Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:9][C:10]1[CH:14]=[CH:13][N:12]([C:2]2[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[N:11]=1
Reactant: Brc1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1ccc(Br)n1
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and 3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dry N,N-dimethylformamide (88 mL) was added potassium carbonate (48.6 g, 352 mmol), and the reaction mixture was heated to 125° C. for 18 hours. The reaction mixture was cooled to room temperature and poured into ice water (800 mL). A precipitate formed. The precipitated solids were stirred for 1.5 hrs, filtered and washed with water (2×100 mL). The solid filter cake was taken up in methylene chloride and washed sequentially with water, 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic extracts were then dried over magnesium sulfate and concentrated to afford 39.9 g of a pink solid. The crude solid was suspended in hexane and stirred vigorously for 1 hr. The solids were filtered, washed with hexane and dried to afford the title product as an off-white powder (30.4 g) determined to be >94% pure by NMR. This material was used without further purification in Step D.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Cl:14])/[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Cl:14])/[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:16]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
(1R,cis,Z) 2,2-dimethyl-3-[2-chloro-3-oxo-3-(1,1-dimethyl-ethoxy)-1-propenyl]-cyclopropane-carboxylic acid prepared as in Step B of Example 34 of European Pat. No. 0050534 and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[2-chloro-3-oxo-3-(1,1-dimethylethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+15.5°±1° (c=1% in chloroform).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[CH:26]=[O:27])[C:17]#[N:18].[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C@:36]([OH:51])([C@H:43]([S:45][CH:46]([CH2:49]O)[CH2:47][OH:48])[CH3:44])[CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1>ClCCl>[C:17]([C:16]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[C@H:26]2[O:48][CH2:47][C@H:46]([S:45][C@H:43]([CH3:44])[C@:36]([C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])([OH:51])[CH2:37][N:38]3[CH:42]=[N:41][CH:40]=[N:39]3)[CH2:49][O:27]2)=[C:14]([F:13])[CH:15]=1)#[N:18]
Reactant: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
791 mg (4.16 mmol) of p-toluenesulfonic acid monohydrate were added to a solution of 760 mg (3.77 mmol) of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]-benzonitrile [obtained as described in Example 1(ii) above] and 1.36 g (3.77 mmol) of (2R,3 R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2 -hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350] in 13 ml of dichloromethane. The resulting mixture was concentrated using a rotary evaporator. 13 ml of dichloromethane and 13 g of 4A molecular sieves were added to the resulting residue and the mixture was then stirred at ambient temperature overnight. At the end of this time, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture. The molecular sieves were removed by filtration and the filtrate was partitioned between ethyl acetate and water. The organic layer was dried and concentrated under reduced pressure. The resulting oil residue was purified by chromatography on a silica gel (20 a) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to afford 1.42 g (yield 69%) of the title compound as an amorphous solid. The spectral data were identical to those of the title compound of Example 1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:30])[N:8]=[CH:9][C:10]=1[NH:11][C:12]([C:14]1[C:19]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[N:18][CH:17]=[C:16]([CH:27]2[CH2:29][CH2:28]2)[N:15]=1)=[O:13])=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH:27]1([C:16]2[N:15]=[C:14]([C:12]([NH:11][C:10]3[CH:9]=[N:8][N:7]([CH3:30])[C:6]=3[C:4]([OH:5])=[O:3])=[O:13])[C:19]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[N:23][CH:22]=3)=[N:18][CH:17]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)cnn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Temperature: 85 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a suspension of 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.13 g, 2.77 mmol) in ethanol (15 ml) and water (12 ml) was added 1N NaOH (3.32 ml) at r.t. under argon atmosphere. The yellow suspension was stirred at 85° C. for 1 h. After cooling down to r.t., the mixture was treated with 1M HCl (3.3 ml) and stirred for 30 min. The product was collected by filtration, washed with water and EtOH, and dried to yield a light yellow solid (1.0 g, 95%).
Reaction SMILES: [Br-].[CH:2]1([CH2:8][NH:9]CC2CCCCC2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C([Sn](CCCC)(CCCC)C1[N:23]=CSC=1)CCC>CN(C=O)C>[NH:23]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1
Reactant: C1CCC(CNCC2CCCCC2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: [Br-]
Solvent: CN(C)C=O
Product: c1ccc2[nH]ncc2c1
Temperature: 135 °C
Reaction time: 19 h
Yield: 75.6 %

