylmethyl)-2,5-dihydro-4-hydroxy-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester, sodium salt. The previous sodium salt is dissolved in 1 liter of water and 325 ml of 2N hydrochloric acid is added to precipitate a large taffy-like clump of material which gradually crystallizes. The clumps are broken up in a mortar and the mixture filtered, washed with water and dried to afford 143.2 g of (S)-5-(cyclohexylmethyl)-2,5-dihydro-4-hydroxy-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester after dissolution in 10% methanol-chloroform at room temperature, charcoaling and concentration; mp 176°-180° C.; [α]D23 =-68.9° (c=1.02% methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=O.C(OP(Cl)(=O)OCC)C.[NH2:25][C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[C:28]([CH3:34])[CH:27]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[C:28]([CH3:34])[CH:27]=1)=[O:9]
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Reactant: Cc1cc(N)cc(C)c1O
Agent: CCOP(=O)(Cl)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(OC)c(C=CC(=O)Nc2cc(C)c(O)c(C)c2)c1
Reaction time: 1 h
Yield: 71 %

Procedure:
Under ice-cooling, 4.16 g of 2,5-dimethoxycinnamic acid is dissolved in 50 ml of acetonitrile, and to the resultant solution are added 3.03 g of triethylamine, then 4.13 g of diethylphosphorochloridate. After the mixture is stirred for one hour, 2.74 g of 4-amino-2,6-dimethylphenol is added and the reaction mixture is stirred at room temperature. After completion of the reaction, ice chips are added, and then 5 % aqueous sodium hydrogen carbonate solution is added. The crystals precipitated are collected by filtration, and washed with isopropyl ether. The crystals obtained are recrystallized form ethyl acetate to give 4.64 g of 4-(2,5-dimethoxycinnamoylamino)-2,6-dimethylphenol as white crystals.
Reaction SMILES: [Li]CCCC.[C:6]([C:9](=[C:14]([NH2:19])[C:15]([F:18])([F:17])[F:16])[C:10]([O:12][CH3:13])=[O:11])(=[O:8])[CH3:7].[F:20][C:21]([F:28])([F:27])[C:22](OCC)=O.O>CCCCCC.C1COCC1>[F:16][C:15]([F:17])([F:18])[C:14]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:6]([OH:8])[CH:7]=[C:22]([C:21]([F:28])([F:27])[F:20])[N:19]=1
Reactant: COC(=O)C(C(C)=O)=C(N)C(F)(F)F
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a flame dried 3-liter, four-necked flask equipped with nitrogen inlet, low temperature thermometer, 500 ml addition funnel and mechanical stirrer is charged 147 ml (1.05 ml) of diisopropylamine and 600 ml of dry tetrahydrofuran. The resulting solution is cooled to -78° C. using an acetone-dry ice bath. To this is slowly added 618 ml (1.05 mol) of 1.7M n-BuLi in hexane at such a rate that the reaction temperature was kept below -60° C. After stirring at -78° C. for 1 hour, a solution of 106 g (0.50 mol) of methyl 2-acetyl-3-amino-4,4,4-tri-fluoro-2-butenoate from Example 2 in 400 ml of dry THF was added in such a rate that the reaction temperature was kept below -60° C. The reaction mixture turned yellow and a solid suspension formed. After 1 hour of stirring at -78° C., the reaction mixture was treated with 59.5 ml (0.50 mol) of ethyl trifluoroacetate in such rate that the reaction temperature was kept below -60° C. This reaction mixture was left at -78° C. for 1 hour, then warmed to room temperature (the yellow suspension disappeared and a yellow solution was formed) and stirred for 2 hours. The resulting solution was poured into 1 L of H2O and extracted with ether (3×700 ml). The combined ether layers were washed with H2O (2×800 ml) and the combined aqueous layers were acidified with concentrated HCl (pH~2). The acidified aqueous layer was extracted with CHCl3 (3×1000 ml), dried (MgSO4) and reduced in vacuo affording 120.85 g of a yellow solid. The crude was recrystallized from ether/hexane to give 103.28 g (71%) of pyridine product; mp 62°-75° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]4[CH:43]=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=4)=[CH:28][CH:27]=3)[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]4[CH:43]=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=4)=[CH:28][CH:27]=3)[CH2:20][CH2:21][C:22](=[O:25])[CH2:23][CH2:24]2)=[CH:15][CH:14]=1
Reactant: OC1CCC(c2ccc(OCc3ccc4ccccc4n3)cc2)(c2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: ClCl
Agent: c1cc[nH+]cc1
Product: O=C1CCC(c2ccc(OCc3ccc4ccccc4n3)cc2)(c2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a mixture of 4,4-bis(4-(2-quinolylmethoxy)phenyl)cyclohexanol (resulting from Example 4) (1.13 g, 2 mmol) and molecular sieves (3 g) in CH2 Cl2 (40 mL) was added PCC (0.65 g, 3 mmol) and the resulting mixture was stirred at room temperature for 30 min. The mixture was filtered through the Celite, the filtrate was concentrated in vacuo to 10 mL and then chromatographed (silica gel, 4:1 CH2Cl2 /EtOAc) to afford 0.25 g of 4,4-bis(4-(2-quinolylmethoxy) phenyl)cyclohexanone.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][CH:21]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][OH:19])[CH:10]=2)[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:24][CH:25]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:10]=2)[N:3]=1
Reactant: [H][H]
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C#CCCO)c2)N=C1N
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(CCCCO)c2)N=C1N
Yield: 61 %

