Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH2:8].[S:9]1[CH2:15][C:13](=[O:14])[NH:12][C:10]1=S.CCN(C(C)C)C(C)C>C(#N)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:10]1[S:9][CH2:15][C:13](=[O:14])[N:12]=1
Reactant: Cc1ccsc1CN
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccsc1CNC1=NC(=O)CS1
Temperature: 0 °C
Reaction time: 72 h
Yield: 31.3 %

Procedure:
To a solution of 3-methyl-thiophen-2-ylmethylamine (700 mg, 5.5 mmol) and Rhodanine (732 mg, 5.5 mmol) in acetonitrile (30 mL) was added DIPEA (1.91 mL, 11 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.52 g, 5.6 mmol) was added in one portion. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (200 mL) and ethyl acetate (250 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in dichloromethane (150 mL) and washed with water (100 mL) and brine solution. After drying over anhydrous magnesium sulfate, the filtrate was removed under the vacuum and the residue was dissolved in dichloromethane (10 mL) and diluted with hexanes (10 mL). After cooling in the refrigerator overnight, the solids were collected by filtration and washed with dichloromethane. After drying in air, 390 mg (31.5% yield) of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one was isolated as a light yellow amorphous solid: EI-HRMS m/e calcd for C9H10N2OS2 (M+) 226.0235. found 226.0232.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=1.[Li+].[CH3:16]C([N-]C(C)C)C.CI>C1COCC1.CC(OC)(C)C>[CH3:1][C:2]1([CH3:16])[CH:7]=[CH:6][CH2:5][C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[C:3]1=[O:14]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)=CCC1(C)CCC=C(C)C1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: COC(C)(C)C
Product: CC(C)=CCC1(C)CC=CC(C)(C)C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone (5.00 g, 26 mmol) was added to a solution of LDA (prepared from diisopropylamine (3.15 g, 31.2 mmol) and n-BuLi (1.6M in hexane, 19.5 ml, 31.2 mmol)) in THF (50 ml) at −78° C. The mixture was stirred for 1 h at −78° C. Methyl iodide (5.54 g, 39 mmol) was added and the solution was allowed to warm to room temperature over night. The mixture was diluted with MTBE and washed with portions of H2O and brine, dried (MgSO4) and concentrated in vacuo to yield 7 g of a slightly yellow oil which was distilled (bp.42° C./0.005 mbar) to give 4.5 g (84%) of an olfactorily clean oil. 1H-NMR (400 MHz, CDCl3): 5.72-5.68 (m, 1H), 5.63-5.59 (m, 1H), 5.06-4.99 (m, 1H), 2.36-2.08 (m, 4H), 1.70 (s, 3H), 1.59 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.07 (s, 3H) ppm. GC/MS (EI): 206 (M+, 15), 191 (8), 137 (19), 123 (25), 109 (100), 96 (34), 91 (9), 81 (28), 67 (24), 41 (33). IR (ATR): 3023s, 2966s, 2926m, 1703vs, 1456s, 1376m, 1203w, 1033s, 713s cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:20]=1>O1CCCC1.C(O)C.[Pt](=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:20]=1
Reactant: COc1ccc(C=Cc2cc3cc(Br)ccc3o2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CCc2cc3cc(Br)ccc3o2)cc1
Reaction time: 4 h
Yield: 75.4 %

Procedure:
128 g of 5-bromo-2-[2-(4-methoxyphenyl)vinyl]benzofuran as a mixture of two stereoisomers was dissolved in a solvent mixture of 1.3 l of tetrahydrofuran and 0.7 l of ethanol. The resulting solution was mixed with 3.0 g of platinum dioxide and subjected to 4 hours of catalytic hydrogenation under normal pressure. Thereafter, the catalyst was removed by filtration, the resulting filtrate was concentrated, and crystals thus precipitated were collected by filtration and washed with ethanol. In this way, 97.08 g of 5-bromo-2-[2-(4-methoxyphenyl)ethyl]benzofuran was obtained.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:35]([CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:29][C:28]([F:27])([F:38])[F:39])=[CH:31][CH:32]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C1N(Cc2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
Light yellow viscous oil. MS (ESI): 503.10 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 4-(trifluormethoxy)-benzylamine.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21])O.[C:22]1(C)C(C)=CC=CC=1>O>[CH2:22]=[N:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:13]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[C:7]=1[O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1OC1CCCC1
Reactant: O=C1CCCN1CO
Reactant: Cc1ccccc1C
Solvent: O
Product: C=Nc1cccc(N2CCCC2=O)c1OC1CCCC1
Yield: 51.6 %

