Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:13]([CH2:20][C:21]([NH:23][C:24]1[C:25]2[N:26]=[CH:27][N:28]([C:37]=2[N:38]=[CH:39][N:40]=1)[C@@H:29]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[CH2:30]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:35][CH2:34][C@H:33]2[O:36][C@@H:29]([N:28]3[C:37]4[N:38]=[CH:39][N:40]=[C:24]([NH:23][C:21](=[O:22])[CH2:20][O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:25]=4[N:26]=[CH:27]3)[CH2:30][C@@H:31]2[OH:32])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(COc1ccccc1)Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)O1

Procedure:
The synthesis of this product is carried out by reacting 1.1 eq of p-nitrobenzoyl chloride with 6-N-phenoxyacetyldeoxyadenosine for 4 hours in pyridine. After hydrolysis of the excess reagent, almost complete evaporation of the pyridine, and ethyl acetate/sodium bicarbonate extraction, the ethyl acetate phase is evaporated to dryness. The product is obtained by column chromatography with a gradient of methanol in chloroform (elution 4% methanol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]3[CH2:10][CH2:11][CH:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]3=[N:7][C:6]=2[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1>CN(C=O)C.O>[CH:34]1([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:3]=[CH:4][C:5]4[N:9]5[CH2:10][CH2:11][CH:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]5=[N:7][C:6]=4[CH:19]=3)=[CH:29][C:30]=2[C:39]([F:40])([F:41])[F:42])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Reactant: CCOC(=O)CC1CCn2c1nc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCn2c1nc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.4 %

Procedure:
Ethyl 2-(6-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetate (0.1 g, 0.384 mmol) was dissolved in DMF (1.0 mL) and cesium carbonate (0.150 g, 0.461 mmol) and 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (0.111 g, 0.423 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 h and then warmed to 40° C. After stirring for 1 h, the reaction mixture was diluted with water and extracted three times with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (126 mg). LCMS m/z=487.4 [M+H]+; 1H NMR (400 MHz, CDCl3) 5 ppm 1.26 (t, J=7.2 Hz, 3H), 1.55-1.65 (m, 2H), 1.67-1.78 (m, 2H), 1.81-1.91 (m, 2H), 2.04-2.14 (m, 2H), 2.36-2.47 (m, 1H), 2.62 (dd, J=16.4, 9.7 Hz, 1H), 2.97-3.07 (m, 1H), 3.16 (dd, J=16.8, 3.8 Hz, 1H), 3.33-3.43 (m, 1H), 3.64-3.74 (m, 1H), 3.97-4.05 (m, 1H), 4.09-4.21 (m, 3H), 5.09 (s, 2H), 6.87 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.56-7.61 (m, 2H), 7.68 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[CH:20]1([C:23]([NH2:25])=[O:24])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(OCC)(=O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([OH:19])=[C:5]2[C:10]([CH:11]=[C:2]([NH:25][C:23]([CH:20]3[CH2:22][CH2:21]3)=[O:24])[N:3]=[CH:4]2)=[CH:9][N:8]=1
Reactant: NC(=O)C1CC1
Reactant: Oc1c(-c2ccccc2Cl)ncc2cc(Cl)ncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2cnc(-c3ccccc3Cl)c(O)c2cn1)C1CC1
Temperature: 90 °C
Yield: 39.6 %

Procedure:
A mixture of 7-chloro-3-(2-chlorophenyl)-2,6-naphthyridin-4-ol (75 mg, 0.26 mmol), cyclopropanecarboxamide (66 mg, 0.77 mmol), chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-i-pr-1,1′-biphenyl)][2-(2-aminoethyl) Ph]Pd(II) (40 mg, 0.05 mmol), (dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-i-pr-1,1′-biphenyl (28 mg, 0.05 mmol), and cesium carbonate (250 mg, 0.77 mmol) in tetrahydrofuran (2 mL) was heated at 90° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1.0M citric acid in water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (35 mg, 40%). 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.51 (d, J=6.6 Hz, 1H), 8.82 (s, 1H), 8.53 (s, 1H), 7.55 (m, 1H), 7.46 (m, 4H), 2.15-2.04 (m, 1H), 0.88 (m, 4H). LCMS (Method E): RT=3.746 min, M+H+=340.0.
Reaction SMILES: O[N:2]=[C:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1.N.[H][H]>C(O)C.[Ni].O>[NH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)Cc1ccc(CC2CCCC2=NO)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(CC2CCCC2N)cc1
Yield: 98.2 %

