Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[O:12][C@H:6]([CH:7]([C:9]([OH:11])=[O:10])[OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:23](O)[CH3:24]>>[CH2:23]([O:10][C:9]([CH:7]([OH:8])[C@H:6]1[O:12][C@@H:1]([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[C@H:2]([OH:3])[C@@H:4]1[OH:5])=[O:11])[CH3:24]
Reactant: CCO
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)C(=O)O)[C@@H](O)[C@H]1O
Product: CCOC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Yield: 78 %

Procedure:
In an analogous manner, by the reaction of free adenosine-5'-carboxylic acid with ethanol, there is obtained adenosine-5'-carboxylic acid ethyl ester in a yield of 78% of theory (m.p. 204°-205° C.) and by the reaction of free adenosine-5'-carboxylic acid with n-butanol, there is obtained adenosine-5'-carboxylic acid n-butyl ester in a yield of 54% of theory (m.p. 167° C.).
Reaction SMILES: [CH2:1]([C@H:8]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C@@H:9]([OH:42])[CH:10]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:11][C:12]([CH3:29])([CH3:28])[CH2:13][CH2:14][O:15][C:16]([O:18]C1C=CC([N+]([O-])=O)=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:51]>O1CCCC1.C(OCC)C>[CH2:1]([C@H:8]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[C@@H:9]([OH:42])[CH:10]([NH:30][S:31]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)(=[O:33])=[O:32])[CH2:11][C:12]([CH3:28])([CH3:29])[CH2:13][CH2:14][O:15][C:16](=[O:18])[NH2:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COc1ccc(S(=O)(=O)NC(CC(C)(C)CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)NC(CC(C)(C)CCOC(N)=O)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
To a solution of the product from step 1 (520 mg, 0.73 mmol) in tetrahydrofuran (10 mL) at 5° C. was added ammonium hydroxyde (30%, 2 mL) and the reaction was stirred at 5° C. for 40 minutes. The mixture was diluted with ethyl ether, washed with saturated sodium bicarbonate, dried (magnesium sulfate), and evaporated to provide the title compound (490 mg) containing p-nitrophenol (˜10%). 1H NMR (DMSO-d6): δ 0.93 (3H, s), 0.96 (3H, s), 1.2 (9H, s), 1.6 (2H, t), 2.45 (1H, dd), 2.78 (1H, d), 2.85-2.95 (2H, m), 3.3-3.6 (3H, m), 3.7 (1H, quartet), 3.8 (3H, s), 3.96 (2H, t), 5.0 (1H, d), 6.4 (2H, br s), 6.6 (1H, d), 7.05 (2H, d), 7.10-7.25 (5H, m), 7.7 (2H, d).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cc(F)c(F)cc4F)nc23)CC1
Yield: 87.8 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.055 mMol) 2,4,5-trifluorobenzoyl chloride, 0.015 gm (86%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][N:25]([CH3:34])[C:26]([CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[O:27]>>[CH3:24][N:25]([CH3:34])[C:26](=[O:27])[CH2:28][CH2:29][CH2:30][C:31]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:32]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CN(C)C(=O)CCCC(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCCC(=O)N(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-dimethylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-(dimethylamino)-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+NH4]=927; RT=1.16 min; UPLC Method I
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([S:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=C1.S1C=CC(SC2C=C[C:23]([N+:26]([O-])=O)=[CH:22]C=2)=C1.NC1C=CC=CC=1>>[N:26]1[CH:23]=[CH:22][CH:5]=[CH:4][C:3]=1[S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:11])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccsc2)cc1
Reactant: Nc1ccc(Sc2ccsc2)cc1
Solvent: Nc1ccccc1
Product: Nc1ccc(Sc2ccccn2)cc1

Procedure:
4-(3-Thienylthio)aniline: 4-(3-Thienylthio)-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method A1. A3j. General Method for Substituted Aniline Formation Via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[C:7]([NH:8][CH:19]2[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17][CH2:18]2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cncnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncnc2N)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4,5-diaminopyrimidine (1.0 g, 9.1 mmol), N-(t-butoxycarbonyl)-4-piperidone (3.0 g, 15 mmol) and sodium triacetoxyborohydride (1.2 g, 5.6 mmol) in dichloroethane (60 mL) was stirred at room temperature for 3 d. The reaction was partitioned between chloroform (200 mL) and 3N sodium hydroxide (30 mL). After drying over magnesium sulfate, the organic phase was concentrated to give the title compound as a tan gum. MS 294 (M+1)
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C([N:19](CC)CC)C.COC(Cl)=O.N>C(#N)C>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:19])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: N
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])cc(C(N)=O)cc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 91.1 %

