Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].C(O)(=O)C.[CH2:18]([O:25][C:26]1[CH:33]=[C:32]([I:34])[CH:31]=[CH:30][C:27]=1[CH:28]=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([BH3-])#N.[Na+]>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:33]=[C:32]([I:34])[CH:31]=[CH:30][C:27]=1[CH2:28][NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:11][CH:10]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCOc1cc(I)ccc1C=O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCCCCOc1cc(I)ccc1CNc1ccc(CC(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A solution of ethyl(4-aminophenyl)acetate (1.76 g, 9.84 mmol) and acetic acid (0.71 ml) in DMF (71 ml) is added to a solution of 2-heptyloxy-4-iodobenzaldehyde of Step c (3.1 g, 8.94 mmol), acetic acid (0.71 ml) in DMF (71 ml). The mixture is stirred for 12 hours and then 1.12 g of sodium cyanoborohydride (17.89 mmol) is added. The mixture is heated at 60° C. for 4 hours. The desired product is extracted by addition of ethyl ether. The organic phase is washed with brine and then with water, dried with magnesium sulfate and concentrated using a rotary evaporator. The product is purified by chromatography on a silica column, eluted with a heptane/ethyl acetate 9:1 mixture. After evaporation of the solvents, 4.11 g (96%) of the expected compound are recovered in the form of a yellow oil.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18](=[O:20])[CH3:19])[CH:14]=1>C1COCC1>[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18]([OH:20])([C:1]#[CH:2])[CH3:19])[CH:14]=1
Reactant: CC(=O)c1cc(COC2CCCCO2)on1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cc(COC2CCCCO2)on1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of ethynylmagnesium bromide (2.93 mL of a0.5M solution in THF, 1.47 mmol) at 0° C. was slowly added 1-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}ethanone (220 mg, 0.98 mmol) in THF (5 mL). The reaction mixture was allowed to warm to RT and stirred for 45 minutes. The reaction mixture was quenched with aqueous saturated NH4Cl solution (10 mL) and the organics were removed in vacuo. The product was extracted into EtOAc (20 ml×2) and the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute column, 10-30% EtOAc in heptanes) to give the title product as a pale yellow oil: 1H NMR (250 MHz, CDCl3) delta 1.93-1.40 (9H, m), 2.66 (1H, s), 2.85 (1H, s), 3.69-3.46 (1H, m), 3.93-3.79 (1H, m), 4.94-4.54 (3H, m), 6.38 (1H, s); LC-MS: m/z=+251.95 (M+H)+.
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH3:8][C:9]([CH3:11])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:8][C:9]1([CH3:11])[O:6][C@@H:2]([CH2:3][CH2:4][OH:5])[CH2:1][O:7]1
Reactant: OCC[C@H](O)CO
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OC[C@H](CCO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To (S)-(−)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml) and p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) were added and the mixture was stirred at room temperature overnight. To the reaction mixture, triethylamine (4 ml) was added and the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel 350 g, elution solvent: ethyl acetate/heptane=18/82→6/4) to obtain the title compound (30.2 g, yield: 73%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[CH:19]([N:22](C(C)C)[CH2:23][CH3:24])(C)[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>CN(C=O)C>[CH2:19]([N:22]([CH2:23][CH3:24])[C:8]([C:6]1[N:7]=[C:2]([NH2:1])[C:3]2[N:4]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=1)=[O:10])[CH3:20]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nc(C(=O)O)cn2nc(-c3ccco3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cn2nc(-c3ccco3)nc2c(N)n1

Procedure:
A solution of 8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid (20 mg, 0.082 mmol; see Example 8 above), diisopropylethylamine (14 μL, 0.082 mmol), HATU (47 mg, 0.123 mmol), and diethylamine (0.163 mmol) in DMF (300 μL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was purified by HPLC (C18, H2O:MeCN gradient). 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=6.9 Hz, 6H), 3.41 (m, 4H), 6:76 (dd, J3.4, 1.7 Hz, 1H), 7.18 (dd, J=3.4, 0.7 Hz, 1H), 7.69 (br. s, 2H), 7.96 (dd, J=1.7, 0.7 Hz), 8.34 (s, 1H). MS: m/z 301 (M+1).
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC.[CH2:39]([N:45]1[CH2:50][CH:49]2[CH:47]([C:48]2([C:52]2[CH:57]=[CH:56][CH:55]=[C:54](I)[CH:53]=2)[CH3:51])[C:46]1=[O:59])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:39]([N:45]1[CH2:50][CH:49]2[CH:47]([C:48]2([CH3:51])[C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:53]=2)[C:46]1=[O:59])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(I)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
To tris(dibenzylideneacetone)dipalladium (0) (4.4 mg, 4.80 μmol) in tetrahydrofuran (1 ml) at room temperature was added triphenylarsine (5.9 mg, 19.2 μmol). After 5 min, 2-(tributylstannyl)pyridine (0.10 g, 0.29 mmol) in tetrahydrofuran (1 ml) was added followed by 3-hexyl-6-(3-iodophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 67, 77 mg, 0.19 mmol) in tetrahydrofuran (1 ml). The reaction mixture was stirred at room temperature for 16 h and then refluxed for 2 h. The cooled reaction mixture was concentrated in vacuo and chromatographed on silica gel eluting with hexane:ethyl acetate (1:1 then 0:1) to give the title compound as a colourless oil (67 mg, 100%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][CH:15]=[N:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C1COCC1>[CH3:24][C:22]1[CH:23]=[C:19]([NH:18][C:2]2[C:3]3[CH:17]=[CH:16][CH:15]=[N:14][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=2)[NH:20][N:21]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1nc(-c2ccccc2)nc2ncccc12
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(-c3ccccc3)nc3ncccc23)[nH]n1
Temperature: 65 °C
Yield: 50.7 %

