Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][C:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>O1CCCC1.CN(C)C=O>[OH:36][C:28]1([CH2:27][NH:26][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[N:3]=2)=[O:13])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: NCC1(O)CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)NCC2(O)CN3CCC2CC3)c2ccccc21
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A suspension of 1-methyl-1H-indazole-3-carboxylic acid (1.76 g, 0.0101 mole) in anhydrous tetrahydrofuran (6 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 0.0115 mole). After a few minutes bubbling commenced and the solid dissolved, and, after a few more minutes, a precipitate formed. The suspension was diluted with anhydrous N,N-dimethylformamide (3 ml), stirred for two hours, then degassed over 15 minutes under a stream of nitrogen. A solution of the free base of 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol (2.03 g, 0.013 mole) in anhydrous tetrahydrofuran (6 ml) was added, and the mixture was stirred at room temperature for 18 hr and at 50° C. for 4 hr, then concentrated in vacuo. The residue was partitioned between 1.0N sodium carbonate (50 ml) and toluene (75 ml) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (2×30 ml) containing some 2-propanol). The combined organic solution was concentrated in vacuo, and the residual gum washed with water (50 ml) to remove most of the imidazole and then dried azeotropically with toluene. The gum was taken up in tetrahydrofuran and filtered through alumina (eluted with 20% methanol/tetrahydrofuran) and the concentrated filtrate was recrystallized from acetonitrile to afford 1.23 g (39%) of the title compound as a pale yellow solid; mp 147°-149° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C([N-]C(C)C)(C)C.[Li+].[CH:17](=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH3:22]>C1COCC1>[OH:4][CH:3]([CH2:5][C:17](=[O:23])[CH:18]=[CH:19][CH:20]=[CH:21][CH3:22])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: CC=CC=CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC=CC=CC(=O)CC(O)CC(=O)OC
Temperature: -78 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
To a cold (-30° C.) solution of methyl acetoacetate (41.5 g, 357 mmol) in THF (500 mL) was added lithium diisopropylamide (476 mL, 1.5M solution in cyclohexane, 714 mmol). The resultant solution was stirred for 15 minutes at -30° C. After cooling to -78° C., 2,4-hexadienal (34.3 g, 357 mmol) was added and the solution stirred for 10 minutes at -78° C. and for 16 hours at ambient temperature. The solution was concentrated under reduced pressure and the residual syrup was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine (2x), dried (Na2SO4), and concentrated. The residue was purified by chromatography on silica gel (diethyl ether:hexane/2:1) to afford 18.5 g (24.4%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH2:6][C:5](C)(C)[CH2:4][C:3]=1[Br:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1
Reactant: CC1(C)CC(Br)=C(Br)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(C2=C(Br)CCC2)cc1
Yield: 24.1 %

Procedure:
Under nitrogen, 1.3 g (5.1 mmol) of 1,2-dibromo-4,4-dimethylcyclopentene (Step 8) was reacted with 600 mg (4.3 mmol) of 4-fluorophenylboronic acid (Lancaster) in 23 mL of toluene, 15 mL of ethanol, and 10 mL of 2M Na2CO3 in the presence of 250 mg (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (Na2SO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane gave 250 mg of 1-(2-bromocyclopenten-1-yl)-4-fluorobenzene (38 in Synthetic Scheme X when R1 and R2 =CH3, R5 =F, R3, R4, R6, and R7 =H) as a pale yellow oil which was reacted with 200 mg (1.2 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 1) in 5.2 mL of toluene, 3.4 mL of ethanol, and 2.2 mL of 2M Na2CO3 in the presence of 40 mg (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux for 6 h and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (Na2SO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane gave 120 mg of 1-[2-(4-fluorophenyl)-4,4-dimethyl cyclopenten-1-]-4-(methylthio)benzene (41 in Synthetic Scheme X when R1 and R2 =CH3, R5 =F, R10 =SCH3, R3, R4, R6, R7, R8, R9, R11, and R12 =H) as an oil: NMR (CDCl3) d 1.20 (s, 6HO0, 2.42 (s, 3H), 2.63 (s, 4H) , 6.90 (t, J=8 Hz, 2H) , 7.00-7.18 (m, 4H) , 7.30-7.60 (m, 2H) .
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](Cl)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[C:18]([NH2:20])=[O:19].[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:34][CH2:35]1)=[O:31])[O:28][C:11]1[C:10]2[C:15](=[CH:16][C:7]([O:6][CH3:5])=[C:8]([C:18]([NH2:20])=[O:19])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(N)=O
Temperature: 70 °C
Reaction time: 23 h
Yield: 88 %