Procedure:
A mixture of bromide (IXb-75) (120 mg, 0.24 mmol), N,N-dicyclohexylmethylamine (52 mg, 0.27 mmol), 4-(tributylstannyl)thiazole (138 mg, 0.37 mmol), dihydrogen dichlorobis(di-tert-butylphosphinito-kP)palladate(2-) (7 mg, 0.01 mmol) in DMF (3 mL) was stirred at 135° C. for 19 h. The mixture was then cooled to RT and partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with EtOAc (2×15 mL). The combined organic solutions were dried (MgSO4), filtered and concentrated. The orange residue was purified by LCMS (column LUNA 10μ C18(2) 00G-4253-V0 250×50 mm) using water-acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford azaindole (I-116) (24.1 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 1.51-1.67 (m, 4H), 2.03-2.16 (m, 6H), 2.57-2.64 (m, 1H), 3.04-3.12 (m, 5H), 3.82 (t, J=6.0 Hz, 2H), 3.84-3.87 (m, 2H), 6.44 (d, J=3.4 Hz, 1H), 7.31 (d, J=3.4 Hz, 1H), 7.80 (d, J=1.9 Hz, 1H), 8.01 (s, 1H), 8.05 (d, J=1.9 Hz, 1H), 10.29 (br s, 1H).
Reaction SMILES: C(N(CC)[C:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:17][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[O:5])C.[OH-:30].[K+]>O.C(O)C>[C:23]([O:22][C:21]([NH:20][C@H:18]([CH3:19])[CH2:17][C:13]1[C:12]2[C:16](=[C:8]([O:7][CH2:6][C:4]([OH:30])=[O:5])[CH:9]=[CH:10][CH:11]=2)[NH:15][CH:14]=1)=[O:27])([CH3:24])([CH3:26])[CH3:25]
Reactant: [OH-]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC(=O)OC(C)(C)C)c[nH]c12
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC(=O)OC(C)(C)C
Yield: 99 %

Procedure:
A solution of tert-butyl (R)-[2-(7-diethylcarbamoylmethoxy-1H-indol-3-yl)-1-methylethyl]carbamate (0.35 g, 0.87 mmol) and potassium hydroxide (0.39 g, 7 mmol) in water (4 mL) and ethanol (6 mL) is stirred at 60° C. for 8 hours. After cooling, the mixture is concentrated and acidified by addition of water (30 mL) and acetic acid. The resultant is extracted with chloroform, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give the desired (R)-[3-(2-(tert-butoxycarbonylamino)propyl)-1H-indol-7-yloxy]acetic acid (0.30 g, yield: 100%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13]C(C3SC4C=CC=C(Cl)C=4C=3)=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH3:37])[C:31]([C:38]([OH:40])=O)=[CH:30]2.C(OC(N1CCN(C2C=CC(N)=CN=2)CC1)=O)(C)(C)C>>[N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:38]([C:31]3[N:32]([CH2:36][CH3:37])[C:33]4[C:29]([CH:30]=3)=[CH:28][C:27]([Cl:26])=[CH:35][CH:34]=4)=[O:40])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1cc2c(Cl)cccc2s1
Reactant: CCn1c(C(=O)O)cc2cc(Cl)ccc21
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Product: CCn1c(C(=O)Nc2ccc(N3CCNCC3)nc2)cc2cc(Cl)ccc21

Procedure:
With a method similar to that used for the preparation of 4-chloro-benzo[b]thiophene-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide, 5-chloro-1-ethyl-1,4-indole-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide was prepared from 5-chloro-1-ethyl-1H-indole-2-carboxylic acid and 4-(5-amino-pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester. LCMS for C20H22Cl N5O calcd. (m/e) 383, observed 384 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:8](=[O:12])[C:7](=[O:13])[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]=2[O:3]1.[OH:19][CH2:20][CH:21]([CH2:23][OH:24])O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:19][CH2:20][CH:21]1[CH2:23][O:24][C:7]2([C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]3[O:3][C:2]([CH3:18])([CH3:1])[CH2:11][CH2:10][C:9]=3[C:8]2=[O:12])[O:13]1
Reactant: OCC(O)CO
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CO)O1)C2=O
Yield: 36 %