Procedure:
To a solution of 4-chloro-2-phenyl-pyrido[2,3-d]pyrimidine (J. Pharm. Belg., 29, 1974, 145–148) (109 mg, 0.45 mmol) in THF (15 mL) was added 3-amino-5-methyl pyrazole (48 mg, 0.5 mmol) and the resulting mixture heated at 65° C. overnight. The mixture was cooled to room temperature and the resulting suspension was filtered and washed with Et2O. The solid was dissolved in a mixture EtOH:water and the pH adjusted to pH 7. The aqueous was extracted twice with ethyl acetate and the combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, DCM-MeOH gradient) to afford IV-31 as an off-white solid (69 mg, 50%): mp 234° C.; 1H NMR (DMSO) δ 2.14 (3H, s), 5.99 (1H, s), 7.20–7.40 (3H, m), 7.40–7.50 (3H, m), 8.60 (1H, d), 8.79 (1H, d), 12.82 (1H, br s); IR (solid) 2957, 2921, 2857, 1644, 1560, 1459, 1427; MS 303.2 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH2:18][C:12]=2[CH:11]=[CH:10][CH:9]=1>C(#N)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH2:18][C:12]=2[CH:11]=[CH:10][C:9]=1[N+:1]([O-:4])=[O:2]
Reactant: COc1cccc2c1CCCC(=O)C2
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34.6 %

Procedure:
To potassium nitrate in acetonitrile (50 mL) and trifluoroacetic anhydride (100 mL) at 0° C. was added dropwise 1-methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one (25 g, 0.131 mol) in 50 mL acetonitrile. The reaction was stirred for 2.5 hours while warming to RT. The reaction was concentrated without heat on a rotary evaporator. MeOH was added and stirred briefly. Reconcentrated and worked-up by partitioning between dichloromethane and sat. sq. sodium bicarbonate solution. The organic layer was separated and dried (Mg2SO4), concentrated and purified by chromatography ISCO (330 g silica cartridge: gradient elution−10 to 50% EA:HEX over 60 minutes) affording two isomers. The title compound was the later eluting (10.7 grams, 34.6% yield). 1H-NMR (400 MHz, CDCl3) 7.70 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 2H), 3.13-3.09 (m, 2H), 2.60 (t, J=7.0 Hz, 2H), 2.10-2.03 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCOc1ccc(-c2ccc(O)cc2)cc1

Procedure:
20.0 g (0.107 mol) of 4,4′-dihydroxybiphenyl, 10.0 g (0.070 mol) of 3-bromo-1-propanol and 15.0 g (0.109 mol) of potassium carbonate are heated under reflux in 300 ml of acetone for 16 h. The batch is subsequently filtered, and the filtrate is evaporated. The residue is taken up in MTB ether, washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is chromatographed on silica gel with toluene/ethyl acetate (1:1). Crystallisation from toluene/ethyl acetate gives 4′-(3-hydroxypropoxy)biphenyl-4-ol as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[C:4]([F:19])[CH:3]=1.C1(C)C=CC=CC=1>[Pd].CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[C:4]([F:19])[CH:3]=1
Reactant: CCCC1CCC(C=Cc2ccc(Br)cc2F)CC1
Agent: [Pd]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCC1CCC(CCc2ccc(Br)cc2F)CC1
Yield: 75.5 %

