Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])(=[O:4])[CH2:2][OH:3].[OH-].[K+].Cl>CO.O>[C:1]([CH:5]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])[CH2:2][OH:3]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)OCC)C(=O)CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(=O)CO

Procedure:
A clear, yellow solution of ethyl 8-glycoloyl-12 -hydroxyheptadecanoate (7.9 g., 0.02 mole) and potassium hydroxide (2.24 g., 0.04 mole) in 90% aqueous methanol (50 ml.) is stirred at 25° under nitrogen for 20 hours. The reaction solution is evaporated in vacuo at 40° leaving a residual red oil which is dissolved in water (200 ml.). The resulting solution is acidified with concentrated hydrochloric acid (10 ml.) and extracted with ether (2 × 200 ml.). The organic extract is washed with saturated brine (2 × 200 ml.), dried over sodium sulfate, filtered and evapoated in vacuo at 40°-50° providing the title compound as a slightly impure, deep yellow oil (6.3 g., 92%).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:46][C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[N:49]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[N:48]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[C:59]([O:58][C:56]([N:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:47]([CH2:46][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:4]2=[O:34])=[N:48]1)=[O:57])([CH3:62])([CH3:61])[CH3:60]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 427 mg of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 5 mL of dry DMF at 0° C. is added 2.2 mL of a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene. The reaction mixture is stirred for 30 min at 0° C. and a solution of 311 mg of 3-Bromomethyl-1-tert-butoxycarbonyl indazole, prepared as in Intermediate 1, in 2 mL of dry DMF is added dropwise. The reaction mixture is stirred overnight at rt, poured into water and the product extracted with ethyl acetate (2×15 mL). The solvent is removed in vacuo and the residue is purified by silica gel flash column chromatography (MeOH 1% CHCl3 99%) to afford 420 mg of the title compound: 1H NMR (400 MHz, CDCl3) δ8.03 (d, 1H, J=8.3), 7.86 (d, 1H, J=8.0), 7.51-7.18 (m, 14H), 7.10 (m, 1H), 6.94 (m, 1H), 5.02 (m, 1H,J=6.8), 4.32 (dd, 1H, J=8.9, 4.7), 4.24 (d, 1H, J=16.4), 4.22 (d, 1H, J=16.4), 3.85 (dd, 1H, J=16.5, 8.9), 3.53 (dd, 1H, J=16.5, 4.7), 1.64 (s, 9H), 1.07 (d, 6H, J=6.8).
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)c(OC)cc21
Yield: 32 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (51 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine were combined to prepare the title compound (32 mgs, 32%) as a white foam. 1H-NMR (CDCl3): δ 10.24 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.85 (d, J=14.4 Hz, 2H), 7.56 (s, 1H), 7.43-7.37 (m, 2H), 7.23 (t, J=7.6 Hz, 1H), 6.71 (s, 1H), 6.53 (s, 1H), 3.91 (s, 3H), 2.68-2.54 (m, 1H), 2.28 (broad s, 2H), 2.17-2.09 (m, 1H), 1.27 (brad s, 2H), 1.18 (t, J=7.1 Hz, 3H). LC/MS: found (M+H)+=504.24; MP: 82-85° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCCCCC>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCOc1ccc2ccccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCCCCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 57.5 %

Procedure:
Mitsunobu coupling is carried out as follows: 4-hydroxybenzaldehyde (0.92 g), 6-(2-naphthyloxy)hexanol (1.83 g), and triphenylphosphine (1.97 g) are dissolved in THF (25 ml) and cooled to 15° . Diethyl azodicarboxylate (1.2 ml) is added dropwise, and the mixture stirred at room temperature for 60 hrs. The reaction mixture is diluted with hexane and filtered to remove solids. The filtrate is concentrated and chromatographed with 25% v/v hexane in dichloromethane to provide 4-[6-(2-naphthyloxy)hexyloxy] benzaldehyde (1.5 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=O)[CH:3]=1.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[C:14]=1C.O.Cl[C:24]1C=CC=CC=1Cl>>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=2[CH3:24])[C:12]([O:11][CH3:10])=[O:21])[C:4](=[O:5])[CH:3]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: COC(=O)c1cccc(N)c1C
