Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])=[N:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][C:4]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])=[N:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccncn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccncn1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-pyrimidyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>C1COCC1>[F:16][C:17]1[C:22]([Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccnc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
n-Butyllithium (1.6 M in hexane, 0.920 mL, 10.99 mmol) was added to 2,2,6,6-tetramethylpiperidine (2.024 mL, 11.99 mmol) in THF (50 mL) at −50° C. Following the addition, the mixture was stirred at 0° C. for 20 min and then cooled down to −100° C. 2-Fluoropyrazine (980 mg, 9.99 mmol) in THF (5 mL) was then added dropwisely. After 5 min, tributyltin chloride (3.25 mL, 11.99 mmol) in THF (5 mL) was added dropwisely and stirring was continued for 1 h. The reaction was quenched with a solution of 35% aqueous HCl, ethanol, THF (1:4:5) and allowed to warm to 20° C. The reaction mixture was diluted with sat. aqueous NaHCO3 (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated aqueous NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as orange oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column eluting with 50% CH2Cl2/hexanes to give 2-fluoro-3-(tributylstannyl)pyrazine (2980 mg, 7.70 mmol, 77% yield) as colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H); 8.02 (s, 1H); 1.46-1.68 (m, 6H); 1.12-1.42 (m, 12H); 0.88 (t, J=7.23 Hz, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:36].CO>>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: CO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 80 °C

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.371 mmol) and ammonia in MeOH 7M (6 ml, 42.0 mmol) and heating to 80° C. overnight, the title compound was obtained as an off-white solid (158 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (s, 1H), 7.93 (d, J=5.1 Hz, 1H), 7.40-7.56 (m, 3H), 7.35-7.41 (m, 1H), 7.28-7.35 (m, 1H), 7.20-7.28 (m, 1H), 6.71 (s, 2H), 5.79 (d, J=5.1 Hz, 1H), 1.35 (s, 9H). MS (ESI): 520.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.C(N(C(C)C)CC)(C)C.[Cl:18][C:19]1[C:20](=[O:31])[C:21]2[C:26]([C:27](=[O:30])[C:28]=1Cl)=[CH:25][CH:24]=[CH:23][CH:22]=2.O>C1C=CC=CC=1>[Cl:18][C:19]1[C:20](=[O:31])[C:21]2[C:26]([C:27](=[O:30])[C:28]=1[NH:1][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: NCc1cnccn1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: O=C1C(Cl)=C(NCc2cnccn2)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
2-(Aminomethyl)pyrazine (3.2 g) and diisopropylethylamine (5.8 ml) were added to a solution of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene (3.0 g) in benzene (90 ml) and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction solution and the resulting precipitate was removed by filtration and then the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with chloroform) to give 2-chloro-1,4-dihydro-1,4-dioxo-3-[(2-pyrazinylmethyl)amino]naphthalene (0.23 g) as a light brown powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[N:23](COCC[Si](C)(C)C)[CH:24]=[C:25]([C:27]#[N:28])[N:26]=3)=[O:21])=[C:15]([C:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6].CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=3)=[O:21])=[C:15]([C:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCN(C(=O)NCCO)CC2)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)NCCO)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid (2-hydroxy-ethyl)-amide (as prepared in the previous step, 95 mg, 0.16 mmol) in 3 mL of DCM was added 0.10 mL of EtOH followed by 1.0 mL of TFA. The resulting solution was stirred at RT for 6 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-8% MeOH/DCM) gave 68 mg (92%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.09 (d, 1H, J=8.4 Hz), 8.00 (s, 1H), 7.15 (dd, 1H, J=8.4, 2.2 Hz), 5.79 (m, 1H), 4.15 (dd, 2H, J=13.3, 1.1 Hz), 3.61 (t, 2H, J=5.9 Hz), 3.27-3.32 (m, 2H), 2.90 (ddd, 2H, J=13.0, 13.0, 2.5 Hz), 2.73 (dddd, 1H, J=12.1, 12.1, 2.6, 2.6 Hz), 2.26 (m, 4H), 1.73-1.88 (m, 6H), 1.62 (dddd, 2H, J=12.6, 12.6, 12.6, 4.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C25H30N6O3, 463.2 (M+H), found 463.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:26])([F:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([N:1]=[CH:23][C:21]2[O:22][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([F:25])([F:10])[F:26])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Reactant: Nc1cc(Cl)ccc1O
Product: Oc1ccc(Cl)cc1N=Cc1ccc(-c2ccccc2C(F)(F)F)o1