Procedure:
To dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), followed by heating and stirring at 70° C. for 23 hours. After the reaction mixture was allowed to cool down to room temperature, water (50 mL) was added, and the produced crystals were collected by filtration to give 1.56 g of the titled compound (88% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH:11]([NH2:14])([CH3:13])[CH3:12]>>[CH:11]([NH:14][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])([CH3:13])[CH3:12]
Reactant: CC(C)N
Reactant: N#Cc1cccc(CBr)c1
Product: CC(C)NCc1cccc(C#N)c1

Procedure:
The title compound was prepared following general procedure 10, starting from 3-(bromomethyl)benzonitrile and isopropyl amine. It was isolated as a yellow liquid (5.7 g, 92%). 1H NMR (DMSO-d6, 400 MHz) δ 7.73 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.49 (m, 1H), 3.56 (s, 2H), 2.75 (m, 1H), 0.83 (d, J=8.8 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)cc(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To a solution of 2-hydroxy-3-methyl-benzoic acid (10 g, 66.7 mmol, 1.0 eq) in acetic acid (100 mL) was added bromine (10.66 g, 66.7 mmol, 1.0 eq) slowly over 5 min. The mixture was stirred at room temperature for 24 h, then water was added slowly and the mixture was stirred for a further 30 min. The precipitate was collected by filtration and was washed with water and dried to give the title compound as a white solid (13.7 g, 90%).
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH3:11])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:1]([N:5]1[C:9]([NH:10][C:12](=[O:14])[CH3:13])=[CH:8][C:7]([CH3:11])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C)nn1C(C)(C)C

Procedure:
To 1-(tert-butyl)-3-methyl-1H-pyrazol-5-amine (110 g, 0.71 mol), acetic anhydride (73 ml, 0.71 mol) was added dropwise with stirring. The reaction mixture was stirred for 1-2 h at 20-35° C. Thereafter the reaction mixture was washed with excess of hexane and filtered to obtain the title compound as a yellow solid. MP: 118-120° C.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=1>CC(N(C)C)=O>[C:3]1(=[O:13])[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:18][CH:17]=2)[C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)C(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C

Procedure:
A suspension of 22.4 g. (0.447 mole) of sodium hydride (50% in mineral oil) in 200 ml. dimethylacetamide is treated dropwise by the addition of 59.6 g. (0.406 mole) phthalimide in 500 ml. dimethylacetamide. The mixture is stirred for 2 more hours at room temperature and then treated dropwise with 100 g. (0.406 mole) α-bromo-p-pivaloyl toluene in 300 ml. dimethylacetamide. The resulting mixture is stirred at room temperature for 18 hours and then the solvent is removed in vacuo. The residue is taken up in methylene chloride/water and the layers separated. The water layer is washed twice with methylene chloride and the combined methylene chloride layers washed twice with water, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting solid is triturated with ether to give 4'-(phthalimidomethyl)pivalophenone; m.p. 138°-140.5° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[NH:34]1[CH2:42][CH2:41][CH2:40][CH:36]([C:37]([OH:39])=[O:38])[CH2:35]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:34]5[CH2:42][CH2:41][CH2:40][CH:36]([C:37]([OH:39])=[O:38])[CH2:35]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: O=C(O)C1CCCNC1
Agent: OC1CCNC1
Product: O=C(O)C1CCCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)C1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with nipecotic acid. A yellow solid 128 was obtained (0.034 g, 66%). 1H-NMR (CDCl3, 400 MHz) δ 1.64-1.74 (m, 1H), 1.92-1.99 (m, 1H), 2.06-2.13 (m, 2H), 2.88-2.95 (m, 1H), 3.50-3.57 (m, 1H), 3.68-3.74 (m, 2H), 3.90-3.96 (m, 1H), 4.28-4.36 (m, 4H), 6.94-6.98 (m, 2H), 7.03-7.07 (m, 2H), 7.09 (d, J=1.9 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 8.32 (d, J=6.2 Hz, 1H); MS (APCI) m/z 517 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:21]Br>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:21][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[NH:1][CH:2]=1
Reactant: BrBr
Reactant: O=C(Nc1cnc2[nH]ccc2c1)OCc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cnc2[nH]cc(Br)c2c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Benzyl 1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (9.48 g, 35.5 mmol) in chloroform (100 mL) was cooled to 5° C. and treated dropwise with bromine (1.86 mL, 36.21 mmol, 1.02 Eq). The reaction was allowed to to stir at 0° C. for 1 hour and then at room temperature for 1 hour. The mixture was diluted with DCM and washed with a 1:1 sat. aq. sodium thiosulfate/sodium bicarbonate solution (200 mL). The organic layer was separated and the aqueous layer taken to pH 12 and re-extracted with EtOAc. The combined organics were dried over magnesium sulphate, filtered and dried under vacuum and the resultant brown solid triturated with diethyl ether/EtOAc to give 10.24 g (83%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[Br:13][C:14]1[CH:19]=[C:18]([N+]([O-])=O)[CH:17]=[C:16]([Br:23])[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=1[O:12][C:18]1[CH:17]=[C:16]([Br:23])[N:15]=[C:14]([Br:13])[CH:19]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1Oc1cc(Br)nc(Br)c1