Procedure:
A mixture of a solution of 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (0.26 g, 0.65 mmol) in ethanol and 5% palladium on charcoal (26 mg) was placed on a Paar hydrogenator at 40 psi hydrogen for 8 hrs. The reaction mixture was filtered through a celite pad. The filtrate was concentrated in vacuo. The resultant residue was purified by flash chromatography on silica gel, 5% methanol/ ethyl acetate as eluent, to give the title product as a white solid, 0.16 g (61% yield), mp 63-66° C.; 1H NMR (DMSO-d6) δ 1.4 ((2H, 2H); 1.5 (m, 1 H); 2.5 (2H, under DMSO peak) 2.95 (s, 3 H); 3.3 (q, 2 H); 4.3 (t, 1 H); 6.6 (b, 2H); 7.1 (m, 3H); 7.15 (t, 2F); 7.2 (m, 3 H); 7.4 (d, 2 H); MS [(+)ESI] m/z=404 [M−H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNCCCC
Reactant: Cc1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1cccc(C)c1
Yield: 94.8 %

Procedure:
According to the general procedure B, 3-chlorotoluene (127 mg, 1.00 mmol) reacted with N,N-di-n-butylamine (155 mg, 1.20 mmol) using 0.5 mol % Pd(OAc)2, 1 mol % of ligand, and sodium tert-butoxide (115 mg, 1.20 mmol) at 100° C. for 27 h in toluene to give the title compound (208 mg, 94%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.15 (t, 1H, J=Hz), 6.53 (app.bd, 3H, J=3.3 Hz), 3.31 (t, 4H, J=7.5 Hz), 2.37 (s, 3H), 1.63 (m, 4H), 1.42 (m, 4H), 1.02 (t, 6H, J=7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 148.27, 138.73, 129.02, 116.05, 112.39, 108.94, 50.74, 29.45, 22.02, 20.36, 14.01. GC/MS (EI): m/z 219 (M+). Anal. Calcd for C15H25N: C, 82.13; H, 11.49; N, 6.38. Found: C. 81.85; H, 11.57; N, 6.47.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[NH:25]C(=O)OC(C)(C)C)[C:11]([C:13]2([CH3:16])[CH2:15][CH2:14]2)=O)[CH:6]=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(#N)C.ClCCl>[CH3:24][O:23][C:20]1[CH:19]=[C:18]2[C:17]([C:10]([CH2:9][C:7]3[N:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=3)=[C:11]([C:13]3([CH3:16])[CH2:15][CH2:14]3)[NH:25]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(C(Cc2cccc(C#N)n2)C(=O)C2(C)CC2)c(NC(=O)OC(C)(C)C)c1
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Cc3cccc(C#N)n3)c(C3(C)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 44.5 h
Yield: 82.8 %