Procedure:
Using 2-amino-4-chlorophenol and 5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 3.76 g of 4-chloro-2-{[5-(2-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 86%).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]#[N:24])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:25][CH3:26])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH2:24])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:25][CH3:26])[CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c1c(OCC#N)cccc1n2Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1c(OCCN)cccc1n2Cc1ccccc1
Temperature: 85 °C
Yield: 85 %

Procedure:
To a mixture of [(9-benzyl-6-methoxy-9H-carbazol-4-yl)oxy]acetonitrile (0.43 g, 1.26 mmol) in dry THF (20 mL) is added borane-methylsulfide complex (0.36 mL, 3.8 mmol). The mixture is heated at 85° C. overnight. Methanol is slowly added to the mixture until gas evolution ceased. The solvents are removed under reduced pressure. Methanol (20 mL) is added then removed under reduced pressure. Methanol (50 mL) and concentrated hydrochloric acid (10 mL) is added to the mixture and heated at 65° C. overnight. The mixture is neutralized with saturated potassium carbonate and partitioned between water and CH2Cl2. The layers are separated and the organic layer washed twice with water (100 mL). The CH2Cl2 is dried over anhydrous sodium sulfate and concentrated. Column chromatography with silica gel (60 mL) using 4% CH3OH in CH2Cl2 gave 0.371 g (85%) of the title compound; IR (drift) 1581, 1488, 1467, 1452, 1440, 1343, 1323, 1289, 1271, 1211, 1167, 1150, 1031, 742, 727 cm−1. HRMS (FAB) calcd for C22H22N2O2+H1 347.1759, found 347.1761. % Water (KF): 0.17. 1H NMR (CDCl3) δ3.28, 3.92, 4.28, 5.47, 6.65, 6.95, 7.02, 7.09, 7.21, 7.32, 7.87; Anal. Calcd for C22H22N2O2: C, 76.15; H, 6.41; N, 8.07. Found: C, 75.90; H, 6.38; N, 7.99.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][N:7]([CH:10]([CH3:12])[CH3:11])[CH2:6][CH2:5]1.[C:20]1([CH2:26][C:27]([Cl:29])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[ClH:29].[CH3:1][O:2][CH2:3][C:4]1([N:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:27](=[O:28])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][CH2:8][N:7]([CH:10]([CH3:12])[CH3:11])[CH2:6][CH2:5]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COCC1(Nc2ccccc2)CCN(C(C)C)CC1
Solvent: c1ccccc1
Product: COCC1(N(C(=O)Cc2ccccc2)c2ccccc2)CCN(C(C)C)CC1
Product: Cl
Reaction time: 3.6 h

Procedure:
To a stirred mixture of 5.5 parts of 4-(methoxymethyl)-1-(1-methylethyl)-N-phenyl-4-piperidinamine in 56 parts of benzene is added dropwise a solution of 13.8 parts of benzeneacetyl chloride in 45 parts of benzene at 26°-32° C. Upon completion, stirring is continued first for one hour at 26°-32° C. and further for 3.60 hours at 38°-55° C. After cooling, the precipitated product is filtered off and converted into the hydrochloride salt in a mixture of 2-propanol and 2-propanone (5:1 by volume). The salt is filtered off and dissolved in absolute ethanol. After standing for 72 hours at room temperature, the precipitated product is filtered off, washed with a small amount of 2-propanone and dried, yielding 1.05 parts of N-[4-(methoxymethyl)-1-(1-methylethyl)-4-piperidinyl]-N-phenylbenzeneacetamide hydrochloride; mp. 249.1° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([N+:12]#[C-:13])([CH3:11])([CH3:10])[CH3:9].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>Cl(O)(=O)(=O)=O>[C:8]([NH:12][C:13]1[N:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:2]2=[N:1][C:20]=1[C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=Cc1cccnc1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1ncccn1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2cccnc2)nc2ncccn12