Procedure:
In an autoclave, a solution of 75.1 g (0.27 mole) of ethyl 4-[(2-hydroxyiminocyclopentyl)methyl]benzeneacetate in 800 ml of anhydrous ethanol saturated with NH3 is combined with about 37.5 g of Raney Nickel in water. The mixture is stirred under 80 atmospheres of hydrogen, at 80° C. during 4 hours. After cooling, the catalyst is filtered and rinsed with ethanol. The concentrated filtrate under reduced pressure, gives 69.3 g (yield=98.3%) of an orange oil which crystallizes but which is used without any other purification.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:29]=[CH:28][C:14]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:13][C:12]=1[CH3:30])=[O:8])C.O.[OH-].[Li+]>C1COCC1.O>[C:4]([CH2:5][NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:29]=[CH:28][C:14]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:13][C:12]=1[CH3:30])=[O:8])([OH:31])=[O:3]
Reactant: CCOC(=O)CNC(=O)NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the ethyl ester from Example 32 (0.050 g, 0.10 mmol) in THF (20 ml) and water (5 ml) was added lithium hydroxide monohydrate (0.020 g, 0.45 mmol). The mixture was stirred at room temperature for 4 h. The mixture was concentrated in vaicuo and the residue diluted with water then washed with diethyl ether. The aqueous layer was acidified to pH 1 by addition of 1M HCl and extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a white solid; yield 0.046 g (99%).
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:16][CH2:17][CH2:18][CH3:19])[CH2:6][NH:7][CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH2:12][CH2:11][O:10]1)[CH2:2][CH3:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:32][CH2:33][C:34](Cl)=[O:35]>O>[CH2:17]([O:16][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][N:7]([CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH2:12][CH2:11][O:10]1)[C:34](=[O:35])[CH2:33][Cl:32])[CH2:18][CH3:19]
Reactant: CCCOC(CNCC1OCCC(C)O1)OCCC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCOC(CN(CC1OCCC(C)O1)C(=O)CCl)OCCC

Procedure:
N-(2,2-Dipropoxyethyl)-N-(4-methyl-1,3-dioxan-2-yl-methyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-dipropoxyethyl)-N-(4-methyl-1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [NH2:1][S:2][O:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29]CC)=O)=[N:12]2)=[CH:7][CH:6]=1.[OH-].[NH4+:33]>CO>[NH2:1][S:2][O:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([NH2:33])=[O:29])=[N:12]2)=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1nn(-c2ccc(OOSN)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Agent: [OH-]
Solvent: CO
Product: NSOOc1ccc(-n2nc(C(N)=O)c3c2-c2cc([N+](=O)[O-])ccc2CC3)cc1
Yield: 68 %