Procedure:
2-Cyclopentoxyaniline (10.0 g, 0.057 mole), N-methylolpyrrolidone (9.75 g, 0.85 mole) and xylene (25 cc) were refluxed under azeotropic conditions with the removal of 1.5 cc of water. The xylene was removed by rotary evaporation and the product was crystallized from 100 cc of hexane to yield 8.0 g (51.6%) of product, m.p. 87°-87.5° C.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:10](C(OC)=O)[N:11]=1)=[O:5].[CH3:31][Mg+].[Br-].CC[O:36][CH2:37][CH3:38]>>[F:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:10]([C:37]([OH:36])([CH3:38])[CH3:31])[N:11]=1)=[O:5]
Reactant: CCOCC
Reactant: C[Mg+]
Reactant: COC(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: [Br-]
Product: CC(C)(O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Into a solution of Compound 35 (100 mg, 0.24 mmol) in 5 mL of Et2O was added dropwise MeMgBr (1.0 M solution in THF, 1.2 mL) at 0° C. The mixture was stirred at room temperature for 1 hour and quenched with 10 mL of H2O. The solution was extracted with Et2O. The combined extracts were dried and concentrated. The residue was purified by column chromatography on silica gel (10-70% EtOAc in hexanes) to give Compound 68 (91 mg, 91%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH2:5][N:6]1[CH2:10][CH:9]([CH2:11][CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:7]1=[O:33].[CH2:38]([O:40][C:41](=[O:53])[C:42]([O:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1)([CH3:44])[CH3:43])[CH3:39].N#N>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:53])[C:42]([O:45][C:46]1[CH:47]=[CH:48][C:49]([O:52][CH2:12][CH2:11][CH:9]2[CH2:10][N:6]([CH2:5][C:4]3[CH:34]=[CH:35][C:36]([CH3:37])=[C:2]([CH3:1])[CH:3]=3)[C:7](=[O:33])[N:8]2[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:50][CH:51]=1)([CH3:44])[CH3:43])[CH3:39]
Reactant: COc1ccc(CN2C(=O)N(Cc3ccc(C)c(C)c3)CC2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 108.9 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethyl ester (2.54 g, 4.86 mmol), 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (0.99 g, 4.01 mmol) and CS2CO3 (1.73 g, 5.31 mmol) in DMF (60 mL) was heated at 55° C. for under N2 for 16 h. The reaction mixture was cooled to room temperature, quenched with aqueous 1 N HCl (25 mL), and worked up extractively with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 4:1 hexanes:acetone to afford 2.51 g (99%) 2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. MS (ES+) Calc'd for C34H43N2O6 (M+1) 575. Found m/z 575 (100%). 1H NMR.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:14])([F:13])[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.Cl[C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>CO>[F:4][C:5]([F:13])([F:14])[C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1cccnc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a flask containing a solution of 45.4 grams (0.21 mole) 25% sodium methoxide in 100 milliliters of methanol were added 81.5 grams (0.5 mole) 3-trifluoromethylphenol and 15.8 grams (0.1 mole) 2-chloronicotinic acid. The reaction mass was heated and the methanol distilled off. The pot temperature was raised to 180° C. and held at that level for one hour. The mixture was then cooled to 100° C. and poured into 500 milliliters ice water. The aqueous mixture was extracted with 3 portions of 200 milliliters each, of diethyl ether, then acidified with glacial acetic acid. A solid precipitated, which was filtered, washed with water and dried, to give 25.8 grams (91.2% of theoretical yield) of 2-(3-trifluoromethylphenoxy)nicotinic acid, m.p. 149°-151° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.C[Si]([N:15]=[C:16]=[N:17][Si](C)(C)C)(C)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:10][C:6]1[CH:5]=[C:4]([C:2](=[N:17][C:16]#[N:15])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=NC#N)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
Following the procedure of Cuccia, S. J.; Fleming, L. B.; France, D. J. Synth. Comm. 2002, 32 (19), 3011-3018: 3-Bromoacetophenone (2.0 g, 10 mmol, 1 eq), was dissolved in 20 mL DCM. A 1.0 N solution of titanium tetrachloride in DCM (20 mL, 20 mmol, 2 eq) was added dropwise over 15 min and the resulting mixture was stirred at 25° C. for 1 h. Bis-trimethylsilylcarbodiimide (5.0 mL, 22 mmol, 2.2 eq) in 5 mL of DCM was added over 15 min and the reaction was stirred for 16 h under argon. The reaction was poured onto 200 mL of an ice/water mixture and extracted with 3×200 mL of DCM. The combined organic phase was dried over MgSO4, filtered, and concentrated to give 2.3 g (100%) of (1-(3-bromophenyl)ethylidene)cyanamide (DB1, R4=Me) as a white solid: 1H NMR (CDCl3) 8.16 (t, J=1.8 Hz, 1H), 7.94 (dd, J=1.7, 1.1 Hz, 1H), 7.76 (dd, J=1.7, 1.1 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 2.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N+:8]([O-])=[CH:7][CH:6]=[CH:5]2.C[Si]([C:19]#[N:20])(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:19]#[N:20])[CH:6]=[CH:5]2
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc2c(ccc[n+]2[O-])cc1Cl
Solvent: CC#N
Product: COc1cc2nc(C#N)ccc2cc1Cl
Temperature: 80 °C
Yield: 76.9 %

