Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:36]=[C:37]([CH2:41][N:42]([CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])C(=O)C(F)(F)F)[CH:38]=[CH:39][CH:40]=1>CC(O)C.Cl.C(Cl)Cl.CO>[CH3:52][N:51]([CH3:53])[CH2:50][CH2:49][NH:42][CH2:41][C:37]1[CH:36]=[C:35]([NH:34][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CN(C)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)O
Product: CN(C)CCNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1
Temperature: 180 °C
Yield: 24.2 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (75 mg, 0.16 mmol) (prepared according to a procedure similar to that described in Example 27, Step C) and N-[(3-aminophenyl)methyl]-N-[2-(dimethylamino)ethyl]-2,2,2-trifluoroacetamide (58 mg, 0.20 mmol) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The mixture was heated to 180° C. in a microwave for 25 min. The reaction mixture was diluted with 20 mL DCM and 5 mL MeOH, and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM, and the combined organic layers were dried over Na2SO4, filtered, and purified by flash chromatography to give the title compound (24 mg, 24% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.94 (s, 1H), 9.52 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.51 (d, J=9.2 Hz, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.74 (s, 1H), 7.46-7.60 (m, 4H), 7.36 (d, J=7.9 Hz, 1H), 7.26 (t, J=8.1 Hz, 2H), 7.12-7.21 (m, 2H), 6.92 (d, J=7.7 Hz, 1H), 6.53 (d, J=5.2 Hz, 1H), 3.66 (s, 2H), 2.54-2.57 (m, 2H), 2.27-2.33 (m, 2H), 2.08 (s, 6H). MS (ESI) m/z=620 [M+H]+.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([O:7][CH3:8])=[O:6].CO>O>[CH3:8][O:7][C:5](=[O:6])[C@H:4]([OH:3])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCC(O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCC[C@@H](O)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 4.9 %

Procedure:
Lipase P-30 (Amano from Pseudomonas fluorescens) (1 g, 5% by weight) was dissolved in 140 ml of H2O and the pH of the solution adjusted to 7.5 with a 1N solution of NaOH. Racemic methyl 2-hydroxydecanoate (20.12 g, 0.995 mol) (CP-112,994) was added to the enzyme solution and the pH controlled to maintain a range of 6-8. The reaction was stirred at room temperature for 10 hours (total of 46.5 mL of 1N NaOH added) and worked up by addition of 140 ml of methanol. The aqueous alcohol was extracted with hexane (3×200 mL). The hexane extracts were combined and dried (MgSO4). Following concentration, the desired (R)-methyl-2-hyroxydecanoate (10.08 g, 0.049 mol, 50%) was obtained: [α]D =-3.1° (c=1, MeOH). The aqueous extracts were acidified to pH 1-2 with HCl and extracted with two portions of ethyl acetate (200 mL). The combined extracts were dried (MgSO4) and concentrated to give (S)-2-hydroxydecanoic acid (8.91 g, 0.047 mol, 47%): mp 70°-72°; [α]D =-1.7° (c=1, MeOH).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[O:17])=[N:13][CH:14]=2)O1.Br[C:31]1[CH:36]=[CH:35][C:34]([C:37]2([O:41][CH2:42][C:43]([OH:45])=[O:44])[CH2:40][CH2:39][CH2:38]2)=[C:33]([F:46])[CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O.C(O)C.CN(C)C(=O)C>[F:46][C:33]1[CH:32]=[C:31]([C:9]2[CH:14]=[N:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:36]=[CH:35][C:34]=1[C:37]1([O:41][CH2:42][C:43]([OH:45])=[O:44])[CH2:40][CH2:39][CH2:38]1
Reactant: O=C(O)COC1(c2ccc(Br)cc2F)CCC1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCO
Product: O=C(O)COC1(c2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)nc3)cc2F)CCC1
Temperature: 90 °C

Procedure:
A 25 mL vial was charged with the product from Example 60C (459 mg, 1.128 mmol), the product from Example 60B (342 mg, 1.128 mmol), dibasic potassium phosphate (590 mg, 3.38 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium (II) dichloride (7.38 mg, 0.011 mmol), N,N-dimethylacetamide (4 mL), ethanol (4.00 ml) and water (2 mL). The suspension was stirred and heated to 90° C., whereupon the reaction became homogenous. After heating at 90° C. for 1 hour; the reaction was cooled to room temperature. The resulting suspension was poured into water (200 mL). The mixture was acidified to pH 1 with 1 M HCl. The solid was filtered, washed with water, and air-dried to give the title product. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62-1.71 (m, 1 H), 1.96-2.07 (m, 1 H), 2.39-2.49 (m, 4 H), 3.69 (s, 2 H), 7.38 (d, J=7.12Hz, 1 H), 7.47-7.61 (m, 4 H), 7.65-7.71 (m, 2 H), 8.07 (s, 1 H), 8.17 (dd, J=2.7 and 8.8 Hz, 1 H), 8.71 (d, J=2.7 Hz, 1 H), 9.68 (s, 1 H), 10.65 (s, 1 H), 12.5 (br s, 1 H). MS (ESI) m/z 504 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:12](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[CH:12][NH:9][C:4]=2[C:3]=1[O:10][CH3:11]
Reactant: O=CO
Reactant: COc1c(Br)ccc(N)c1N
Product: COc1c(Br)ccc2nc[nH]c12
Temperature: 100 °C