Procedure:
A solution of methyl 4-fluoro-2-hydroxybenzoate (2.00 g), 2,6-dibromo-4-nitropyridine (3.65 g), and cesium carbonate (4.21 g) in N,N-dimethylformamide (100 mL) was heated to 55° C. for 16 hours, cooled, added to water, and extracted with 50% ethyl acetate in hexanes. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography on silica gel using 30-50% ethyl acetate in hexanes.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12]CC)=[O:11])[CH2:5][CH2:6][Cl:7].Cl>>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([OH:12])=[O:11])[CH2:5][CH2:6][Cl:7]
Reactant: CCOC(=O)c1ccccc1N(CCCl)CCCl
Agent: Cl
Product: O=C(O)c1ccccc1N(CCCl)CCCl
Reaction time: 8 h
Yield: 60.1 %

Procedure:
Ethyl 2-[N,N-bis(2-chloroethyl)amino]benzoate (950 mg; 3.3 mmol) was added to 15 ml of concentrated hydrochloric acid, followed by stirring for 8 hours under heating and reflux. The solvent was distilled out under reduced pressure and the residue was purified by chromatography on a silica gel column (methylene chloride→acetone), whereby 520 mg of white powder were obtained (yield: 61%).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1cc(Br)ccc1F
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccc1F

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 5-bromo-2-fluorobenzenesulfonamide (231 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (180 mg, 35%). MS (ISP) 587.2[(M+H)+]; mp 247-249° C.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:12])[N:4]2[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:3]=12.[CH3:18][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[CH:9]([N:6]1[C:7](=[O:8])[C:2]([O:1][CH3:18])=[C:3]2[C:16](=[O:17])[NH:15][CH2:14][CH2:13][N:4]2[C:5]1=[O:12])([CH3:10])[CH3:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)n1c(=O)c(O)c2n(c1=O)CCNC2=O
Solvent: CCOCC
Solvent: CO
Product: COc1c2n(c(=O)n(C(C)C)c1=O)CCNC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 9-hydroxy-7-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (1.0 g, 4.2 mmol) in MeOH (30 mL) was added trimethylsilyldiazomethane (7 mL of a 2.0 M solution in ether, 14 mmol). The mixture was stirred at ambient temperature for 24 h. The solvent was removed in vacuo and the residue was triturated in MeOH and the solid was collected by filtration to give the title compound as a solid. HPLC RT=2.07 min (Method A); ES MS (M+H)=254; 1H NMR (400 MHz, DMSO-d6) δ 8.64 (2, 1H), 5.03 (septet, J=7 Hz, 1H), 3.86 (m, 2H), 3.66 (s, 3H), 3.37 (m, 2H), 1.38 (d, J=7 Hz, 6H).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]([C:13]1[C:14]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH3:12].[OH-].[Na+]>O>[OH:19][C:15]1[C:14]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:13]([CH2:11][CH3:12])[CH:18]=[CH:17][C:16]=1[CH:4]=[O:5]
Reactant: CCc1cccc(O)c1NCCNC(C)=O
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc(C=O)c(O)c1NCCNC(C)=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A scrupulously dry flask was charged with anhydrous DMF (15 ml) and cooled in ice under argon. Phosphorus oxychloride, POCl3, 1.5 ml (1.15 eq) was added slowly dropwise to the stirred solution. After the addition was complete, the flask was removed from the ice bath and allowed to reach ambient temperature. This was accompanied by a color change to yellow. The flask was heated in a 40° C. bath for one hour. It was removed from the heat, and once at ambient temperature, a DMF solution of 3-(ethyl)(2-acetylaminoethyl)aminophenol (8; 3.2 g, 14 mmol) was added via addition funnel. After the addition was complete, the flask was returned to the 40° C. bath and stirred overnight. The reaction was cooled to 0° C. and 25 ml 10% NaOH was added, the mixture was allowed to warm to ambient temperature and was then placed in a 40° C. bath. Additional NaOH was added to achieve pH >10. Water (50 ml) was added. After 15 minutes the flask was removed from the bath and the pH adjusted to 5-5.5 with 1N HCl. The mixture was transferred to a separatory funnel and extracted with 4×100 ml ethyl acetate. The pooled organic fractions were washed with water (1×75 ml), predried with Na2SO4, and then dried with MgSO4 overnight. The solution was collected by filtration and the volatiles removed by rotary evaporation to yield the crude product (2.9 g). The material was purified by flash chromatography on silica, 45×150 mm column, eluting with 200 ml each of 2.5%, 5%, and 10% methanol/chloroform purified yield of(2-hydroxy-4-(ethyl)(2-acetylaminoethyl)aminobenzaldehyde) (9) was 1.52 g (45%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:20](OCC)(OCC)(OCC)[CH3:21]>C(O)(=O)C.CO>[CH3:20][C:21]1[N:11]([C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
To a solution of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (131 mg, 0.469 mmol) in acetic acid (1.3 mL) was added triethyl orthoacetate (275 μL, 1.50 mmol). The mixture was stirred at 120° C. for 30 min. After cooling to room temperature, the mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (60 mg, 42%). LCMS calculated for C15H18N3O2S (M+H)+: m/z=304.1. Found: 304.1.
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[N:4][CH:5]=[C:6]([C:18]=1[OH:19])[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:8].[CH3:21][O-:22].[Na+].CO>CN(C)C=O.[Cu]I>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]2[C:18]([OH:19])=[C:2]([O:22][CH3:21])[C:3]([CH3:20])=[N:4][CH:5]=2)=[CH:12][CH:13]=1
Reactant: C[O-]
Reactant: Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1Br
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1c(C)ncc(C(=O)NCc2ccc(F)cc2)c1O
Temperature: 105 °C
Reaction time: 1.67 h
Yield: 86.9 %