Procedure:
The material of Step 2 (718 mg, 0.0016 mol), conc. ammonium hydroxide (30 mL), and methanol (15 mL) were stirred in a stoppered flask for 72 hours. Contents were filtered to give a light amber solid (606 mg). The solid was recrystallized from acetonitrile to give the product as a light amber solid, 450 mg (68% yield). FABHRMS m/z 414.0902 (M+H, C18H16N5O5S requires 414.0872). 1H NMR (DMSO-d6/300 MHz) 8.15-7.95 (m, 3H); 7.83 (d, 2H); 7.80-7.40 (m, 6H); 3.20-2.95 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[CH:32](O)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][N:29]([CH:32]=[O:33])[CH2:30][CH2:31]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Reactant: O=CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCN(C=O)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (8.0 mg, 0.0174 mmol), formic acid (1.3 μL, 0.0349 mmol), TBTU (11.2 mg, 0.0349 mmol), DIPEA (20 μL, 0.09 mmol) and DCM (1 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=7.1 Hz, 3 H), 1.90-2.07 (m, 2 H), 2.10-2.23 (m, 2 H), 2.90 (td, J=12.9, 2.9 Hz, 1 H), 3.32-3.37 (m, 1 H), 3.89 (ddd, J=13.5, 2.2, 2.0 Hz, 1 H), 4.41-4.56 (m, 2 H), 5.28 (q, J=7.2 Hz, 1 H), 7.18 (t, J=8.6 Hz, 1 H), 7.30-7.53 (m, 3 H), 7.58 (s, 1 H), 7.90 (s, 1 H), 8.07 (s, 1 H), 8.31 (d, J=1.8 Hz, 1H). MS (ES+): m/z 486.00 (100) [MH+]. HPLC: tR=3.30 min (ZQ3, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[C:11]([NH:8][CH2:7][C:6]1[CH:15]=[C:2]([C:27]2[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccc(-c2cc(CNC(C)(C)C)c(O)c(-c3ccccc3)c2)cn1
Temperature: 64 °C
Yield: 80.2 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.659 g, 1.91 mmol), (6-methoxypyridin-3-yl)boronic acid (0.438 g, 1.5 equiv), and potassium carbonate (1.056 g, 4 equiv) in 2-methoxyethyl ether (10 mL) and water (2 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (110 mg, 5 mol %) was added and the resulting mixture was heated at 61-67° C. for 2.5 hours. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatograph to give 3-((tert-butylamino)methyl)-5-(6-methoxypyridine-3-yl)-[1,1′-biphenyl]-2-ol (0.555 g) as yellow oil. 0.28 g of the oil was dissolved in ethanol and a solution of tartaric acid (0.108 g) in ethanol was added. The resulting precipitate was filtered and rinsed with ethanol to give 3-((tert-butylamino)methyl)-5-(6-methoxypyridine-3-yl)-[1,1′-biphenyl]-2-ol tartarate (100 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16].N1C=CC=CC=1>ClCCl>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]([NH:1][CH2:2][CH:3]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)=[O:16])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 16 h
Yield: 121.4 %

Procedure:
tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate (1.10 g, 5.91 mmol) was dissolved in dichloromethane (50 mL), and thereafter, 4-nitrophenyl chloroformate (1.19 g, 5.91 mmol) and pyridine (0.47 g, 5.91 mmol) were added to the obtained solution. The obtained mixture was stirred for 16 hours. Thereafter, the reaction solution was concentrated in vacuo to obtain tert-butyl 3-((((4-nitrophenoxy)carbonyl)amino)methyl)azetidine-1-carboxylate (2.52 g, quant) in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[F:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: COc1nc2cc(F)ccc2nc1N
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
2-Amino-6-fluoro-3-methoxyquinoxaline (580 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 756 mg of the titled compound (yield, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:12])=[CH2:11].[H][H]>CO.[Pd]>[CH:10]([C:4]1[CH:5]=[CH:6][C:7]([NH2:9])=[N:8][C:3]=1[O:2][CH3:1])([CH3:12])[CH3:11]
Reactant: [H][H]
Reactant: C=C(C)c1ccc(N)nc1OC
Agent: [Pd]
Solvent: CO
Product: COc1nc(N)ccc1C(C)C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of 5-fluoro-6-isopropenyl-pyridin-2-ylamine (crude from Step 1, 8.47 mmol) in methanol (17.5 mL) was added 10% palladium on carbon (123 mg) at room temperature. A hydrogen balloon (1 atm) was attached and the mixture was stirred overnight. After 18 hours, the mixture was filtered over Celite, concentrated onto silica gel, and chromatographed (10% to 40% ethyl acetate in hexanes) to give 5-isopropyl-6-methoxypyridin-2-amine (740 mg, 53% over two steps). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 7.26 (d, J=7.8 Hz, 1H), 6.07 (d, J=8.1 Hz, 1H), 4.19 (br. s, 2H), 3.90 (s, 3H), 3.08 (m, 1H), 1.17 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[PH:4](=[O:7])([OH:6])[OH:5].[CH2:8]([C:10]([CH2:38][CH3:39])([CH:12](I)[C:13]1[N:17]=[CH:16][N:15]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1)[CH3:11])[CH3:9].O>C(O)C>[PH:4](=[O:5])([OH:7])[OH:6].[CH2:8]([C:10]([CH2:38][CH3:39])([CH:12]([S:2][CH3:1])[C:13]1[N:17]=[CH:16][N:15]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1)[CH3:11])[CH3:9]
Reactant: CCC(C)(CC)C(I)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C[S-]
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(C)(CC)C(SC)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 5 h
Yield: 68.9 %