Procedure:
A 1 L four-necked round bottom flask fitted with a magnetic stirrer was dried and cooled under a stream of nitrogen then charged with 4-bromo-3-methoxy-benzene-1,2-diamine (61 g, 0.28 mol, 1.0 equiv.) in formic acid (200 mL). The reaction mixture was heated at 100° C. for 2 h, cooled and quenched with ice water (1 L). The reaction mixture was basified with 10% NaOH solution and extracted with ethyl acetate (2×1000 mL). The separated organic layers were combined, washed with brine solution (750 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (30-50% EtOAc) to afford 6-bromo-7-methoxy-1H-benzoimidazole (36 g, crude) as a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 4.26 (br, 3H), 7.16 (s, 1H), 7.29-7.32 (d, 1H), 8.19 (s, 1H), 12.67 (br, 1H).
Reaction SMILES: Cl.[C:2]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3].[C:23]([O:27][C:28](=[O:42])[CH2:29][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:31](O)=[O:32])([CH3:26])([CH3:25])[CH3:24].Cl.CN(C)CCCN=C=NCC.C1C=C2N=NN(O)C2=CC=1.O>CN(C=O)C.CCOCC.C(N(CC)CC)C>[C:23]([O:27][C:28](=[O:42])[CH2:29][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:31]([N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH:9]3[CH2:10][CH2:11][CH:6]([C:2]([CH3:5])([CH3:3])[CH3:4])[CH2:7][CH2:8]3)[CH:14]=2)[CH2:19]1)=[O:32])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C1CCC(Oc2ccc3c(c2)CCNC3)CC1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)CC(NC(=O)OC(C)(C)C)C(=O)N1CCc2cc(OC3CCC(C(C)(C)C)CC3)ccc2C1
Temperature: 50 °C
Yield: 64.4 %

Procedure:
A mixture of 6-(4-tert-butyl-cyclohexyloxy)-1,2,3,4-tetrahydro-isoquinoline HCl salt, (80 mg, 0.25 mmol), 2-tert-butoxycarbonylamino-succinic acid 4-tert-butyl ester (143 mg, 0.49 mmol), triethylamine (41 uL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol) and HOBT monohydrate (10 mg, 0.06 mmol) in DMF (2.0 mL) was heated at 50° C. for 4 hrs. The solution was diluted with ether and washed with water. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified via a silica gel column eluted with EtOAc in hexanes from 0 to 20% to give desired product (90 mg, yield: 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:22])([CH3:23])[CH2:19][OH:20])[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)CO)ccc2n1C

Procedure:
The above compound was prepared from 2-[3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methyl-propanoic acid and lithiumaluminium hydride using a procedure analogous to that of Example 125.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=3)[CH:18]=1)[N:9]=[C:8]2[NH:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:37]=[CH:36]2)(=O)C.[NH4+].[OH-]>CO>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=3)[CH:18]=1)[N:9]=[C:8]2[NH:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:37]=[CH:36]2
Reactant: COc1cc2nc(-c3cccc(NC(=O)c4cccnc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nc(-c3cccc(NC(=O)c4cccnc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-(nicotinamido)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.163 g, 0.299 mmol) in MeOH (15 mL) was added aq. NH4OH solution (0.12 mL). The mixture was stirred at RT for 24 h. The volatiles were removed in vacuo and the residue was triturated with Et2O and dried under vacuum to give tert-butyl 5-(6-hydroxy-7-methoxy-2-(3-(nicotinamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.102 g, 0.188 mmol, 63%). HPLC retention time 5.04 mins.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13](C#N)=[CH:12]1.[OH-].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15]([CH3:21])[CH:16]=[C:17]([CH3:20])[N:18]=2)[CH:13]=[CH:12]1
Reactant: Cc1cc(C)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(C)c2ccn(-c3ccc(C(C)C)cc3Br)c2n1
Yield: 65.7 %