Reactant: Clc1ccccc1Cl
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(O)cc2=O)c1
Temperature: 110 °C
Yield: 40 %

Procedure:
4-Hydroxy-6-methyl-2-pyrone (22.9 g, 181.6 mmol) and methyl-3-amino-2-methylbenzoate (25 g, 151.3 mmol) were suspended in 50 ml of 1,2-dichlorobenzene in a 250 ml, 3-necked round bottom flask equipped with a J-Kem temperature controller probe, a Dean-Stark trap, and a heating mantle. The reaction was heated to 165° C. for 15 minutes, during which, water and some 1,2-dichlorobenzene was collected in the Dean Stark trap. The reaction was allowed to cool to about 110° C. At this point, 200 ml of toluene was added. The flask was plunged into a 0° C. ice bath while stirring. “Oiling out” occurred. Perhaps too much toluene was added so some of the solvent was removed in vacuo. The oil went back into solution and a light brown precipitate remained. The toluene mixture was allowed to stir for 72 hours at room temperature. A precipitate was collected on a filter pad. The precipitate was filtered and washed 3 Limes with toluene, 3 times with 50° C. water to remove excess pyrone, and dried in vacuo to give a tan solid (16.5 g, 40% yield). 1H NMR (300 MHz, CD3OD) δ 8.06 (dd, J=8.06, 1.61 Hz, 1H), 7.80 (d, J=1.61 Hz, 1H), 7.56 (d, J=3.06, Hz, 1H), 6.15 (dd, J=2.42, 0.81 Hz, 1H), 5.86 (d, J=2.42 1H), 3.94 (s, 3H), 2.15 (s, 3H), 1.91 (s, 3H); ES-MS m/z 274 (M+H). ES-HRMS m/z 274.1066 (M+H calcd for C15H16NO4 requires 274.1074).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[S:25])[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2C(OCC)=O)=[C:4]([F:26])[CH:3]=1>[OH-].[K+]>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([NH:12][C:13](=[S:25])[N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)=[C:4]([F:26])[CH:3]=1
Reactant: CCOC(=O)N1CCCCN1C(=S)Nc1cc(OC(C)C)c(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Product: CC(C)Oc1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of ethyl 2-(4-chloro-2-fluoro-5-(1-methylethoxy)phenylaminothioxomethyl)-3,4,5,6-tetrahydro-1(2H)pyridazinecarboxylate (0.8 g) in a 5% ethanolic potassium hydroxide solution (10 ml) was heated under reflux for 3 hours. After being allowed to cool to room temperature, ethanol was removed under reduced pressure. The residue was dissolved in ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 0.3 g of 2-(4-chloro-2-fluoro-5-(1-methylethoxy)phenylaminothioxomethyl)- 3,4,5,6-tetrahydro-(1H,2H)-pyridazine. M.P., 113°-114.5° C. NMR δ (ppm): 1.35 (6H, d), 1.7 (4H, m), 2.95 (2H, m), 3.45 (1H, t), 4.2 (2H, m), 4.4 (1H, m), 6.95 (1H, d), 8.25 (1H, d), 9.85 (1H, m).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O.[Na].C(OCC)(=O)[CH2:27][C:28]([C:30](OCC)=[O:31])=[O:29]>>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=2)[C:30](=[O:31])[CH:28]([OH:29])[CH2:27]1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: COc1cccc(F)c1C=O
Agent: [Na]
Product: COc1cccc(F)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to general procedure 10A (GP10A) and general procedure 10B (GP10B) using commercially available (4-(trifluoromethoxy)phenyl)methanamine, commercially available 2-fluoro-6-methoxybenzaldehyde, and commercially available diethyl oxalacetate sodium salt. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 400.22 g/mol.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.CN(C1C=CC=CN=1)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[O:12]=[C:5]1[CH:6]2[CH2:7][CH:8]3[CH2:9][C:2]([O:1][C:22](=[O:24])[CH3:23])([CH2:3][CH:4]1[CH2:10]3)[CH2:11]2
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(=O)OC12CC3CC(C1)C(=O)C(C3)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 5-hydroxy-2-adamantanone (2.6 g, 15.66 mmoles) in dichloromethane (DCM)(50 mL) was treated with dimethylaminopyridine (DMAP)(2.1 g, 17 mmoles) and acetic anhydride (2.3 mL, 23 mmoles) and stirred overnight at 50° C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as an off-white solid.