Procedure:
To a suspension of 4-methyl-3,5-dinitrobenzoic acid (3) (1.5 g) in acetonitrile (22.5 g, 30 mL) and triethylamine (0.87 g, 1.2 mL) at −10° C. is slowly added a solution of methylchloroformate (0.723 g, 0.6 m-L) in acetonitrile (2.25 g, 3 mL). The resulting mixture is agitated at −10° C. for about 1 hour, whereupon ammonia gas (excess) is bubbled though the mixture for about 30 minutes. The resultant mixture is allowed to age at about −5 to −10° C. for 12 hours, whereupon the mixture is added to a mixture of ice and water (100 mL). The solid that precipitates is filtered and dried to provide 4-methyl-3,5-dinitrobenzamide (6) (1.36 g, 91% Yield).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=[NH:4].[NH4+:11].[Cl-]>CCO.O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([NH2:11])=[NH:4]
Reactant: [NH4+]
Reactant: COC(=N)c1ccccn1
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: N=C(N)c1ccccn1

Procedure:
To a solution of pyridine-2-carboximidic acid methyl ester (1 eq, 176 mmol, 24 g) in EtOH (150 ml), a solution of NH4Cl (1 eq, 176 mmol, 9.5 g) in water (40 ml) is added. The resulting mixture is refluxed for 5 h. The solvents are evaporated and the residue is recrystallized from EtOH yielding the title compound; [M+H]+=122.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([OH:16])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>CN(C)C=O>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([O:16][CH2:17][CH:19]3[O:21][CH2:20]3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: BrCC1CO1
Reactant: Oc1cc(-c2cccc(Cl)c2)on1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(-c2cc(OCC3CO3)no2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
29.6 g (0.153 moles) of sodium methoxide (as a 28% w/v methanolic solution) were added to a solution of 30.0 g (0.153 moles) of 5-(m-chlorophenyl)-3-hydroxyisoxazole in 300 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. At the end of this time, 41.9 g (0.306 moles) of epibromohydrin were added dropwise, and the mixture was stirred for a further 3 days. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The resulting mixture was washed with 800 ml of a 10% w/v aqueous solution of sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, eluted with a 2:1 by volume mixture of benzene and ethyl acetate, to give a solid residue, which was recrystallized from diisopropyl ether, to give 23.6 g (yield 73.5%) of the title compound as colorless needles, melting at 86°-87° C.
Reaction SMILES: O=C(CC)C[N:4]1[CH:8]=[C:7](C2C=CC=CC=2)[N:6]=[CH:5]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:6]1[C:7]2=[N:4][CH:8]=[CH:7][NH:6][CH:8]2[NH:4][CH2:5]1
Reactant: CCC(=O)Cn1cnc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=CNC2NCNC2=N1
Temperature: 20 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
2-[1(S)-{1,1-Dimethylethoxy)carbonylamino}-2-phenylethyl]-1-(2-oxo-butyl)-4-phenyl-1H-imidazole (60 mg) in a mixture of 10% TFA in DCM was stirred at about 20° C. for about 3 hours and then concentrated under reduced pressure. The resulting intermediate dihydro-imidazo-pyrazine was dissolved in methanol and borohydride supported on resin (AMBERLITE® IRA 400, Aldrich, 2.5 mmol BH4−/g; 4 eq) was added. The pH was maintained at about 5 by addition of drops of TFA. After about 2 hours of stirring at about 20° C., the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/Heptane 7:3; Rf=0.30). The tetrahydro-imidazo-pyrazine was obtained as a single diastereoisomer in 86% yield (38 mg). NMR (1H, 400 MHz, CDCl3) δ: 7.80-7.10 (m, 11H, arom. H), 4.28 (dd, 1H, 3J=10 Hz, 3J=3 Hz, H8), 3.95 (dd, 1H, 2J=11.5 Hz, 3J=3.6 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=3.0 Hz), 3.60 (t, 1H, 2J=3J=11.5 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=10. Hz), 2.98 (m, 2H), 1.85 (s, 1H, NH), 1.55 (m, 2H, CH2), 0.95 (t, 3H, CH3). NMR (13C, 100 MHz, CDCl3): 146.3, 140.9, 138.0, 134.4, 129.4, 128.6, 128.5, 126.6, 126.5, 124.8, 113.8, 55.9, 54.4, 50.2, 40.0, 26.6, 10.0.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>C(#N)C>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][O:1][C:2]1[CH:18]=[CH:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:9]=[C:4]2[CH:3]=1
Reactant: Clc1ccccc1CBr
Reactant: O=c1cc(N2CCOCC2)nc2cc(O)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc(N2CCOCC2)nc2cc(OCc3ccccc3Cl)ccn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
8-Hydroxy-2-morpholinyl-4H-pyrido[1,2-a]pyrimidin-4-one (59 mg, 0.24 mmol) was dissolved in acetonitrile (10 ml) and then treated with anhydrous potassium carbonate (197 mg, 1.4 mmol) followed by 2-chlorobenzylbromide (46 mg, 0.29 mmol) and the mixture was stirred at 80° C. overnight. Upon cooling the mixture was adsorbed directly onto silica, then eluted through a silica column using ethyl acetate. The purified product was obtained as a tan solid (34 mg).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:25]>CS(C)=O>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)=[O:25])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: O
Reactant: CCc1ccc(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)cc1
Solvent: CS(C)=O
Product: CCc1ccc(C(=O)/C(=N\C2CCCC2)n2ncc(C#N)c2N)cc1
Reaction time: 24 h
Yield: 10 %