Procedure:
A mixture of compound (75) (75.0 g, 231.0 mmol) and 5%-palladium on carbon (0.5% sulfur, 50% water-containing article) (2.82 g, 3 wt %) was agitated for 18 hours under a hydrogen atmosphere in a toluene (300 mL)-IPA (100 mL) solvent. The reaction mixture was filtered and a solvent of a filtrate was distilled off by an evaporator. The residue was passed through silica gel column chromatography and recrystallized from heptane-ethanol, and thus 4-bromo-2-fluoro-1-(2-(4-propylcyclohexyl)ethyl)benzene (76) (57.1 g, yield 75.5%) was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C([O-])([O-])=O.[K+].[K+].Br[CH:17](Br)[CH3:18]>CC(C)=O.O>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH2:18][CH2:17]1
Reactant: CNc1ccccc1O
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN1CCOc2ccccc21
Reaction time: 22 h
Yield: 85.1 %

Procedure:
0.97 g of 2-(N-methylamino)-phenol were dissolved in 50 ml acetone, followed by the addition of 2 g of K2CO3 dissolved in water. To this suspension was added slowly a solution of 2.66 g of dibromoethane in acetone. The reaction mixture was stirred for 22 hours under reflux. Acetone was evaporated and 200 ml of EtOAc were added and the organic layer was washed 3× with 0.1N HCl and 3× with brine. The remaining organic layer was dried over MgSO4 and filtrated. EtOAc was removed under reduced pressure affording 1 g of pure 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:19](Cl)(=[O:24])[CH2:20][CH2:21][CH:22]=[CH2:23]>C1COCC1.O>[CH2:7]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:24])[CH2:20][CH2:21][CH:22]=[CH2:23])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: C=CCCC(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of (4R)-4-(phenylmethyl)-1,3-oxazolidin-2-one (50 g, 282 mmol) in THF (300 mL) was dropwise added n-BuLi in THF (2.4 M, 176 mL, 423 mmol) under nitrogen at −78° C., and the resulting mixture was stirred at −78° C. for 1 hour. Then 4-pentenoyl chloride (49 mL, 423 mmol) was dropwise added. After stirring at −78° C. for another 1 hour, the reaction mixture was allowed to warm up to room temperature and stirred overnight. After diluting with water, the mixture was extracted with ethyl acetate (2×400 mL). The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to afford the title compound (68 g, 93%) as a light yellow oil. MS (ES+) C15H17NO3 requires: 259, found: 260 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:32])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Reactant: NC1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)c1c(O)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Yield: 78.7 %

Procedure:
Cyclohexylamine (2.95 mL, 25.78 mmol) was added to a solution of Compound 39 (4.4 g, 12.89 mmol) in toluene (50 mL) and refluxed for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 4.0 g (78%) of white solids. M.P. 130–134° C. 1H NMR (DMSO-d6): δ 1.37 (m, 5H), 1.56 (m, 1H), 1.67 (m, 2H), 1.88 (m, 2H), 3.87 (m, 1H), 5.29 (s, 2H), 7.17 (m, 2H), 7.23 (m, 1H), 7.33 (m, 1H), 7.46 (dd, J=3.9, 9.1 Hz, 1H), 7.57 (td, J=2.9, 8.3 Hz, 1H), 7.81 (dd, J=2.9, 8.8 Hz, 1H). EIMS m/z 394 (M+1).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[S:3].Cl[CH2:17][CH:18]=O>C(O)C>[S:3]1[CH:18]=[CH:17][N:4]=[C:2]1[NH:1][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=CCCl
Reactant: CS(=O)(=O)Nc1cccc(NC(N)=S)c1
Solvent: CCO
Product: CS(=O)(=O)Nc1cccc(Nc2nccs2)c1
Yield: 93.4 %

Procedure:
N-(3-thioureidophenyl)methanesulfonamide 54 (1.14 g, 4.65 mmol) and 50% aq. chloroacetaldehyde solution (3.65 mL, 23.25 mmol) were taken into ethanol and refluxed for 2 hours. Reaction mixture was concentrated and aq. Saturated NaHCO3 was added. Resulting light brown solid was filtered and washed with water, dried under high vacuum to obtain N-(3-(thiazol-2-ylamino)phenyl)methanesulfonamide 55 (1.17 g, 93% yield). Resulting product was further used without further purification. MS (ES) m/z 270 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6]1)[OH:4].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C1COCC1>[CH3:10][C:7]1([CH3:11])[O:6][C@@H:5]([C@@H:3]([OH:4])[CH2:2][NH:1][C:13](=[O:12])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][O:8]1
Reactant: CC1(C)OC[C@H]([C@@H](O)CN)O1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H](O)[C@H]1COC(C)(C)O1