Procedure:
To a solution of 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (1.21 g, 5 mmol) in benzene (12 ml) is added glycerol (0.92 g, 10 mmol) and p-toluenesulfonic acid monohydrate (0.28 g, 1.5 mmol). The resulting mixture is refluxed for 6 hours. After removal of the solvent, product is purified by column chromatography on silica gel eluting with 30% ethyl acetate in methylene chloride to provide 0.57 g (36% yield) as a light yellow solid, which is a mixture of diasteromers. M.p. 44-46° C.; 400 MHz 1H NMR (CDCl3) δ: 1.41 (s, 6H), 1.73-1.82 (m, 2H), 2.36-2.42 (m, 1H), 2.48-2.54 (m, 1H), 3.72-3.78 (m, 1H), 4.18 (d, J=2.5 Hz, 1H), 4.20-4.29 (m, 1H), 4.40 (t, J=8.0 Hz, 1H), 4.71-4.74 (m, 1H), 4.85 (d, J=8.8 Hz, 1H), 7.38-7.44 (m, 2H), 7.54-7.56 (m, 1H), 7.75-7.78 (m, 1H); LCMS: Calc. for C18H21O5: 217; Found 217.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.CCCCCC>C1(C)C=CC=CC=1>[C:22]([C:16](=[CH:15][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][N:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:23]
Reactant: CCCCc1ccc(N)nc1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCc1ccc(NC=C(C#N)C(=O)OCC)nc1

Procedure:
A solution of 2-amino-5-n-butylpyridine (3.72 g., 23.43 mmoles) and ethyl ethoxymethylenecyanoacetate (3.96 g., 23.43 mmoles) in toluene was heated for 10 minutes by means of an oil bath maintained at 100°. The solution was cooled and treated with Skellysolve B (200 ml.). The mixture was triturated for 18 hours at room temperature and then filtered. The collected title compound (4.3 g., 67.2%) had m.p. 69°-73°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: COc1ccc(N)c(CO)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N)c(CN2CCOCC2)c1

Procedure:
N-(2-Amino-5-methoxy-benzyl)-morpholine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and morpholine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride) 3280 cm-1NH2 ; 3410 cm-1NH2 ; 2830 cm-1OCH3 ; 2800 cm-1N-alkyl; 1500 cm-1C=C; 1600 cm -1 C=C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]2[C:12](=[O:15])[NH:13][N:14]=[C:4]2[C:3]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([N:13]1[C:12](=[O:15])[N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[N:2]([CH3:1])[C:3](=[O:16])[C:4]2=[N:14]1)(=[O:19])[CH3:18]
Reactant: Cn1c(=O)c2n[nH]c(=O)n2c2cccnc21
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)n1nc2c(=O)n(C)c3ncccc3n2c1=O

Procedure:
A mixture of 1.8 g. of 5-methyl-pyrido(2,3-e)(1,2,4)triazolo(4,3-a)pyrazine-1,4-(2H,5H)dione in 25 ml. of acetic anhydride and 50 ml. of acetic acid was stirred and refluxed for 5 hours.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](Nc1cncc(-n2cnc3ccc(N)cc32)n1)c1ccccc1
Product: C[C@H](Nc1cncc(-n2cnc3ccc(NC(=O)c4ccccc4)cc32)n1)c1ccccc1
Yield: 76.7 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-amine (50 mg, 0.15 mmol) and benzoyl chloride (21 mg, 0.15 mmol) furnished the product (50 mg, 76%) after chromatography.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1ncccn1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ncccn4)cc3CC[C@@H]12
Yield: 23.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloropyrimidine (53 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (23%) of the title compound as an oil. FDMS: m/e=339.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])=[O:7].[Br:16]C1OC(C(O)=O)=CC=1>>[Br:16][C:5]1[O:1][C:2]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[O:7])=[CH:3][CH:4]=1
Reactant: O=C1CCCCCN1C(=O)c1ccco1
Reactant: O=C(O)c1ccc(Br)o1
Product: O=C1CCCCCN1C(=O)c1ccc(Br)o1

Procedure:
Synthesized as for N-(2-furoyl)caprolactam (Example X) using 5-bromo-2-furoic acid in place of 2-furoic acid.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[C:15]([O:24][CH3:25])[N:14]=1.Cl.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33][CH2:32]2>CN(C=O)C>[CH3:25][O:24][C:15]1[C:16]([N+:21]([O-:23])=[O:22])=[C:17]([O:19][CH3:20])[N:18]=[C:13]([N:34]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:28]([F:27])([F:40])[F:39])[CH:30]=3)[CH2:35]2)[N:14]=1
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Reactant: COc1nc(Cl)nc(OC)c1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (0.669 g, 4.4 mmol) was added to a mixture of 4a (0.438 g, 2 mmol) and 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.487 g, 2.05 mmol) in DMF (5 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 5b (0.76 g, 1.98 mmol, 99%).
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16]C)=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([OH:16])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cnc(OC)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ncc(C(=O)O)cc1OC1CCCC1
Reaction time: 4 h
Yield: 59.3 %