Procedure:
A 50 mL flask containing acetonitrile (6.0 mL) was charged with 6-chloro-7-methoxyquinoline 1-oxide (0.25 g, 1.19 mmol), TEA (0.33 mL, 2.39 mmol), and trimethylsilyl cyanide (0.48 mL, 3.58 mmol). The reaction mixture was heated at 80° C. for 2 h, cooled to room temperature and concentrated in vacuo. The residue was basified using saturated Na2CO3 and the product was extracted with DCM. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to afford 6-chloro-7-methoxyquinoline-2-carbonitrile (0.20 g) MS [M+H+]=219.4.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:18])[C:6](=[O:17])[C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1N1CCCC1)(=[O:3])[CH3:2].C(O)(=[O:21])C>O1CCCC1.O.ClCCl>[C:1]([O:4][CH:5]([CH3:18])[C:6](=[O:17])[CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)C(=O)C1=C(N2CCCC2)CCC1
Reactant: CC(=O)O
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)OC(C)C(=O)C1CCCC1=O

Procedure:
Stir a mixture of 1-oxo-1-(2-(pyrrolidin-1-yl)cyclopent-1-enyl)propan-2-yl acetate (952.0 g), acetic acid (1500 mL) and water (1500 mL) in tetrahydrofuran (3000 mL) at room temperature for 2 days. Dilute the mixture with water (1200 mL) and dichloromethane (1200 mL). The organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (eluting with 3% to 10% ethyl acetate in petroleum ether) to give 1-oxo-1-(2-oxocyclopentyl)propan-2-yl acetate as oil (573.4 g, 2.89 mol, 72.6% for 2 steps).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].I[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[C:16]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Reactant: N#Cc1ccc(I)cc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccc(C#N)cc2)CC1

Procedure:
The title compound was synthesized in analogy to example 116, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-morpholin-4-yl-methanone and 4-iodobenzonitrile.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21]Cl)[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N-:25]=[N+:26]=[N-:27].[Na+].[N-]=[N+]=[N-].[K+].O>CN(C)C=O>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21][N:25]=[N+:26]=[N-:27])[CH:18]=[CH:17][N:16]4[C:23]=3[CH3:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CCl)ccn12
Reactant: [N-]=[N+]=[N-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CN=[N+]=[N-])ccn12
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.3 %

Procedure:
A mixture of 2-amino-6-[2-(7-chloromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (1.3 g), sodium azide (0.5 g) and potassium azide (1.3 g) in N,N-dimethylformamide (26 ml) was stirred for 17 hours at ambient temperature and the mixture was poured into water. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated with diethyl ether to give 2-amino-6-[2-(7-azidomethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (1.21 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[CH2:15]([B-](F)(F)F)[CH2:16][CH2:17][CH3:18].[K+]>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: CCCC[B-](F)(F)F
Reactant: COC(=O)c1cc2ccc(Br)cc2o1
Agent: [K+]
Product: CCCCc1ccc2cc(C(=O)OC)oc2c1
Yield: 66.8 %