Procedure:
Aminoalcohol 23 was dissolved in THF and BOC2O was added and stirred for several hrs. The solvent was removed and the product purified using silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH3:24][N:25]1[C:29]([Sn](CCCC)(CCCC)CCCC)=[CH:28][N:27]=[C:26]1[CH:43]=[O:44].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:29]3[N:25]([CH3:24])[C:26]([CH:43]=[O:44])=[N:27][CH:28]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C=O)n1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cnc(C=O)n4C)sc23)c(Cl)cc1Cl
Temperature: 110 °C
Yield: 52.2 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (443.2 mg, 0.93 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole-2-carbaldehyde (743.1 mg, 1.86 mmol), dichlorobis(triphenylphosphine)palladium(II) (33.0 mg, 0.047 mmol) and triethylamine (103.2 mg, 1.02 mmol) in 8.0 mL of 1,4-dioxane is heated at 110° C. for 3 hours. After cooling, the mixture is treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in dichloromethane to 50% ethyl acetate in dichloromethane to provide 222.7 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(2-formyl-1-methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 225–227° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 4.08 (d, 3H), 7.41 (s, 1H), 7.63 (s, 1H), 7.77 (s, 1H), 7.90 (s, 1H), 8.67 (s, 1H), 9.77 (s, 1H), 9.87 (s, 1H); MS 458.1, 460.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:10])([C:5]([F:9])([F:8])[CH2:6][OH:7])[CH2:3][OH:4].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[F:1][C:2]([F:10])([C:5]([F:9])([F:8])[CH2:6][O:7][CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][OH:4]
Reactant: BrCC=Cc1ccccc1
Reactant: OCC(F)(F)C(F)(F)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCC(F)(F)C(F)(F)COC/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 52.6 %

Procedure:
To a solution 2,2,3,3-tetrafluoro-1,4-butanediol (2.0 g, 12.3 mmol) in dimethylformamide (30 mL) was added 60% sodium hydride (0.140 g, 18.4 mmol). The mixture was stirred at room temperature for 1.30 hours. Then, a solution of cinnamyl bromide (3.2 g, 12.3 mmol) in dimethylformamide (40 mL) was added. The mixture was stirred at room temperature overnight and concentrated. The residue was dissolved with ethyl acetate (50 mL), washed with water (2×25 mL) and brine (25 mL), dried (Na2SO4), and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from pure n-hexane to 5:1) gave the title compound (1.8 g, 54%) as oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2.[NH2:25][CH2:26][CH2:27][CH2:28][NH2:29].C1(C)C=CC=CC=1>O>[CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][CH:11]([NH:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2
Reactant: CC1(C)C2CCC(C2)C1CCC(=O)CCC1C2CCC(C2)C1(C)C
Reactant: NCCCN
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC(C2)C1CCC(CCC1C2CCC(C2)C1(C)C)NCCCN

Procedure:
1,5-Di-(3,3-dimethylnorborn-2-yl)-3-pentanone (6.04 g., 0.02 mole) and 1,3-diaminopropane (0.10 mole) in 150 ml. toluene is heated at reflux overnight with a Dean-Stark water separator. The cooled solution is concentrated under reduced pressure. The residue is dissolved in ethanol and hydrogenated with PtO2 at room temperature and 40 psi hydrogen pressure. The platinum catalyst is filtered off and the ethanol removed under vacuum. The residue is dissolved in ether and the ether solution washed several times with water to remove the excess 1,3-diaminopropane. The ether extracts are dried over anhydrous sodium sulfate and concentrated under vacuum to leave the diamine product, 1-[1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentyl]-1,5-diazapentane.
Reaction SMILES: [Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11].[CH3:26][Al](C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[C:17]([Br:25])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:8]([OH:13])=[C:9]([CH:10]([OH:11])[CH3:26])[CH:12]=1
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Reactant: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C(C)C)c(O)c(C(C)O)c2)c1Br
Temperature: 4 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
5-(2,6-Dibromo-3-methyl-4-nitrophenoxy)-2-hydroxy-3-isopropylbenzaldehyde of Part 8D (210 mg, 0.44 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 4° C. Me3Al in toluene (0.355 mL, 0.67 mmol, 2N) was added to the mixture and the reaction was stirred for 16 hours at room temperature. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Filtration through a pad of silica gave 195 mg (93%) of 4-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-(1-hydroxyethyl)-6-isopropylphenol as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].CCN=C=NCCCN(C)C.Cl>O1CCCC1.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]2=[O:19])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(Br)cc1Cl
Yield: 91.6 %

Procedure:
A solution of 4-bromo-2-chlorobenzoic acid (2.00 g, 8.5 mmol), N-hydroxysuccinimide (1.07 g, 9.3 mmol) and EDCl (1.79 g, 9.3 mmol) in tetrahydrofuran/N,N-dimethylformamide (3:1; 40 mL) was stirred at room temperature for 18 h. The reaction was concentrated and water (50 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried (Na2SO4), concentrated, and dried in vacuo to give 1-[(4-bromo-2-chlorobenzoyl)oxy]-2,5-pyrrolidinedione (2.59 g, 92%) as an off-white solid which was used directly in the next step without further purification.