Procedure:
A light brown solution of 3-(cyclopentylamino)-2-(4-ethylphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (56.4 mg, 0.177 mmol) in DMSO (17.7 mL) was stored for 35 days at RT. Within 24 h, it became a dark brown solution. After 35 days, LCMS analysis indicated the absence of starting material and the presence of a strong desired peak. Then, it was poured into water (1 L) and the resulting cloudy brown solution was extracted with EA (2×200 mL). Then, the combined extracts were washed with water and brine solution (2 L) to wash the DMSO. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give the red brown paste which was purified using an ISCO (120 g) column chromatography eluting with 0-40% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 5.9 mg (10% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(4-ethylphenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 1.28 (t, J=7.7 Hz, 3H), 1.40-2.00 (br m, 8H), 2.75 (q, J=7.7 Hz, 2H), 3.78 (p, J=6.1 Hz, 1H), 6.78 (br s, 2H), 7.36 (d, J=8.3 Hz, 2H), 7.42 (s, 1H), 7.81 (d, J=8.3 Hz, 2H). LC/MS calcd. for C19H21N5O3 (m/e) 367.4, obsd. 368.0 (M+H, ES+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:3]=1
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
A solution of ethyl 5-chloro-3-(trifluoromethyl)-1H-pyrazole-1-acetate (218 mg, 0.85 mmol) in tetrahydrofuran (1 mL) was treated with sodium hydroxide (0.2 mL, 50% aqueous solution) in water (0.6 mL), and stirred at ambient temperature for 4 h. The reaction mixture was then diluted with water (15 mL) and was concentrated under reduced pressure. The reaction mixture was acidified with concentrated hydrochloric acid to pH 1. The resulting mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated to give 140 mg of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[C:7](Cl)(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>[OH-].[Na+].CCOCC>[C:7]([N:1]([CH3:2])[CH2:3][C:4]([OH:6])=[O:5])(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(=O)Cl
Reactant: CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCCC(=O)N(C)CC(=O)O
Reaction time: 1 h
Yield: 100.9 %

Procedure:
Sarcosine (1.78 g, 20 mmol) was dissolved in 1N NaOH solution (40 ml) and Et2O (40 ml) was added. After cooling in an ice bath a solution of hexanoyl chloride (3.1 ml, 22 mmol) in Et2O (10 ml) was added dropwise. The mixture was stirred cold for 1 hour. The pH was then adjusted to about 8 by adding 1N NaOH solution (about 3 ml) and the mixture was stirred at room temperature 45 minutes. NaOH solution was added to about pH 9-10. The layers were separated and the aqueous layer was washed with Et2O (50 ml). After acidification of the aqueous layer with concentrated HCl and saturation with solid KCl, the product was extracted into CHCl3 (3×70 ml). The combined CHCl3 extracts were washed with saturated NaCl solution (25 ml), dried (MgSO4), and freed of solvent leaving the title compound as an oil (3.78 g, quant.) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C1C(=O)N([Cl:20])C(=O)C1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:20])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Solvent: C1CCOC1
Product: Oc1ccc2cc(Br)ccc2c1Cl