Procedure:
Methyl-6-butylbenzofuran-2-carboxylate was synthesized as in Example 3.1 using methyl-6-bromobenzofuran-2-carboxylate (195 mg, 0.76 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (188 mg, 1.15 mmol) in place of hexylboronic acid to give methyl-6-butylbenzofuran-2-carboxylate (118 mg, 67%). Used without further characterization.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42]>CN(C=O)C>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reaction time: 8 h
Yield: 44.7 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (1.834 g, 5.22 mmol) was heated at 60° C. with potassium carbonate (2.89 g, 20.88 mmol) in DMF (23 ml) for 1 hour. Phenylmethyl 2-(3-bromopropyl)-1-piperidinecarboxylate (2.131 g, 6.26 mmol) was added and heating continued at 50° C. overnight (20 hours). The reaction mixture was partitioned between water (250 mL) and ethyl acetate (150 mL). The aqueous was further extracted with ethyl acetate (100 ml). The combined organic layers were washed with brine (100 ml) and passed through a hydrophobic frit to dry, then stripped to dryness (rotary evaporator) to give an orange liquid. The material was loaded onto 2×70 g aminopropyl cartridge and eluted on the Flashmaster system in gradient of 0-100% ethylacetate in cyclohexane over 40 mins. Appropriate product fractions were combined and evaporated in vacuo to give the title compound as a clear oil (1.16 g).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O1CCCC1.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[C:10](=[O:12])[CH3:11])=[CH:23][CH:24]=1
Reactant: CC(=O)N(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(=O)N(Cc1ccc(N)cc1)Cc1ccc(N)cc1
Temperature: 80 °C
Yield: 110.6 %

Procedure:
A mixture of the product from Example 68A (250 mg, 0.759 mmol), iron powder (424 mg, 7.59 mmol), and ammonium chloride (203 mg, 3.80 mmol) in ethanol (1 mL), tetrahydrofuran (1 mL) and water (0.250 mL) was heated at 80° C. for 18 hours. The mixture was allowed to cool to rt, filtered, rinsed with methanol, and concentrated in vacuo. The residue was partitioned between EtOAc and H2O, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (226 mg, 90%). MS (ESI) m/z 269.9 (M+H)+
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].OC(C(F)(F)F)=O.[NH2:30][CH2:31][C:32]([CH3:37])([CH3:36])[C:33]([OH:35])=[O:34].C[O-].[Na+]>CCO>[CH2:16]([C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:30][CH2:31][C:32]([CH3:37])([CH3:36])[C:33]([OH:35])=[O:34])=[O:4])[N:6]=[CH:7]2)=[CH:12][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 38.6 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (19 mg, 0.065 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (60 mg, 0.26 mmol) and NaOMe (28 mg, 0.52 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water (30 mL) and EtOAc (30 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 9.5 mg of the title compound. MS: (+) m/z 379.17 (M+1).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]1([C:22]2[NH:26][N:25]=[C:24]([NH2:27])[CH:23]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([NH:27][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)(=[O:8])=[O:9])[CH:11]=3)[NH:25][N:26]=2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Nc1cc(C2CC2)[nH]n1
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 5-cyclopropyl-1H-pyrazole-3-amine as the starting materials.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:9]([F:12])([F:11])[F:10])=[CH:5]\[C:6]([O-])=[O:7].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>O.C(OCC)C>[CH3:24][N:3]1[C:4]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:6](=[O:7])[N:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)[C:22]1=[O:23]
Reactant: COc1ccc(N=C=O)cc1
Reactant: N/C(=C\C(=O)[O-])C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CI
Product: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1
Temperature: -20 °C
Yield: 43.6 %

Procedure:
In a flask was placed 8.27 g (0.207 mole) of a 60% suspension of sodium hydride in mineral oil. The mineral oil was removed by washing the sodium hydride twice with heptane. To the flask was then added 300 mL of tetrahydrofuran. This suspension was cooled to -20° C. at which it was maintained during the dropwise addition of 37.9 g (0.207 mole) of 3-amino-4,4,4-trifluorocrotonate. This mixture was allowed to stir for 10 minutes before the dropwise addition of 30.83 g (0.207 mole) of 4-methoxyphenyl isocyanate was commenced. Upon completion of addition, the reaction mixture was heated at reflux for approximately 16 hours. At the conclusion of this period the reaction mixture was cooled to ambient temperature, and 28.56 g (0.207 mole) of potassium carbonate and 58.75 g (0.228 mole) of methyl iodide were added to it. The reaction mixture was then heated at reflux for seven hours. At the conclusion of this period the reaction mixture was cooled, and diethyl ether and water were added to it. The aqueous phase was separated from the organic phase. The latter was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, leaving a residue. This residue was passed through a column of silica gel, eluting with ethyl acetate/heptane mixtures starting with 1:8 and concluding with 1:1. The product-containing fractions were combined, and the solvent was evaporated under reduced pressure, yielding 27.1 g of 1-methyl-3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione. The NMR spectrum was consistent with the proposed structure.