Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[CH:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O.N1C=CC=CC=1>>[Cl:17][C:12]1[C:11](=[O:13])[O:10][C:9](=[O:14])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1C=C(c2ccc(Cl)cc2)C(=O)O1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C1OC(=O)C(c2ccc(Cl)cc2)=C1Cl
Temperature: 11 °C
Reaction time: 0.5 h

Procedure:
With ice-cooling, 15.0 g (72 mmol) of 3-(4-chlorophenyl)furan-2,5-dione were added to 72 ml of thionyl chloride, and the mixture was admixed dropwise over a period 10 min with 11.5 g (145 mmol) of pyridine, the temperature being maintained at 10-12° C. The mixture was stirred at 10-12° C. for 30 min, heated at 75° C. for 10 min using a preheated heating bath and allowed to cool, and excess thionyl chloride was removed at 60° C. under reduced pressure. The residue was boiled with 200 ml of toluene and filtered, and the residue was again boiled with 100 ml of toluene and filtered whilst still hot. The filtrate was concentrated under reduced pressure and the residue was boiled with 100 ml of petroleum ether, cooled, filtered off, washed once more with petroleum ether and dried under reduced pressure. Yield: 16.2 g, m.p. 110-112° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:38])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[C:15]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[C:18]([CH3:30])([CH3:29])[C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:30][C:18]1([CH3:29])[C:16]2[N:17]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:38])=[CH:7][CH:8]=3)[N:13]=[C:14]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[C:15]=2[CH2:21][CH2:20][NH:19]1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3c(n2)C(C)(C)N(C(=O)OC(C)(C)C)CC3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)c3c(n2)C(C)(C)NCC3)cc1
Reaction time: 1 h

Procedure:
Step 2—Synthesis of compound wa: (S)-tert-butyl 2-(4-(3-ethylureido)phenyl)-8,8-dimethyl-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.0861 g, 0.000164 mol) in Methylene chloride (2.00 mL, 0.0312 mol) was added Trifluoroacetic Acid (0.38 mL, 0.0049 mol). The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated, diluted with sat NaHCO3, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.19 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.17 (t, J=5.5, 1H), 4.02 (d, J=6.9, 1H), 3.86 (d, J=11.1, 1H), 3.70 (dd, J=11.2, 2.5, 1H), 3.61 (t, J=11.0, 2H), 3.44 (dd, J=22.6, 9.4, 2H), 3.18-3.04 (m, 2H), 2.90-2.77 (m, 2H), 2.55 (t, J=5.1, 2H), 1.40 (d, J=6.9, 6H), 1.22 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+425.2 (M+H)+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[CH3:36][C:37]1[N:42]=[C:41]([C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[C@H:48]([N:52]2[CH2:55][C:54]4([CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[CH2:53]2)[CH2:47][CH2:46]3)[CH:40]=[CH:39][N:38]=1>CCOC(C)=O.ClCCl>[CH3:36][C:37]1[N:42]=[C:41]([C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[C@H:48]([N:52]2[CH2:55][C:54]4([CH2:60][CH2:59][N:58]([C:12](=[O:14])[CH2:11][C:7]5[N:6]=[C:5]6[O:4][CH2:3][CH2:2][O:1][C:10]6=[CH:9][CH:8]=5)[CH2:57][CH2:56]4)[CH2:53]2)[CH2:47][CH2:46]3)[CH:40]=[CH:39][N:38]=1
Reactant: O=C(O)Cc1ccc2c(n1)OCCO2
Reactant: Cc1nccc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nccc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)Cc4ccc5c(n4)OCCO5)CC3)C2)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a mixture of 2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl) acetic acid (SM-1aj, 27.27 g, 139.73 mmol), dichloromethane (495 mL), and triethylamine (67.74 mL, 468.03 mmol) was added 1,1′-carbonyldiimidazole (22.66 g, 139.73 mmol) at 20° C. and the resulting mixture was heated to 40° C. and stirred for 2 hours. The reaction was charged with 2-[(R)-5-(2-methylpyrimidin-4-yl)-indan-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1 h, 49.50 g, 121.51 mmol). The resulting mixture was stirred at 40° C. for 2 