Procedure:
A solution of potassium hydroxide (168 mg) in water (1 mL) is added to a solution of methyl 5-cyclopentyloxy-6-methoxynicotinoate (250 mg) in methanol (3 mL) and the mixture stirred for 4 hours then allowed to stand at room temperature overnight. The mixture is concentrated, the residue dissolved in water and the mixture adjusted to pH 6 by the addition of concentrated hydrochloric acid. The mixture is extracted with ethyl acetate, the extracts dried (MgSO4) and concentrated to give a cream solid. The solid is dried at 100° C. to give 5-cyclopentyloxy-6-methoxynicotinic acid (140 mg), m.p. 191-2° C. [Elemental analysis: —C, 60.7; H, 6.43; N, 5.78%. calculated: —C, 60.75; H, 6.37; N, 5.90%.].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][Si:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:39]1([CH2:45][S:46][CH:47]([C:51](O)=[O:52])[C:48](O)=[O:49])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:16][C:6]1[CH:5]=[C:4]([C:17]2[O:19][C:48](=[O:49])[C:47]([S:46][CH2:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:51]([OH:52])[CH:18]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][Si:9]([CH3:14])([CH3:15])[C:10]([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc(C)c1O[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared by Method A using 3',5'-dimethyl-4'-[[dimethyl(l,l-dimethylethyl)silyl]oxy] acetophenone (1.50 g, 5.39 mmol), trimethylsilyltriflate (1.24 mL, 6.47 mmol), triethylamine (1.50 mL, 10.78 mmol), methylene chloride (13 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 137-139° C.; 1H NMR (400 MHz, DMSO-d6) δ0.21 (s, 6 H), 0.99 (s, 9H), 2.22 (s, 6 H), 3.96 (s, 2 H), 6.54 (s, 1 H), 6.99 (d, 1 H), 7.21 (m, 5 H), 7.44 (m, 2 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=O.[CH3:32][NH2:33].O>CCO>[CH3:32][NH:33][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[CH:8]2)=[O:2]
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 80 °C

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.085 mmol) and methylamine (1 mL, 2M in THF) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., 3 mL of water was added. The resulting suspension was filtered, and the crude solid was purified by silica gel chromatography (0-20% EtOAc/CH2Cl2+1% AcOH) to give 13 mg of the title compound as a white solid. MS: (+) m/z 411.01 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.O>CN(C)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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][O:28][CH3:27])=[CH:31][CH:32]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)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: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 110 °C
Yield: 105.3 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.00 g, 3.26 mmol) in N,N-dimethylacetamide (15 mL). Add potassium carbonate (1.29 g, 9.36 mmol), 4-methoxymethylbenzeneboronic acid (649 mg, 3.90 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0225 g, 0.034 mmol), then water (5 mL) and degas with nitrogen for 30 min. Heat at 110° C. for 18 hr. under nitrogen. Cool to room temperature, add water (20 mL) and extract with DCM (3×20 mL). Combine the DCM extracts and pass through an IST Phase Separator Frit® and concentrate. Purify (silica gel chromatography, eluting with 20:80 ethyl acetate:isohexane), to give 3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester as a yellow oil (1.32 g, 105%). MS (ES): m/z=385 [M+H]+.
Reaction SMILES: [CH:1]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14].C[O-].[Na+]>C(O)C>[CH:1]1([C:6]2[N:7]=[C:13]([OH:14])[CH:12]=[C:11]([C:10]([F:20])([F:19])[F:9])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: N=C(N)C1CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nc(C2CCCC2)n1
Temperature: 85 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
To a solution of cyclopentanecarboximidamide (3.0 g, 27.1 mmol) in ethanol (100 mL) was added ethyl 4,4,4-trifluoro-3-oxobutanoate (5.0 g, 27.1 mmol) and sodium methoxide (1.76 g, 32.5 mmol). The mixture was stirred at 85° C. for 16 h. After this time, the mixture was concentrated, diluted with ethanol (10 mL), and the suspension was chilled to 0° C. HCl (2M, 50 mL) was added and the suspension was filtered and washed with water. The solid was dried under heat and vacuum to afford the title compound (2.24 g, 36%) as a white solid. MW=232.20. 1H NMR (DMSO-d6, 500 MHz) δ 12.96 (s, 1H), 6.67 (s, 1H), 3.03 (quin, J=8.2 Hz, 1H), 2.00-1.92 (m, 2H), 1.83-1.67 (m, 4H), 1.64-1.53 (m, 2H); APCI MS m/z 233 [M+H]+.