Reaction SMILES: [C:1]1([SnH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:17][CH:18]=[CH2:19])(=[O:16])[CH3:15]>C1CCCCC1>[C:14]([O:17][CH2:18][CH2:19][Sn:7]([CH2:19][CH2:18][O:17][C:14](=[O:16])[CH3:15])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:16])[CH3:15]
Reactant: c1ccc([SnH2]c2ccccc2)cc1
Reactant: C=COC(C)=O
Solvent: C1CCCCC1
Product: CC(=O)OCC[Sn](CCOC(C)=O)(c1ccccc1)c1ccccc1

Procedure:
Diphenyltin dihydride and vinyl acetate were introduced in stoichiometric amount into a Pyrex® tube containing anhydrous cyclohexane. The reaction mixture was exposed to ultraviolet rays for 1 hour at 30° C. The solvent was then removed under vacuum at ambient temperature. The product, obtained quantitatively, had the following formula:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:35]([Si:39]([CH3:50])([CH3:49])[O:40][CH2:41][CH2:42][N:43]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44]1)([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:35]([Si:39]([CH3:50])([CH3:49])[O:40][CH2:41][CH2:42][N:43]1[CH:47]=[CH:46][C:45]([NH:48][C:8](=[O:10])[C@@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:44]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(O)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionic acid (92 mg, 0.32 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 190 μL, 0.35 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (80 μL, 0.64 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 78 mg, 0.32 mmol) in methylene chloride (1 mL) and the reaction was allowed to warm up to 25° C. and stirred for 2 h. After this time the reaction quenched with a small amount of methanol and then diluted with methylene chloride. The reaction was then transferred to a separatory funnel and washed with 1 N aqueous hydrochloric acid solution (1×10 mL) and then a saturated brine solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40M column, silica gel, 40% ethyl acetate/hexanes) (40S column, Silica gel, 20% ethyl acetate/hexanes) to afford N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionamide as a colorless gum: [α]25589=−14.5° (c=0.22, methanol); ES-HRMS m/e calcd for C26H38N3O2SiF3 (M+H)+ 510.2758, observed 510.2749; 1H NMR (400 MHz, DMSO-d6) δ ppm −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.06-1.18 (m, 2H, CH2), 1.37-1.79 (m, 8H, 4×CH2), 2.08-2.18 (m, 1H, CH), 3.84 (t, J=5.1 Hz, 2H, OCH2), 3.90 (dd, J=9.4, 5.3 Hz, 1H, ArCH), 4.04 (t, J=5.1 Hz, 2H, NCH2), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.54-7.72 (m, 4H, Ar), 10.72 (s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][CH:11]([CH2:15][CH3:16])[CH:12]([OH:14])[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27].[H-].[Na+].[CH2:31]1COCC1>>[CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][CH:11]([CH2:15][CH3:16])[CH:12]([O:14][CH3:31])[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27]
Reactant: C1CCOC1
Reactant: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)O
Agent: [H-]
Agent: [Na+]
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinic acid methyl ester (50 mg, 0.123 mmol) in dry THF was added NaH and stirred for 20 min. An excess of Mel was added and the resulting mixture was stirred at rt overnight. The mixture cooled to rt and quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give an oil. The oil was purified through silica gel column chromatography using 20% ethyl acetate in hexane as an eluent to give the title compound as a clear oil. 1H NMR(CDCl3) d 8.20(d, 1H), 7.00(s, 2H), 6.14&6.10(two sets of s, 1H), 3.859s, 3H), 3.47(m, 1H), 3.39&3.37(two set of s, 3H), 2.08(s, 3H), 2.06(s, 6H), 1.75(m, 1H), 1.58(m, 1H), 1.14(t, 3H), 0.95(t, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=[N:9][OH:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[F:1][C:2]1[C:3]([C:8]([Cl:11])=[N:9][OH:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ON=Cc1ncccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ncccc1F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoropicolinaldehyde oxime (1.0 g, 7.1 mmol) in DMF (15.8 mL) was added N-chlorosuccinimide (1.05 g, 7.85 mmol). The r×n was heated to 50° C. After 30 min, the r×n was added to ice water and extracted with EtOAc. The collected organic layers were washed with H2CO (2×50 mL), brine (30 mL), dried (MgSO4) and filtered. Concentration provided 3-fluoro-N-hydroxypicolinimidoyl chloride as a yellow solid, which was taken through to the next step.