Procedure:
To a solution of tert-butyl {2-[1-(6-cyanopyridin-2-ylmethyl)-2-(1-methylcyclopropyl)-2-oxoethyl]-5-methoxyphenyl}carbamate (270 mg) in acetonitrile/dichloromethane (2.1 mL/2.1 mL) was added trifluoroacetic acid (2.1 mL) under ice-cooling, and the mixture was stirred at room temperature for 44.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane), and then purified by aminopropylated silica gel column chromatography to obtain the title compound (163 mg). 1H-NMR (CDCl3) δ ppm: 0.70-0.78 (2H, m), 0.81-0.89 (2H, m), 1.33 (3H, s), 3.82 (3H, s), 4.39 (2H, s), 6.70 (1H, dd, J=2.3, 8.5 Hz), 6.80-6.85 (1H, m), 7.12-7.22 (2H, m), 7.47-7.53 (1H, m), 7.59 (1H, t, J=7.8 Hz), 7.87 (1H, br s).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:13].[Cl:14]OC(C)(C)C.O.[OH-].[NH4+]>C(OCC)C.ClOC(C)(C)C>[NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])([CH3:12])[CH2:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[F:13]
Reactant: CC(C)(C)OCl
Reactant: CC1(C)Cc2ccc(F)c(N)c2O1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC1(C)Cc2c(Cl)cc(F)c(N)c2O1
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A solution of 39.27 g (0.217 mole) of 7-amino-2,3-dihydro-2,2-dimethyl-6-fluorobenzofuran in 750 mL of diethyl ether was cooled to -5° C to 0° C., and 23.54 g (0.217 mole) of t-butyl hypochlorite was added in a dropwise manner during a fifteen minute period. The temperature rose to 10° C., but was lowered to 0°-5° C. at which the reaction mixture stirred for 20 minutes. Gas chromatographic analysis showed that the reaction was incomplete, and an additional 4.54 g (0.042 mole) of t-butyl hypochlorite was added. The mixture was stirred at 0°-5° C. for an hour after which gas chromatographic analysis showed that the reaction was still incomplete. Therefore, an additional 1.82 g (0.017 mole) of t-butyl hypochlorite was added to the reaction mixture, and stirring was continued for one more hour. At the conclusion of this period the reaction was determined to have been completed, and it was poured into 400 mL of water. To this mixture was added 100 mL of 10% ammonium hydroxide. The aqueous and organic phases were separated. The aqueous phase was washed with diethyl ether, and this wash was combined with the organic phase. The combined material was dried over anhydrous sodium sulfate, filtered, and the solvent 20 evaporated from the filtrate under reduced pressure, leaving a dark red oil as the residue. This oil was passed through a column of silica gel, eluting with petroleum ether:diethyl ether (9:1). Product-containing fractions were combined, and the solvent was evaporated under reduced pressure, yielding 40.24 g of 7-amino-4-chloro-2,3-dihydro-2,2-dimethyl-6-fluorobenzofuran as a red oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[N:12]([CH3:18])[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C.Cl>C(OCC)(=O)C>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[N:12]([CH3:18])[C:13](=[O:17])[C:14]([CH3:16])=[CH:15][C:10]=1[C:8]([NH:7][O:6][CH2:5][CH2:4][OH:3])=[O:9]
Reactant: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a rapidly stirred mixture of 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (4.2 g, 8.52 mmol) (prepared according to Example 16A, Step 2) above in ethyl acetate (126.00 mL) was added hydrogen chloride (17.05 mL, 17.0493 g, 17.05 mmol). After 2 hours, less than 1% of the starting material remained (by HPLC analysis) and the phases were allowed to settle. The lower aqueous phase was separated and discarded and the organic phase was washed with sodium chloride (42 mL, 15% wt/vol, then 2×25 mL, 9% wt/vol). The volume was then reduced by distillation of solvent (44 mL) at atmospheric pressure (65° C. head temperature). The solution was then cooled to 70° C., and Form 1, 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (40.3265 mg), made according to Example 16A, Step 4, was added. The mixture was stirred for 20 hours at 70° C. The temperature was reduced to 24° C. over 4 hours 15 minutes, and then lowered to 1° C. for 1 hour. The slurry was then filtered, the cake was washed with cold ethyl acetate (17 mL) and the solid was dried in a vacuum oven at 45° C., to provide 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide Form 1 (3.15 g, 76%).
Reaction SMILES: [CH:1]1[C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18](Br)[CH3:19].[H-].[Na+]>CN(C)C=O>[CH:18]([N:8]1[C:7](=[O:16])[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2)([CH3:19])[CH3:17]
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)c2ccccc2Oc2ccccc21
Yield: 37 %