Procedure:
A mixture of 4.00 g of 1(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole and 40 mL of 65% sulfuric acid was refluxed for one hour. The solution was cooled and poured onto ice. Conc. ammonium hydroxide was added until the mixture was alkaline to pH paper. The mixture was extracted with ethyl acetate. The solution was dissolved in 60:40 hexane-ethyl acetate and passed through a short column of silica gel. The eluate was evaporated, and the residue was crystallized from 20 mL of hexane to give 2.45 g (66% yield) of 1-(2-bromo-4-isopropylphenyl)-4,6-dimethyl-7-azaindole. Mass spec: (m+H)+ =343.0818; calculated, 343.0810. Rf =0.57 on silica gel with 70:30 hexane-ethyl acetate.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[N+:18]([C:21]1[N:25]=[CH:24][NH:23][N:22]=1)([O-:20])=[O:19]>CN(C=O)C.O>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([N:23]2[CH:24]=[N:25][C:21]([N+:18]([O-:20])=[O:19])=[N:22]2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: O=[N+]([O-])c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1-n1cnc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.9 %

Procedure:
To a stirring solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) were added K2CO3 (0.68 g, 4.95 mmol) and 3-nitro-1,2,4 triazole (0.45 g, 4.2 mmol) and the resultant reaction mixture was stirred at ambient temperature for 14 h. After completion of reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a pale yellow solid (0.36 g, 45%): mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.69 (s, 1H), 8.45 (d, J=9.3 Hz, 1H), 8.23 (d, J=9.3 Hz, 1H); ESIMS m/z 242.3 ([M−H]−); IR (thin film) 2238, 1705, 1551, 1314 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:17][C:21]2[C:30]3[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=3[F:31])[N:24]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:22]=2[CH3:39])[C:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1cc(-c2ncc(Br)cc2N)c(F)cn1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c(F)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-5′-fluoro-2′-methoxy-2,4′-bipyridin-3-amine (54.1 mg, 0.18 mmol) in dry DMF (3 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (22.1 mg, 0.55 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (55.7 mg, 0.19 mmol) was added in portions. Upon complete addition, the mixture was warmed to 70° C. After 18 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted 5 times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford a yellow residue as N-(5-bromo-5′-fluoro-2′-methoxy-2,4′-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine that was used without further purification.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH:8]1[C:18]2[CH:17]=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[C:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:45])[CH2:30][CH2:31][N:32]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])C(=O)OC(C)(C)C)[CH2:25][CH2:24]3)[C:12]=2[CH:11]=[CH:10][CH:9]=1>>[ClH:1].[CH:19]1[C:15]2[CH:16]=[CH:17][C:18]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13](=[C:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:45])[CH2:30][CH2:31][NH:32][CH2:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH2:27][CH2:28]3)[C:14]=2[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)CN(CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CNCCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 1 h

Procedure:
5 ml of 4 N hydrochloric acid/1,4-dioxane solution was added to 184.1 mg (0.357 mmol) of t-butyl 3-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-3-oxopropyl(neopentyl)carbamate, and they were stirred for 1 hour. The solvent was evaporated under reduced pressure. 5 ml of diethyl ether was added to the residue, and then 1 ml of 4 N hydrochloric acid/ethyl acetate solution was added thereto. The precipitates thus formed were taken by the filtration, washed with diethyl ether and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]([NH2:17])=[S:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:19]([CH:22]=O)[CH:20]=[O:21]>C1COCC1.C(O)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[S:16][C:19]([CH:20]=[O:21])=[CH:22][N:17]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC(Br)C=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(N)=S)C(=O)O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ncc(C=O)s1)C(=O)O
Temperature: 25 °C
Reaction time: 60 h
Yield: 39 %

Procedure:
To a solution of material from Example 112 (3.21 g, 12.19 mmol) in a mixture of THF (107 mL) and acetic acid (29 mL) is added 2-bromomalonaldehyde (3.29 g, 21.79 mmol). The resulting solution is stirred at room temp for 60 h. The reaction is diluted with water (71 mL) and the resulting slurry is stirred at room temp for 1.5 h. The slurry is extracted with EtOAc (3×300 mL), the organic layers combined, washed with brine (1×50 mL), dried over Na2SO4, filtered and evaporated to dryness. The resulting residue is purified by BIOTAGE® Silica gel chromatography on a 80 g Thompson Single Step silica cartridge using a linear gradient from 100% CHCl3 to 25% MeOH/CHCl3 over 9 column volumes to give 1.5 g (39%) of the title compound as an orange/yellow film, 1H NMR (500 MHz, methanol-d4) δ 9.65 (s, 1H), 7.97 (s, 1H), 4.49-4.37 (m, 1H), 3.93 (dd, J=13.9, 4.4 Hz, 1H), 3.72 (dd, J=14.0, 7.7 Hz, 1H), 1.45 (s, 914). LC/MS (Condition A): ret. T=2.46 min, (M+Na) 338.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[Te:4][C:5]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:6]=2[NH+:7]=1.C(=O)(O)[O-].[Na+]>C(OCC)C>[CH3:2][C:3]1[Te:4][C:5]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1ccc2[te]c(C)[nH+]c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2[te]c(C)nc2c1
Yield: 55.4 %