Procedure:
Sodium thiomethoxide (0.24 g) was added to a stirred solution of diethyl 3-iodo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 30) in ethanol (10 ml). The mixture was stirred for five hours, allowed to stand overnight, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-methylthio-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.60 g, m.p. 97-98° C.). NMR (CDCl3): δ 1.3(6H,dt), 1.7-1.9(2H,m), 1.9(3H,s), 2.2-2.4(2H,m), 3.9(1H,t), 4.05(4H,m), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). FAB M/S: MH+ 536.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]([C:12]([NH:14][NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=O)=[CH:10][CH:9]=[N:8]1>C(#N)C>[CH3:6][N:7]1[C:11]([C:12]2[O:27][C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3)=[N:15][N:14]=2)=[CH:10][CH:9]=[N:8]1
Reactant: Cn1nccc1C(=O)NNC(=O)c1ccc(C(F)(F)F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cn1nccc1-c1nnc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 90 °C
Yield: 81.4 %

Procedure:
Phosphorus oxychloride (1.80 mL) was added to an acetonitrile (4.8 mL) suspension of 1-methyl-N′-[4-(trifluoromethyl)benzoyl]-1H-pyrazol-5-carbohydrazide (300 mg) at a room temperature, and the obtained solution was then heated to reflux at 90° C. for 15 hours. Thereafter, the reaction solution was concentrated under a reduced pressure. A saturated sodium carbonate aqueous solution was added to the residue to convert it to a basic solution, and the resulting solution was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration, so as to obtain the title compound (230 mg) in the form of a brown solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][S:2]([CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:23]
Reactant: CSCC(=O)Nc1c(C)cccc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CS(C)=O
Temperature: 5 °C
Reaction time: 1.25 h
Yield: 88 %

Procedure:
To a methylene chloride solution containing 2.09 g (10 mmol) of 2-methylthio-N-(2,6-dimethylphenyl)acetamide was added, in portions over 30 min with stirring at 5° C., 2.16 g (10 mmol) of m-chloroperbenzoic acid (80% solution). The reaction mixture was kept at 5° C. for an additional 1.25 hr. The precipitate formed was filtered and washed twice with methylene chloride. The filtrate and washings were combined, washed once with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to afford white crystalline compound (88% yield), mp 112°-114° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:9][N:8]([CH3:10])[C:3]1[C:2]([NH:1][C:44](=[O:45])[C:43]2[CH:47]=[C:39]([CH2:38][C:32]3[C:33](=[O:37])[C:34]([O:35][CH3:36])=[C:29]([O:28][CH3:27])[C:30](=[O:53])[C:31]=3[CH3:52])[CH:40]=[CH:41][C:42]=2[O:48][C:49](=[O:51])[CH3:50])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CN(C)c1ncccc1N
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3N(C)C)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
3-Amino-2-dimethylaminopyridine (0.154 g, 1.125 mmol), triethylamine (0.114 g, 1.125 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.190 g, 1.125 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.281 g, 0.750 mmol) and the resulting solution was stirred at room temperature for 4 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=95:5) to obtain the titled compound (0.139 g, 0.282 mmol, 38%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 14-1, 61.1 mg, 0.136 mmol) was dissolved in anhydrous dichloromethane (1 mL), and triethylamine (44 μL, 0.319 mmol) and methanesulfonyl chloride (13 μL, 0.168 mmol) were added thereto successively. The reaction mixture was stirred at room temperature for hours and 15 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (68.3 mg) as a colorless amorphous product. (Yield 98%)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[N:24]=[CH:25][CH:26]=[CH:27]3)=[O:35])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2cccnc12
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3cccnc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Quinoline-8-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=488.3.