Procedure:
Following the proceedure described in Example 1, 3.0 grams of 10H-dibenz[b,f][1,4]oxazepin-11-one and 3.7 grams of 2-propyl bromide were reacted in the presence of 0.82 grams of a 50% dispersion of sodium hydride in mineral oil and 50 ml of dry dimethylformamide. The product was purified on the silica gel column (ethyl acetate/hexane, 1:4). The resulting oil was dissolved in petroleum ether which on standing gave 1.33 grams (30% of theory) of 10-isopropyl-10H-dibenz[b,f][1,4]oxazepin-11-one as colorless needles, m.p. 102°-103° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([NH2:13])[N:5]=1.[CH3:14][O:15][CH2:16][CH2:17][OH:18]>>[CH3:14][O:15][CH2:16][CH2:17][O:18][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([NH2:13])[N:5]=1
Reactant: COCCO
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Product: COCCOc1nc(N)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flask with 150 ml 2-methoxyethanol, was added NaH (13 g, 60% dispersion in mineral oil). The mixture was allowed to stir at room temperature for 10 min. Then 6-amino-2-chloroadenine (Compound (1)) (25 g, 0.15 mol) was added. The reaction was refluxed for 2 days while monitoring by LC/MS. Additional NaH (5 g, 60% dispersion in mineral oil) was added and refluxing was continued for another day. After the starting material was consumed, the reaction mixture was cooled to rt (“room temperature”) and the solvent was removed under vacuum. Water was added, and the mixture was neutralized with acetic acid until a solid precipitated. The solid Compound (15) was collected and dried under high vacuum. 1H NMR (DMSO-d6) δ 3.28 (s, 3H), δ 3.61 (t, 2H), δ 4.28 (t, 2H), δ 7.08 (bs, 2H), δ 7.88 (s, 1H), δ 145 (bs, 1H); MS: 210.0 (M+H)+, 208.1 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cl-].C[Al+]C.[OH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([C:24](OCC)=[O:25])[CH:21]=[C:20]([O:29][C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[C:18]=2[CH:19]=1>ClCCCl>[OH:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[C:22]([C:24]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:25])[CH:21]=[C:20]([O:29][C:30]3[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=3)[C:18]=2[CH:19]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CO)oc2c1
Reactant: Cc1ccc(N)nc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cc(CO)oc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To a solution of 2-amino-5-methyl pyridine (305 mg, 2.82 mmol) in DCE (10 mL) at 0° C. was added dimethylaluminum chloride (1M in hexanes, 2.82 mL) drop-wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 2-(hydroxymethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (110 mg, 0.282 mmol) was then added, and the stirring was continued for another 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The product was purified by reverse phase HPLC to give the title compound (90 mg, 71%) as a white solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.27 (s, 3 H) 3.20 (s, 3 H) 4.58 (d, J=5.84 Hz, 2 H) 5.60 (t, J=5.84 Hz, 1 H) 6.61 (s, 1 H) 7.24 (d, J=8.67 Hz, 2 H) 7.66 (dd, J=8.48 , 2.26 Hz, 1 H) 7.70 (s, 1 H) 7.93 (d, J=8.67 Hz, 2 H) 8.06 (d, J=8.48 Hz, 1 H) 8.22 (d, J=2.26 Hz, 1 H) 8.24 (s, 1 H) 10.83 (s, 1 H). LCMS m/z 453.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14]I>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CI
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The general procedure of Referential Example 106 was repeated through use of (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.955 g) and methyl iodide (0.47 mL), to thereby give the title compound as an oily product (0.899 g, 89%).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:14]([N:6]1[C:5]2=[C:4]([CH3:18])[N:3]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:2]([O:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7]1=[O:13])[CH:15]([CH3:17])[CH3:16]
Reactant: COc1ccc(Cn2c(Cl)c3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(Cn2c(Oc3ccccc3)c3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Temperature: 160 °C
Yield: 74.5 %

Procedure:
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (20 mg, 0.051 mmol) is placed in a Biotage microwave vial, and then phenol (24 mg, 0.25 mmol) and cesium carbonate (50 mg, 0.15 mmol) are added. The mixture is heated at 160° C. in a Biotage microwave instrument for 2 h., and then purified by a semi-preparative HPLC to give 17 mg of pure product as off-white solids. MS (ESI) m/z 448.2 [M+H]+.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH:21](I)([CH3:23])[CH3:22]>>[CH:21]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: CC(C)n1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 383 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.15 ml of isopropyl iodide were used. As a result, 144 mg of 3-isopropyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccccc1
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(OCCN)cc1)Oc1ccccc1
Yield: 98.4 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-[4-(2-azidoethoxy)phenyl]-2-phenoxypropionate (3.40 g), which is the product of Reference example 4(g), and palladium on carbon (5%, 350 mg) and the reaction mixture was treated to afford the title compound (3.10 g) as a syrup.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]=O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][CH2:25][CH2:26][CH2:27][P:28](=[O:31])([OH:30])[OH:29].[BH3-]C#N.[Na+]>CO>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][NH:24][CH2:25][CH2:26][CH2:27][P:28](=[O:29])([OH:31])[OH:30])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1ccc(-c2ccc(C=O)nc2-c2ccccc2)cc1
Reactant: NCCCP(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCc1ccc(-c2ccc(CNCCCP(=O)(O)O)nc2-c2ccccc2)cc1

Procedure:
Following General Procedure M, 6-phenyl-5-(4-propylphenyl)pyridine-2-carbaldehyde (Compound 59, 74 mg, 0.25 mmol), (3-amino-propyl)phosphonic acid (34 mg, 0.25 mmol), Bu4NOH (0.25 ml, 0.25 mmol, 1M in MeOH) and NaCNBH3 (15 mg, 0.25 mmol) in MeOH (5 ml) were reacted to produce the title compound as a white solid.