Procedure:
2,5-Dimethylbenzotellurazolium chloride (Example 14) (3.5 g) was treated in an aqueous suspension with sodium bicarbonate in excess of that stoichiometrically required. The free base product was isolated by extraction with diethyl ether and evaporation to dryness. The residue was recrystallized from ≃50 ml isopropanol to yield 1.7 g colorless needles, m.p. 126°-128° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=2[Cl:29])[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1>[C:23]1([S:20]([C:18]2[CH:17]=[CH:16][C:15]([Cl:29])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)(=[O:22])=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(S(=O)(=O)c3ccccc3)ccc2Cl)CC1
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)c1ccc(Cl)c(N2CCNCC2)c1
Temperature: 60 °C

Procedure:
4-(5-Phenylsulfonyl-2-chlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (D4B) was dissolved in 8 ml of 1,4-dioxane/4 M HCl 1:1. The mixture was heated at 60° C. for 1 h. The solvent was evaporated in vacuo to give the title product as a colourless solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=1)=[O:3].[Se](=O)=[O:13]>>[F:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[O:13])[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: CC(=O)c1cc(F)cc(F)c1
Reactant: O=[Se]=O
Product: O=CC(=O)c1cc(F)cc(F)c1
Yield: 85.6 %

Procedure:
(3,5-Difluorophenyl)(oxo)acetaldehyde (28 g, 84%) was prepared from 3,5-difluoro acetophenone (30.0 g, 192.3 mmol) and selenium dioxide (23.55 g, 214.0 mmol) according to the typical procedure used for Preparation 1.
Reaction SMILES: N[C@H](C(O)=O)CCC(=[O:7])N.CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:59][C@@H:60]2[O:65][C@@H:64]([CH2:66][OH:67])[C@H:63]([OH:68])[C@@H:62]([OH:69])[C@@H:61]2NC)[C@@]1(O)C=O>>[O:67]=[CH:66][C@@H:64]([C@H:63]([C@@H:62]([C@@H:61]([CH2:60][OH:59])[OH:7])[OH:69])[OH:68])[OH:65]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Differentiated adipocytes were incubated for a period of 3 days in DMEM (containing 2 mM L-glutamine, 100 iu/ml penicillin, 100 μg/ml streptomycin, 1 nM insulin and 10% FCS) supplemented with or without CLA and/or compound As. The cells were then washed three times with DMEM (containing 1 mM deoxyglucose). Insulin stimulated glucose uptake was carried out according to Iwata et al (Diabetes 2001 50: 1083-1092). Briefly, cells were stimulated with 1 nM insulin in Krebs Ringer Phosphate (KRP) and HEPES buffer [10 mM HEPES, 131.2 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO4, 2.5 mM sodium phosphate buffer, pH 7.4] with 1% BSA at 37° C. After 1-30 minutes the assay was initiated by addition of 10 μl KRP containing 2.5 μCi [3H]2deoxyglucose and 1 mM deoxyglucose. After 1 hr the reaction was terminated by washing the cells 3× with ice-cold DMEM. Cells were then solubilised with 500 μl/well of 1% Triton X-100, 0.2% SDS and 0.2N NaOH for 20 minutes at 37° C. Radioactive incorporation was measured by scintillation counting of 100 μl of each cell lysate.
Reaction SMILES: O[CH:2]([CH2:17][OH:18])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[N:12]=2)[CH2:7][CH2:6][C:5]1=[O:16].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[CH3:15][O:14][C:11]1[N:12]=[C:13]2[C:8]([CH2:7][CH2:6][C:5](=[O:16])[N:4]2[CH2:3][CH:2]2[CH2:17][O:18]2)=[CH:9][CH:10]=1
Reactant: COc1ccc2c(n1)N(CC(O)CO)C(=O)CC2
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(n1)N(CC1CO1)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
A solution of 1-(2,3-dihydroxypropyl)-7-(methyloxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (2.325 g, 9.226 mmol) in DCM (40 ml) and triethylamine (1.915 ml, 13.839 mmol) at 0° C. under argon was treated with methanesulfonyl chloride (0.714 ml, 9.226 mmol) and stirred at 0° C. for 0.5 h. The reaction mixture was then treated with water (100 ml), extracted with DCM (3×100 ml). The organic extracts were dried (MgSO4), and evaporated. The residue was then dissolved in methanol (50 ml) and treated with potassium carbonate (6.366 g, 46.130 mmol) and stirred at rt for 15 min. The reaction mixture was then treated with water (100 ml), extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), evaporated and chromatographed (0-100% ethyl acetate:Hexane) to give the product as a yellow oil (428 mg, 20%).