Reaction SMILES: Cl[Sn]Cl.[N+:4]([C:7]1[C:8]([NH2:16])=[N:9][CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13])([O-])=O.N.C(O)(=O)C>Cl>[NH2:4][C:7]1[C:8]([NH2:16])=[N:9][CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Solvent: CC(=O)O
Product: Nc1cc(C(=O)O)cnc1N
Temperature: 100 °C

Procedure:
See Markwald, W. Chem. Ber. 1984, 27, 1317. To a stirred solution of SnCl2 (4.16 g, 22.0 mmol) in concentrated HCl (11 mL) at 0° C. was added in portions 5-nitro-6-aminonicotinic acid (1.01 g, 5.5 mmol). The resulting orange mixture was then heated to 100° C. under argon for 75 min. The mixture was then cooled to RT and was then placed in an ice bath and neutralized with concentrated aqueous ammonia (to pH 6-7), resulting in a thick cream-colored mixture. The mixture was then acidified to pH 4 with acetic acid and the precipitate collected by filtration, washed with H2O and dried under vacuum overnight to afford the title compound:
Reaction SMILES: [OH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:33])[C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[C:18]([NH:30][CH:31]=[O:32])[CH:17]=2)=[CH:7][CH:6]=1.C>C(O)C>[OH:1][C@H:2]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:33])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:30][CH:31]=[O:32])[CH:17]=2)=[CH:7][CH:6]=1
Reactant: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1OCc1ccccc1
Solvent: CCO
Product: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
Intermediate 6 (2.5 g, 4.8 mmol) was dissolved in 8.0 mL of ethanol and treated with activated charcoal, Darco G-60 (1.25 g). The suspension was stirred at 50° C. for 20 min and then filtered to remove the Darco. To the filtrate was added 10% palladium on activated carbon (250 mg) and the suspension placed on a Parr shaker. The reaction was shaken for 10 h under 30 psi hydrogen gas. The reaction was filtered through celite and concentrated under vacuum to afford compound 1 as a brown gelatinous solid (1.9 g, 4.3 mmol, 91%). 1H NMR (300 MHz, DMSO-d6) δ 2.40-2.68 (m, 6H), 2.92-3.18 (m, 2H), 4.35-4.45 (m, 1H), 4.60-4.69 (m, 1H), 5.22-5.30 (m, 1H), 6.82 (s, 1H), 6.85 (s, 1H), 6.68-6.86 (m, 4H), 7.12-7.36 (m, 5H), 7.95 (d, 1H, J=1.4 Hz), 8.19 (s, 1H), 9.49 (br s, 1H). m/z: [M+H+] calcd for C25H29N3O4 436.2. found 436.4.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][OH:28])=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][CH:33]=[N:34][C:16]1=2)[CH3:14].O[C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][CH:43]=2)[CH:39]=[CH:40][CH:41]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][O:28][C:40]3[CH:39]=[C:38]([C:42]4[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][CH:43]=4)[CH:37]=[CH:36][CH:41]=3)=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][CH:33]=[N:34][C:16]1=2)[CH3:14]
Reactant: COC(=O)c1ccc(-c2cccc(O)c2)cc1
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3cccc(-c4ccc(C(=O)OC)cc4)c3)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
A solution of DEAD (84 μL, 0.54 mmol) in THF (0.5 mL) was added over 2 h to an ice-cold solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (100 mg, 0.34 mmol), methyl 3′-hydroxy-[1,1′-biphenyl]-4-carboxylate (123 mg, 0.54 mmol) and PPh3 (141 mg, 0.54 mmol) in THF (3.4 mL). The reaction mixture was stirred at 25° C. for 12 h then concentrated under reduced pressure. The residue was purified by flash chromatography (toluene:EtOAc, 85:15) to give the title compound (74 mg, 43% yield) as white gummy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([C:25]1([CH2:28][CH2:29][CH3:30])[CH2:27][O:26]1)[CH2:23][CH3:24]>CCO.O>[OH:26][C:25]([CH2:28][CH2:29][CH3:30])([CH2:22][CH2:23][CH3:24])[CH2:27][NH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC1(CCC)CO1
Reactant: Nc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Solvent: CCO
Solvent: O
Product: CCCC(O)(CCC)CNc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
To a stirred solution of 2-(3-(3-aminophenyl)propyl)isoindoline-1,3-dione (0.50 g, 1.78 mmol) in EtOH:H2O (9:1), 2,2-dipropyloxirane (0.45 g, 3.57 mmol) was added and the reaction mixture was stirred under reflux for 36 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave 2-(3-(3-(2-hydroxy-2-propylpentylamino)phenyl)propyl)isoindoline-1,3-dione as a yellow semisolid. Yield (0.22 g, 30%); 1H NMR (400 MHz, DMSO-d6) δ 7.86-7.81 (m, 4H), 6.92 (t, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.41 (d, J=8.0 Hz, 1H), 6.37 (d, J=7.6 Hz, 1H), 4.89 (bs, 1H), 4.16 (s, 1H), 3.59 (t, J=7.2 Hz, 2H), 2.87 (d, J=5.2, 2H), 2.46-2.50 (m, 2H), 1.83-1.90 (quintet, J=7.2 Hz, 2H), 1.42-1.38 (m, 4H), 1.28-1.24 (m, 4H), 0.84 (t, J=7.2 Hz, 6H).