Procedure:
Compound (17) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml tert-butylisonitrile solution (0.2 M, MC), 0.500 ml pyridine-3-carbaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Li]CCCC.CN([CH:17]=[O:18])C>C1COCC1>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([CH:17]=[O:18])=[CH:7][N:6]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 5-bromo-2-methylpyridine (151; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at −78° C. The reaction mixture was stirred at this temperature for 1 h. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at −78° C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 6-methylnicotinaldehyde 152 (5.0 g, 72%).
Reaction SMILES: [C:1]([CH:9]1[CH2:16][C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]1=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20].C(O)(=O)C>C(O)C>[C:2]1([C:1]2[C:9]3[CH2:16][C:12]4[S:13][CH:14]=[CH:15][C:11]=4[C:10]=3[NH:20][N:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C1Cc2sccc2C1=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
5-Benzoyl-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.42 g, 10.0 mmol), hydrazine monohydrate (1.92 mL, 60 mmol), glacial acetic acid (2.7 mL) and ethanol (15 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-Phenyl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (2.4 g, 8.0 mmol) as white solid in 80% yield.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:30]1[C:43]2[C:34](=[N:35][C:36]3[C:41]([C:42]=2[NH:44][C:45]2[CH:46]=[C:47]([NH:53][C:54](=[O:58])[CH:55]([NH2:57])[CH3:56])[CH:48]=[C:49]([CH2:51][OH:52])[CH:50]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1>>[CH:40]1[C:41]2[C:36](=[N:35][C:34]3[C:43]([C:42]=2[NH:44][C:45]2[CH:46]=[C:47]([NH:53][C:54]([CH:55]([NH:57][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:56])=[O:58])[CH:48]=[C:49]([CH2:51][OH:52])[CH:50]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:37]=[CH:38][CH:39]=1
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(F)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(F)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 53.4 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3-fluorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-n icotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:4].[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[CH2:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:27]3[CH2:28][CH2:29][CH:24]([NH:23][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:25][CH2:26]3)=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CCl)c1ccc2c(c1)CCCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(NC(=O)c2ccccc2)CC1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-chloroacetyl-1,2,3,4-tetrahydro naphthalene (20.87 g.), 4-benzamidopiperidine (20.4 g.) and triethylamine (11.1 g.) in dimethylformamide (200 ml.). was stirred for 3 days at room temperature. The crystals which had formed during this time were then filtered off, washed and dried. A portion of this crystalline solid (4.0 g.) was dissolved in ethanol (50 ml.) and acidified with ethanolic hydrogen chloride to give 4.0 g. of the hydrochloride of the title compound, m.p. 270° C (decomp.). (Found: C, 69.5; H, 7.2; N, 6.8; C24H28N2O2.HCl requires C, 69.8; H, 7.1; N, 6.8%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7]C[C:5](=O)[CH2:4][CH2:3]1.[C:9](=[O:12])(O)[O-:10].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[CH3:1][CH:2]1[CH2:7][O:10][C:9](=[O:12])[CH2:5][CH2:4][CH2:3]1
Reactant: O=C([O-])O
Reactant: CC1CCC(=O)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1CCCC(=O)OC1

Procedure:
This was prepared in similar manner to Lactone 1 except using 4-methyl cyclohexanone (50 parts; 0.445m ex. Aldrich) in place of the 3-methylcyclohexanone with appropriate increase in the dichloromethane (1500 ml), sodium bicarbonate (8.1 parts, 1.0M) and 3-chloroperoxybenzoic acid (123 parts; 0.5M). The reaction temperature was maintained below 10° C. throughout. The 5-methyl ε-caprolactone was obtained as a clear yellow oil (49 parts).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([OH:15])=O)=[CH:11][N:12]=2)[CH:9]=1)(=[O:3])[NH2:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.C[NH:28][C:29]1[CH:34]=[C:33]([C:35]2[N:39]=[C:38]([CH:40]3[CH2:43][C:42]([F:45])([F:44])[CH2:41]3)[O:37][N:36]=2)[CH:32]=[CH:31][C:30]=1[CH3:46]>ClCCl.N1C=CC=CC=1>[F:45][C:42]1([F:44])[CH2:41][CH:40]([C:38]2[O:37][N:36]=[C:35]([C:33]3[CH:32]=[CH:31][C:30]([CH3:46])=[C:29]([NH:28][C:13]([C:10]4[N:8]5[CH:9]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=[CH:6][C:7]5=[N:12][CH:11]=4)=[O:15])[CH:34]=3)[N:39]=2)[CH2:43]1
Reactant: NC(=O)c1ccc2ncc(C(=O)O)n2c1
Reactant: CNc1cc(-c2noc(C3CC(F)(F)C3)n2)ccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(C(N)=O)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-carbamoylimidazo[1,2-a]pyridine-3-carboxylic acid (110) (50 mg, 0.172 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (16 uL, 0.189 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated. A stirring mixture of the acid chloride and methyl 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) (23 mg, 0.0861 mmol) in anhydrous pyridine (2 mL) was stirred at room temperature for 20 minutes. The crude product was purified by reverse phase preparative HPLC to give N3-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3,6-dicarboxamide (F62). 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s, 1H), 9.99-9.98 (m, 1H), 8.68 (s, 1H), 8.28 (s, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.98 (dd, J=1.6, 9.2 Hz, 1H), 7.88-7.83 (m, 2H), 7.66 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 3.91-3.84 (m, 1H), 3.22-3.06 (m, 4H), 2.38 (s, 3H). MS m/z 452.14 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C@H:12]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:14][CH2:15][OH:16])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:8]=2)[N:3]=1.CC(C)=[O:32].OS(O)(=O)=O.O=[Cr](=O)=O.OS(O)(=O)=O.O>CC(C)=O>[NH2:1][C:2]1[C:11]([C@H:12]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:14][C:15]([OH:32])=[O:16])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:8]=2)[N:3]=1
Reactant: CC(C)=O
Reactant: Nc1nc2ccc(Oc3ccccc3)cc2cc1[C@@H](CCCO)C1CCCCC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nc2ccc(Oc3ccccc3)cc2cc1[C@@H](CCC(=O)O)C1CCCCC1
Temperature: 0 °C