Procedure:
The title compound was prepared by reacting 6-bromo-2-naphthol (3 g, 13.4 mmol) and NCS (2.47 g, 18.5 mmol) in THF (50 mL) according to method C to yield 2.2 g (64%) of yellow solid: 1H NMR (DMDO-d6): δ 7.34 (1H, d, J=8.87 Hz), 7.69 (1H, dd, J=1.75 Hz, J=6.09 Hz), 7.79 (1H, d, J=8.96 Hz), 7.96 (1H, d, J=9.03 Hz), 8.17 (1H, d, J=1.75 Hz), 10.68(1H, s); MS (ESI) m/z 255/257/259 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[C:17]([CH3:23])=[N:18][C:19]([CH2:20][CH2:21][CH3:22])=[C:12]2[N:11]=1)[CH3:2].[Cl:24][S:25](O)(=[O:27])=[O:26]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:25]([Cl:24])(=[O:27])=[O:26])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[C:17]([CH3:23])=[N:18][C:19]([CH2:20][CH2:21][CH3:22])=[C:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3ccccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
1.64 g (5.25 mmol) of 2-(2-ethoxyphenyl)-6-methyl-8-propyl-3H-imidazo[1,5-α][1,3,5]triazin-4-one (example VI) are added in portions to 3.14 ml of chlorosulfonic acid while cooling with ice. The reaction mixture is stirred at room temperature for 16 hours, then diluted with dichloromethane and poured onto ice water. The organic phase is washed with water and dried over magnesium sulfate and the solvent is removed in vacuo. 2.15 g (99%) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α][1,3,5]triazin-2-yl)-benzene-sulfonyl chloride are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>C1COCC1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:29]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (120 mg, 0.40 mmole), 3-methoxy-benzoyl chloride (81 mg, 0.48 mmole), and triethylamine (0.1 mL, 0.79 mmole) in 5 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 88 mg, 51%). 1H NMR (Acetone-d6, 400 MHz) 2.99-3.21 (m, 2H), 3.22-3.45 (m, 2H), 3.66 (t, J=4.80 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79-3.89 (m, 4H), 4.58 (t, J=4.80 Hz, 2H), 6.29 (d, J=2.02 Hz 1H), 7.13 (dd, J=8.34, 2.53 Hz, 1H), 7.22 (d, J=8.84 Hz, 1H), 7.42 (t, J=7.83 Hz, 1H), 7.47 (d, J=1.77 Hz, 1H), 7.52 (t, J=1.77 Hz, 1H), 7.56 (d, J=7.07 Hz, 1H), 7.80-7.83 (m, 1H), 7.91-7.96 (m, 1H), 9.54 (s, NH). Exact mass calculated for C24H28N4O4 436.2. found 437.5 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)=[CH:5][C:6]([C:10]([O:12]CC)=[O:11])=[N:7][C:8]=1[CH3:9])#[N:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[N:7][C:8]=1[CH3:9])#[N:2]
Reactant: CCOC(=O)c1cc(-c2cccc([N+](=O)[O-])c2)c(C#N)c(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C(=O)O)cc(-c2cccc([N+](=O)[O-])c2)c1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
To a solution of ethyl 5-cyano-6-methyl-4-(3-nitrophenyl)-2-pyridinecarboxylate (2.75 g) in ethanol (30 ml) was added a solution of sodium hydroxide (0.37 g) in water (6 ml). After the mixture was stirred at ambient temperature for 1.5 hours, the reaction mixture was adjusted to pH 2 with 6N hydrochloric acid. The resulting precipitates were filtered off, washed with water, and dried to give 5-cyano-6-methyl-4-(3-nitrophenyl)-2-pyridinecarboxylic acid (2.4 g).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH:15]2[C:23]([NH2:25])=O)=[CH:10][CH:9]=1)[CH3:7]>CN(C=O)C>[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH:15]2[C:23]#[N:25])=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCCC1CCC(c2ccc(CC)cc2)C(C(N)=O)C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCC1CCC(c2ccc(CC)cc2)C(C#N)C1
Reaction time: 1 h

Procedure:
65 g of POCl3 are added dropwise with stirring at 50° to a solution of 24 g of 2-(p-ethylphenyl)-5-n-propylcyclohexanecarboxamide in 500 ml of DMF. After further stirring for one hour the reaction mixture is poured onto ice and worked up as customary to give 2-(p-ethylphenyl)-5-n-propylcyclohexanecarbonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:23][C@H:24]2[CH2:28][CH2:27][CH2:26][O:25]2)(=O)=O)=CC=1>[I-].C([N+](CC)(CC)CC)C.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8](=[NH:11])[N:9]([CH2:23][C@H:24]2[CH2:28][CH2:27][CH2:26][O:25]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: CC(C)(C)c1ccc(N)nc1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(=N)n(C[C@H]2CCCO2)c1
Temperature: 25 °C

Procedure:
A mixture of Example 59B (0.5 g, 3.3 mmol), (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (0.9 g, 3.6 mmol), and tetraethylammonium iodide (0.4 g, 1.6 mmol) in N,N-dimethylformamide (1.0 mL) was heated at 95° C. for 16 hours. After cooling to ambient temperature, the mixture was quenched with saturated NaHCO3 (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. LCMS (APCI+) m/z 235 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)=[C:8]([CH3:20])[C:6]=2[N:7]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([NH:30][CH2:29][CH2:27][OH:28])=[O:16])=[C:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: NCCO
Reactant: Cc1c(-c2cccc(C(=O)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(-c2cccc(C(=O)NCCO)c2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with ethanolamine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide (74 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 2.6 mg of 426. MS (Q1) 515.2 (M)+