hours, monitoring by HPLC for consumption of amine starting material. The reaction temperature was adjusted below 25° C. and charged with water (1500 mL) and stirred for 5 min. The layers were separated and the organic layer was concentrated to dryness and backfilled with EtOAc (1000 mL) and further concentrated to approximately 300 mL. The resulting thick solution was cooled to 20° C. and stirred until crystals formed. The very thick mixture was diluted with EtOAc (1000 mL) and stirred for 5 min, filtered and dried under vacuum at 45° C. to afford the title compound (21.8 g, 35%). MS (ES+) 512.5 (M+H)+. 1H NMR (CDCl3) δ 1.64-1.75 (m, 4H), 1.90-2.00 (m, 1H), 2.14-2.23 (m, 1H), 2.81 (s, 3H), 2.85-2.94 (m, 1H), 3.08-3.20 (m, 5H), 3.45-3.57 (m, 4H), 3.77 (s, 2H), 3.98 (dd, 1H), 4.22-4.28 (m, 2H), 4.41-4.46 (m, 2H), 6.91 (d, 1H), 7.15 (d, 1H), 7.38 (d, 1H), 7.48 (d, 1H), 7.86 (d, 1H), 7.96 (s, 1H), 8.65 (d, 1H).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]([C:19]1[C:23]([NH2:24])=[CH:22][NH:21][N:20]=1)=[O:18].[C:25]([C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33]([CH:37]=1)[C:34](O)=[O:35])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:15][O:16][C:17]([C:19]1[C:23]([NH:24][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([C:25]([CH3:26])([CH3:27])[CH3:28])[CH:30]=[CH:31][C:32]=2[O:38][CH3:39])=[CH:22][NH:21][N:20]=1)=[O:18]
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)O
Reactant: COC(=O)c1n[nH]cc1N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1n[nH]cc1NC(=O)c1cc(C(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a solution of EDC (11.59 g, 60.7 mmol), HOBt (8.19 g, 60.7 mmol) and 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (7.84 g, 55.6 mmol) in DMF (100 ml) was added 5-tert-butyl-2-methoxy-benzoic acid (10.52 g, 50.6 mmol) and the mixture stirred at room temperature overnight. The mixture was reduced in vacuo and the residue partitioned between EtOAc (500 ml) and brine (200 ml), the organic portion was washed with saturated aqueous sodium hydrogen carbonate (200 ml), dried (MgSO4) and reduced in vacuo to yield 4-(5-tert-butyl-2-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester as a pale yellow solid (17.07 g, 93%). (LC/MS (acidic method): Rt 3.12 min, [M+H]+ 332).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1.C1COCC1>[C:17]([O:1][C:2]1[CH:11]=[C:10]([O:12][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCc1cc(=O)oc2cc(OC(=O)C(C)(C)C)cc(OC(=O)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 177.9 %

Procedure:
To a solution of 5,7-dihydroxy-4-propylcoumarin (2) (1.10 g, 5 mmol) in pyridine (12 mL) and THF (6 mL) was added pivaloyl chloride (0.673 mL, 5.5 mmol) and the reaction mixture was allowed to stir at room temperature for 24 h. TLC revealed formation of a new less polar spot and unreacted starting material. In an effort to drive the reaction to completion, pivaloyl chloride (0.50 mL) was added and the reaction continued to stir at room temperature for another 72 h. The pyridinium hydrochloride was removed by filtration and washed a few times with ethyl acetate. The organic solutions were combined and washed, successively, with 1 M HCl (2×25 mL), water (25 mL), aqueous saturated sodium bicarbonate (25 mL). After being dried over sodium sulfate and concentrated under vacuum, the crude product was purified by silica gel chromatography (2:1 hexane/ethyl acetate) to obtain 8b as a white solid (1.90 g, 98% yield). mp 110-112° C.; Rf=0.49 (4:1 hexane/ethyl acetate); 1H-NMR (CDCl3),: 1.03 (3H, t, J=7.8 Hz), 1.36 (9H, s), 1.41 (9H, s), 1.69 (2H, sextet, J=7.4 Hz), 2.81 (2H, t, J=7.8 Hz), 6.22 (1H, s), 6.60 (1H, d, J=2.4 Hz), 7.03 (1H, d, J=2.1 Hz); 13C-NMR (CDCl3): 13.5, 20.7, 26.4, 26.8, 26.9, 36.4, 39.2, 39.4, 108.6, 111.5, 113.4, 114.2, 149.4, 152.7, 154.9, 155.4, 159.9, 177.1; IR (film): 3090, 2971, 2941, 2876, 1757, 1615, 1481, 1422, 1273 cm−1; MS m/e 389 (M+1); Anal. Calcd. for C22H28O6: C, 68.02; H, 7.26. Found: C, 67.77; H, 7.18.
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]2[C@H:18]3[CH2:19][CH2:20][N:21]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:32]I.O>CN(C=O)C>[CH3:32][N:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C@@H:17]2[N:21]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:20][CH2:19][C@@H:18]2[C@@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1c2ccccc2[C@H]2[C@H](CCN2C(=O)OCc2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
Sodium hydride (60% in oil, 120 mg, 3.0 mmol) was suspended in DMF (12 ml), benzyl (3aR*,4R*,9bR*)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (960 mg, 2.5 mmol) was added, and the mixture was stirred at room temperature for 10 min. Thereto was added methyl iodide (426 mg, 3.0 mmol), and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous Na2SO4), and the solvent was evaporated. The residue was subjected to column chromatography using silica gel (30 g) and eluted with hexane-ethyl acetate (5:1, v/v) to give the title compound (330 mg, 33%) as an amorphous form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.O.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:22](=[O:25])(O)[O-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:25][CH3:22])[O:9][CH3:11])=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1ccc(Br)nc1
Yield: 94 %

Procedure:
To a solution of 2-bromo-5-pyridinecarboxaldehyde (1.02 g, 5.48 mmol) in methanol (100 mL) was added p-toluenesulfonic acid hydrate (1.05 g, 5.53 mmol), and the mixture was heated at reflux for 1.5 h. Diluted aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford 2-bromo-5-dimethoxymethylpyridine (1.19 g, 94%) as an oil.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1C(O)=O.CC(N(C)C)=O>O>[F:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1C(=O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 29.2 h

Procedure:
A 250 mL single-neck flask equipped with a condenser and a magnetic stirrer was charged with 30.00 g of 3,4,6-trifluorophthalic acid, and 200 mL of dimethyl acetamide. The reaction mixture was then heated with stirring for 29.2 hr. at a bath temperature of 127° C. The flask was then allowed to cool to room temperature and the contents were poured into 500 mL of water, and extracted with 4×200 mL of ethyl acetate. The combined organic extracts were washed with water (2×200 mL), dried over magnesium sulfate, filtered, and the solvent removed on a rotary evaporator followed by drying at the pump overnight. The crude product was then dissolved in 25 mL of ethyl acetate and introduced at the top of a silica column (4.5 cm ID×56 cm, flushed with hexane). The product was then eluted with 90:10 hexane:ethyl acetate under a slight nitrogen pressure, and the fractions (500 mL each) were monitored by gas chromatography. The fractions containing the product were combined, the solvent removed on a rotary evaporator, and then dried at the pump overnight to give 2,4,5-trifluorobenzoic acid as a light yellow solid. Recrystallization of the product from toluene (50 mL, ca. 60° C.) gave a white product (65.0% overall yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.C(=NO)C1C(=CC=CC=1)O.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:25]1[C:26]([Br:33])=[C:27]([O:31][CH3:32])[CH:28]=[CH:29][CH:30]=1>CN(C)C=O>[Br:33][C:26]1[CH:25]=[CH:30][C:29]([N:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:7]=[N:6]2)=[CH:28][C:27]=1[O:31][CH3:32]
Reactant: OCc1cn[nH]c1
Reactant: COc1cccc(I)c1Br
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-n2cc(CO)cn2)ccc1Br
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of 4-(hydroxymethyl)pyrazole (500 mg, 5.10 mmol), salicylaldoxime (140 mg, 1.019 mmol), cesium carbonate (4.98 g, 15.29 mmol), cuprous oxide (58.2 mg, 0.306 mmol), iodobromoanisole (1.59 g, 5.10 mmol) and N,N-dimethyl-formamide (10 mL) were combined in a microwave vial fitted with an N2 inlet and magnetic stir bar. The reaction mixture was stirred under a nitrogen atmosphere at 90° C. overnight. The reaction mixture was cooled to RT, then filtered through celite, and the filtrate was concentrated in vacuo. The crude material was purified by column chromotography (10% to 60% EtOAc in heptanes) to give (1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-4-yl)methanol (800 mg, MS: 285.3 [M+H+].)
Reaction SMILES: C(O)[CH2:2][CH2:3][CH2:4][OH:5].[CH:7]([CH:9]=C)=[O:8].[CH3:11][CH:12](CO)CO>>[CH3:9][CH2:7][O:8][CH:4]([O:5][CH2:11][CH3:12])[CH:3]=[CH2:2]
Reactant: CC(CO)CO
Reactant: C=CC=O
Reactant: OCCCCO
Product: C=CC(OCC)OCC

Procedure:
U.S. Pat. Nos. 3,929,915, 3,963,754 and JP-A-Sho 61-39613 report a three-step process for preparing 1,4-butanediol which comprises reaction of acrolein with 2-methyl-1,3-propanediol under conventional conditions to produce acrolein acetal (2-vinyl-5-methyl-1,3-dioxane) (Reaction 1), hydroformylation of the acrolein acetal under conventional conditions to produce the corresponding aldehydes (Reaction 2), and hydrolysis and hydrogenation of the aldehyde of 2-vinyl-5-methyl-1,3-dioxane under conventional conditions to obtain a mixture of 1,4-butanediol and 2-methyl-1,3-propanediol (Reaction 3). ##STR4##
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O>O1CCOCC1.O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:4]2([C:4]3[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=3)[CH2:5][CH2:6][CH:1]([OH:7])[CH2:2][CH2:3]2)=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(C2(c3ccc(O)cc3)CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
A mixture of ketal intermediate (2.8 g, 17.7 mmol) and phenol (5.64 g, 60 mmol) in dioxane (10 mL) and water (10 mL) at 0° C. was treated dropwise with conc. H2SO4 (20 mL). The mixture was allowed to warm to room temperature and stirred at this temperature for the next 6 h. The reaction mixture was then poured into ice-water and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried with anhydrous MgSO4 and concentrated in vacuo to provide 4,4-bis(4-hydroxyphenyl)cyclohexanol (5 g) contaminated with phenol.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH3:9].Br[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:8]([O:10][P:11]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[CH:25]=2)[N:20]=[CH:19][CH:18]=1)(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9]
Reactant: FC(F)(F)c1ccc2nccc(Br)c2c1
Reactant: CCOP([O-])OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccnc2ccc(C(F)(F)F)cc12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
1.73 g of tetrakis-(triphenylphosphine)-palladium(O) in 20 ml of toluene is mixed with 4.6 ml of triethylamine, 4.3 ml of diethylphosphite and 8.28 g of 4-bromo-6-trifluoromethyl-quinoline and stirred for three hours at 90° C. Another 0.17 g of tetrakis-(triphenylphosphine)-palladium(O) and 0.4 ml of triethylamine and diethylphosphite each are added and stirred for one hour at 90° C. After cooling, it is diluted with ether, suctioned off, washed with ether and the filtrate is concentrated by evaporation. The product is purified by column chromatography. 8.33 g of 6-trifluoromethyl-quinoline-4-phosphonic acid diethyl ester is obtained as colorless oil.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]([O:32][Si:33]([CH2:38][CH3:39])([CH2:36][CH3:37])[CH2:34][CH3:35])([C:28]([F:31])([F:30])[F:29])/[CH:4]=[CH:5]\[CH2:6][C:7]([CH3:27])([CH3:26])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH2:13]S(C1SC2C=CC=CC=2N=1)(=O)=O.[Li]N([Si](C)(C)C)[Si](C)(C)C.[C:52]([O:55][C@@H:56]1[CH2:61][CH:60](O)[CH2:59][C@@H:58]([O:63][C:64](=[O:66])[CH3:65])[CH2:57]1)(=[O:54])[CH3:53]>C1COCC1>[C:52]([O:55][C@@H:56]1[CH2:61][C:60](=[CH:13]/[CH:12]=[CH:11]/[CH2:10][CH2:9][CH2:8][C:7]([CH3:27])([CH3:26])[CH2:6]/[CH:5]=[CH:4]\[C:3]([O:32][Si:33]([CH2:38][CH3:39])([CH2:34][CH3:35])[CH2:36][CH3:37])([C:2]([F:1])([F:40])[F:41])[C:28]([F:31])([F:30])[F:29])[CH2:59][C@@H:58]([O:63][C:64](=[O:66])[CH3:65])[CH2:57]1)(=[O:54])[CH3:53]
Reactant: CC(=O)O[C@@H]1CC(O)C[C@@H](OC(C)=O)C1
Reactant: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/CS(=O)(=O)c1nc2ccccc2s1)(C(F)(F)F)C(F)(F)F
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/C=C1C[C@@H](OC(C)=O)C[C@H](OC(C)=O)C1)(C(F)(F)F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of 322 mg of (2E,9Z)-2-(12,12,12-Trifluoro-7,7-dimethyl-11-triethylsilanyloxy-11-trifluoromethyl-dodeca-2,9-diene-1-sulfonyl)-benzothiazole in 2 ml of THF was added at −78° 0.5 ml of LiN(SiMe3)2 (1.0 M in THF) and stirring of the red solution was continued for 30 min. To this solution was added at −78° a solution of 107 mg of (1R,3R)-1,3-diacetoxy-5-hydroxy-cyclohexane in 1 ml of THF over 10 min and stirring was continued for 5 h after which time t.l.c. indicated almost completion of the reaction. The mixture was warmed to 22°, washed with sat. aqueous NH4Cl-solution, the organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on a Lobar CN-column (Merck) with CH2Cl2/CH3CN/hexane 15:5:200 to give 230 mg of the pure (t.l.c.) title compound as a colorless oil. IR (neat): 1735 m (CO); MS (El): 613/1 (M−C2H5).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:21]([CH3:34])=[CH:20]2.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:21]([CH3:34])=[C:20]2[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: COc1ccc2c(c1)cc(C)n2CCN1CCOCC1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(c1)c(C(=O)c1ccc(C)c3ccccc13)c(C)n2CCN1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (84 mg, 0.41 mmol) and 4-(2-(5-methoxy-2-methyl-1H-indol-1-yl)ethyl)morpholine (120 mg, 0.44 mmol) in 8 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.5 mL, 0.90 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in CH2Cl2 to give CBX001 (107 mg, 0.24 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.37 (s, 3H), 2.42-2.55 (m, 4H), 2.66 (t, J=6.9 Hz, 2H), 2.78 (s, 3H), 3.59 (s, 3H), 3.68 (t, J=4.2 Hz, 4H), 4.17 (t, J=6.9 Hz, 2H), 6.84 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.38 (d, J=7.0 Hz, 1H), 7.41-7.50 (m, 2H), 7.55 (t, J=7.2 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 13.14, 20.21, 41.74, 53.90, 54.49, 55.80, 57.81, 67.29, 103.91, 110.33, 112.67, 115.61, 124.69, 125.76, 126.30, 126.59, 126.91, 128.42, 130.86, 131.35, 133.25, 136.92, 139.50, 145.98, 156.28, 193.91. MS m/z 443.4 [M+H]+.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH2:29])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:2]1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][CH2:53][OH:54])[CH:46]=2)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[CH2:2]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH:29][C:34]([NH:35][C:36]5[N:37]([C:45]6[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][CH2:53][OH:54])[CH:46]=6)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=5)=[O:33])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:1]1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCC45CC5)n3c2)c2ccccc21
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC56CC6)n4c3)c3ccccc32)n(-c2cccc(OCCO)c2)n1
Yield: 89.2 %

Procedure:
An orange-brown solution of Intermediate 148d (87.2 mg, 0.224 mmol), Intermediate 148e (100 mg, 0.224 mmol) and DIPEA (0.049 mL, 0.28 mmol) in dry dioxane (3 mL) was stirred at 75° C. for 16 h. The cooled solution was concentrated in vacuo, suspended in water (5 mL) and extracted with DCM (2×5 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown gum. Flash chromatography (silica 12 g, 4-8% MeOH in DCM) gave the title compound as a pale yellow solid (138 mg, 89%). LCMS (Method 3): Rt 3.57 min, m/z 691 [MH+].
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:30][C:31]1[C:32]([F:41])=[C:33]2[C:39]([NH2:40])=[CH:38][NH:37][C:34]2=[N:35][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:30][C:31]1[C:32]([F:41])=[C:33]2[C:39]([NH:40][C:5]([C:2]3([CH3:1])[CH2:4][CH2:3]3)=[O:7])=[CH:38][NH:37][C:34]2=[N:35][CH:36]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC1(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
1-Methylcyclopropanecarboxylic acid (435 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (553 mg, 2.17 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 was added (50 mL). The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methylcyclopropanecarboxamide (464 mg, 68.4% yield) was obtained as a solid.