Procedure:
To an ice cold solution of 4-(2-amino-6-phenoxy-quinoline-3-yl)-4-(S)-cyclohexyl-butan-1-ol (0.44 g, 1.12 mmol) in acetone (15 mL) was added Jones reagent (0.7 M solution in a 0.12:1 mixture of concentrated H2SO4:H2O, 16.0 mL, 11.3 mmol) dropwise, and the reaction mixture was stirred for 3.0 h. The excess reagent was quenched by adding isopropyl alcohol, and the resulting slurry was filtered through Celite®. The crude material obtained by removal of the solvent was purified by silica gel column chromatography using 30% MeOH in CHCl3 to yield 4-(2-amino-6-phenoxy-quinoline-3-yl)-4-(S)-cyclohexyl-butyric acid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].CC(=[O:13])C>>[CH3:7][CH:6]([CH:5]([CH3:8])[C:4](=[O:3])[CH3:9])[C:2](=[O:13])[CH3:1]
Reactant: Cc1oc(C)c(C)c1C
Reactant: CC(C)=O
Product: CC(=O)C(C)C(C)C(C)=O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
Compound 219A was made in accordance with the procedures described in Hancock et al. J. Org. Chem. 42,1850-1856 (1977) & Amarnath et al. J. Org. Chem., 60, 301-307 (1995). 2-Propanone (100 mL, 1.1 mol) was refluxed over PbO2 (26.7 g, 0.112 mol) for 28 h. After cooling to rt, the reaction mixture was filtered and the residue was washed with acetone. The filtrate was concentrated under reduced pressure to remove the acetone and then distilled at 20 Torr. The fraction that came over between 100-120° C. was collected to give 6.75 g (42.5%) of 3,4-dimethylhexane-2,5-dione as a light yellow oil.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=24)[N:17]=[CH:16][N:15]([C@H:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[OH:31])[C:14]3=[O:32])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:33][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:3][C:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=24)[N:17]=[CH:16][N:15]([C@H:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[OH:31])[C:14]3=[O:32])=[CH:6][CH:5]=1)([CH3:33])[CH3:2]
Reactant: CC(=O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 6-[(6-acetylpyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 10, 0.018 g, 0.042 mmol) in 1 mL of THF at 0° C. was added methylmagnesium bromide (0.035 mL, 3.0 M diethyl ether solution, 0.10 mmol). After 30 min, the mixture was treated with saturated aqueous ammonium chloride and extracted 2× with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 446.2067 for [M+H]+ [Calc'd for C26H28N3O4, [M+H]+=446.2074]: 1H NMR (400 MHz, CDCl3) δ 8.95-8.93 (m, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 7.85-7.81 (m, 2H), 7.67-7.60 (m, 2H), 7.39 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 4.89-4.80 (m, 2H), 4.33 (s, 2H), 4.25-4.04 (m, 3H), 3.60-3.57 (m, 1H), 3.36-3.28 (m, 1H), 2.30-2.15 (m, 1H), 2.02-1.98 (m, 1H), 1.47 (s, 6H).