Procedure:
The compound 21 (75.2 g, 222 mmol) and copper (I) iodide (21.1 g, 111 mmol) were dissolved in dimethylformamide (750 ml), a 28% sodium methoxide-methanol solution (216 ml, 888 mmol) was added, and the mixture was stirred at 105° C. for 100 minutes. After cooling, ice-water (800 ml) was added, and unnecessary matters were filtered. To the solution was added 2 M hydrochloric acid (443 ml), and crystals were collected by filtration. N-(4-fluorobenzyl)-4-hydroxy-5-methoxy-6-methylnicotinamide 22 (56.0 g, 87%) was obtained as a colorless crystal.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:13][C@H:14]([NH:34][C:35](=[O:37])[CH3:36])[C@H:15]([OH:33])[CH2:16][NH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)C1C=CC=CC=1.[H][H].Cl>C(O)C.[Pd]>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:13][C@H:14]([NH:34][C:35](=[O:37])[CH3:36])[C@H:15]([OH:33])[CH2:16][NH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: [H][H]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(OCc2ccccc2)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reaction time: 21 h

Procedure:
To a solution of compound 10 (0.70 g, 1.2 mmol) in 70 mL of ethanol in a Parr bottle is added 0.33 g of 10% palladium on carbon. The mixture is placed under 20 psi of hydrogen and shaken for 21 h. The mixture is filtered and the catalyst is washed with ethanol. Concentration in vacuo affords a colorless oil, which is treated with ethereal HCl to give a quantitiative yield of hydrochloride 11 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.44 (s, 1H), 7.37 (m, 2H), 7.28 (m, 1H), 6.59 (s, 1H), 6.40 (m, 1H), 6.31 (m, 1H), 4.0 (m, 1H), 3.79 (m, 1H), 2.95 (m, 2H), 2.63 (m, 4H), 2.44 (m, 1H), 2.05 (m, 2H), 1.90 (s, 3H), 1.79 (m, 2H), 1.59 (m, 1H), 1.5–1.3 (m, 3H), 1.26 (d, J=7 Hz, 6H); MS (CI) m/z 457.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]3[CH2:16][O:15]3)[CH:5]=[CH:4][C:3]1=2.[NH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:16][CH:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)[OH:15])=[CH:29][CH:28]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CC1(C)CCC(C)(C)c2cc(C3CO3)ccc21
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NCC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 30.9 %

Procedure:
26 g (110 millimoles) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-oxirane, 15 g (90 millimoles) of ethyl 4-aminobenzoate, 135 g of basic alumina and 450 ml of toluene were refluxed for 2 hours. The solid was then filtered off and the filtrate was evaporated down. After recrystallization from n-heptane with a little ethyl acetate, the residue gave 11.0 g of N-(4-carbethoxyphenyl)-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-aminoethanol. The structure was determined by H-NMR spectroscopy. 3-(4-Carbethoxyphenyl)-5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-oxazolidine: