Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH2:4][CH2:3]1.[CH2:15]([Li])[CH2:16][CH2:17][CH3:18].Cl[Si:21](Cl)([CH3:23])[CH3:22]>>[CH3:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]([Si:21]([CH:15]2[C:5]3[CH2:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:13]=3[CH2:14][CH:17]([CH3:18])[CH2:16]2)([CH3:23])[CH3:22])[CH2:3]1
Reactant: CC1CCC2=C(C1)c1ccccc1C2
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]CCCC
Product: CC1CC2=C(Cc3ccccc32)C([Si](C)(C)C2CC(C)CC3=C2Cc2ccccc23)C1
Yield: 28.9 %

Procedure:
Following the procedure described in example 1 [step (c)], 3methyltetrahydrofluorene (3.00 g, 16.3 mmol), butyllithium (16.30 mmol) and dichlorodimethylsilane (0.99 ml, 8.15 mmol) gave bis-(3-methyltetrahydro-fluorenyl) dimethylsilane (1.00 g, 29%) as a white solid that was recrystallized from hexane; mp 179-180° C., 1H NMR (CDCl3): δ7.38-6.90 (m, 6H, arom), 3.47 (s, 2H, C5), 2.50-2.45 (m, 8H), 2.48 (s, 6H, CH3), 1.87-1.58 (m, 8H), −0.27 (s, 6H, Si—CH3). Analysis calculated for C30H36Si: C, 84.84; H, 8.54. Found C, 84.57; H, 8.70.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH2:30])[CH2:25][O:24]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][C:23]1([CH3:31])[O:27][C@@H:26]([CH2:28][O:29][NH:30][C:19]([C:18]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)=[O:20])[CH2:25][O:24]1
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Reactant: CC1(C)OC[C@H](CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@H](CONC(=O)c2ccc3[nH]ncc3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.5 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (150 mg, 0.38 mmol) and O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (83 mg, 0.57 mmol) in DMF (4 mL) was added EDCI (80 mg, 0.42 mmol), HOBt (56 mg, 0.42 mmol) and DIPEA (70 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 3.5 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (135 mg, 68%). LCMS (Method B): RT=3.45 min, [M+H]+=527.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:21]([O:20][CH2:19][CH2:18][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
5.00 g (24.8 mmol) of tert-butyl 4-hydroxy-1-piperidine carboxylate was dissolved in 100 mL of dimethylformamide and 1.08 g (24.8 mmol) of sodium hydride (55% or more, oily) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 4 hours. Thereafter, 20 mL of a solution of 6.54 g (27.3 mmol) of (2-bromoethoxy)-tert-butyldimethylsilane in dimethylformamide was added dropwise to the reaction mixture under ice-cooling and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate, followed by washing successively with water and a saturated NaCl solution and drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (eluting solvent: hexane/ethyl acetate=100/0-90/10) to obtain 1.65 g (yield: 18%) of the title compound as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[CH2:30](N)[CH2:31][NH2:32]>>[NH:5]1[CH2:30][CH2:31][N:32]=[C:4]1[C:3]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:9][C:2]=1[NH2:1]
Reactant: NCCN
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Nc1cc(N2CCOCC2)ccc1C1=NCCN1
Temperature: 140 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of 2-amino-4-(morpholin-4-yl)benzonitrile 3.65 g (18.0 mmol) in ethylenediamine 20 mL was added phosphorus pentasulfide 4.00 mg (0.018 mmol) and stirred at 140° C. for 16 hours. After cooling to room temperature, the solvent was evaporated. The residue was washed with water and diethyl ether to give the title compound 3.70 g as off-white solid. Yield 83.5%.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:17]1([S:16][CH2:15][CH2:14][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCSc1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCSc1ccccc1
Temperature: 90 °C
Yield: 69.2 %

Procedure:
Potassium phthalimide (5.43 g, 25 mmol) was added to a DMF (50 ml) solution of [(2-bromoethyl)thio]benzene (5,43 g, 25 mmol) and this stirred mixture under N2 was heated at 90° C. for 2 h. After cooling to room temperature, the reaction was filtered. The solvent was stripped from the filtrate under reduced pressure. The residue, dissolved in CH2Cl2 (100 ml), was filtered, concentrated, and flash chromotographed on a 4 inch column eluting with 1 to 6% EtOAc/toluene to produce 4.9 g of the title product.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[N:8][CH:9]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][C:7]1[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][N:8]=1
Reactant: COCCOCCOCc1ncc(C(=O)OC)[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCCOCc1ncc(C(=O)O)[nH]1

Procedure:
2-[2-(2-Methoxy-ethoxy)-ethoxymethyl]-3H-imidazole-4-carboxylic acid methyl ester (460 mg) and lithium hydroxide monohydrate (450 mg) in THF (3 mL) and water (1 mL) were stirred at 58° C. for 10 h. After cooling the mixture was carefully neutralized by the addition of 2 N HCl and concentrated to give crude 2-[2-(2-Methoxy-ethoxy)-ethoxymethyl]-3H-imidazole-4-carboxylic acid. Yield: 905 mg.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[C:18]([C:21]12[CH2:30][C:25]3([OH:31])[CH2:26][CH:27]([CH2:29][C:23]([OH:32])([CH2:24]3)[CH2:22]1)[CH2:28]2)([OH:20])=[O:19]>>[C:18]([C:21]12[CH2:30][C:25]3([O:31][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:26][CH:27]([CH2:29][C:23]([OH:32])([CH2:24]3)[CH2:22]1)[CH2:28]2)([OH:20])=[O:19]
Reactant: O=C(O)C12CC3CC(O)(CC(O)(C3)C1)C2
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(O)(C1)CC(C(=O)O)(C3)C2
Yield: 84 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1-carboxy-3,5-dihydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1-carboxy-3-hydroxy-5-acryloyloxyadamantane (yield: 84%, white solid) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.CCN(CC)CC.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl.CCOC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:23])[CH3:22]
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a stirred solution of 2-amino-5-chloropyridine (0.645 gm 5.0 mmol) in CH2Cl2 (15 mL) was added Et3N (0.80 mL, 6.0 mL, 1.2 eq) followed by addition of ethyl chlorooxoacetate (0.56 mL, 5.0 mmol, 1.0 eq). The mixture was stirred at rt for 2 h. It was diluted with EtOAc; washed with H2O and brine; dried (Na2SO4); and purified by silica gel chromatography to give pure N-(5-chloro-pyridin-2-yl)-oxalamic acid ethyl ester as a white solid (389 mg, yield: 34%). 1H NMR (400 MHz, methanol-d4) δ 8.16 (d, J=2.4 Hz, 1H), 7.97 (d, J=9.4 Hz, 1H), 7.66 (dd, J=8.9, 2.6 Hz, 1H), 4.19 (q, J=6.6 Hz, 2H), 1.20 (t, J=6.6 Hz, 3H) ppm. MS (ESI) 227.0 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C(NC(C)C)(C)C.[Li].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[Cl:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)=[O:23]
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C(Cl)CCl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(CCl)Nc1ccc2cnccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
A 2.0-mL vial equipped with a stirrer bar was charged with 6-aminoisoquinoline (100 mg, 0.7 mmol) in THF (1.0 mL) and cooled to −78° C. Lithium diisopropylamine (40 μL, 0.35 mmol) was added to the reaction at −78° C. followed by dropwise addition of chloroacetylchloride (62 μL, 0.7 mmol). The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was concentrated in vacuo then the solid was triturated with cold methanol. The solid was collected by filtration to afford 2-chloro-N-isoquinolin-6-yl-acetamide (58 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.14 (s, 2H) 8.01 (dd, J=9.08, 1.66 Hz, 1H) 8.45 (d, J=8.98 Hz, 2H) 8.66 (d, J=1.56 Hz, 1H) 11.46 (s, 1H); LCMS: 221 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([CH:15]=O)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24]>>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([CH:15]=[C:22]3[S:18][C:19](=[O:24])[NH:20][C:21]3=[O:23])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)COc2ccc(C=O)cc21
Reactant: O=C1CSC(=O)N1
Product: CCCCN1C(=O)COc2ccc(C=C3SC(=O)NC3=O)cc21

Procedure:
Following the general method as outlined in Example 1, starting from 4-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (intermediate 65) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][C:11]1(O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C[Si]([N:21]=[N+:22]=[N-:23])(C)C>C1(C)C=CC=CC=1>[N:21]([C:11]1([CH3:10])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[N+:22]=[N-:23]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC1(O)CCCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(N=[N+]=[N-])CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.8 %

Procedure:
BF3.Et2O (934 mg, 6.23 mmol) was added drop-wise at 20° C. to a stirred solution of 1-methylcyclopentanol (520 mg, 5.19 mmol) and trimethylsilyl azide (716 mg, 6.23 mmol) in 6 mL of toluene. Then the solution was stirred at room temperature for 16 hours. The organic phase was washed with a 10% solution of NaHCO3 (10 mL), water (5 mL) and brine (5 mL), and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was evaporated at 35° C. under reduced pressure to give 1-azido-1-methylcyclopentane (720 mg) as a crude product. It was used directly in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[CH3:31])=[N:8][CH2:7]1)C.CO.[OH-].[K+]>O1CCCC1>[CH3:31][C:14]1[CH:15]=[C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([OH:32])=[O:3])[CH2:7][N:8]=1)=[CH:19]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(C)c3[nH]2)S1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
To a solution of ethyl[2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (2.59 g), methanol (25 mL), and tetrahydrofuran (25 mL) was added an aqueous solution (15 mL) of potassium hydroxide (1.0 g), and the mixture was stirred at room temperature for 6 hr. The reaction solution was concentrated, acidified with aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (2.33 g, yield 96%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)c2ccccc21
Yield: 28 %

Procedure:
The title compound is prepared from 1-methyl-1H-indole-3-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 28% of theory; LC (method 4): tR=2.05 min; Mass spectrum (ESI+): m/z=345 [M+H]+.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]COC)[C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.O>CO>[C:6]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:5]([OH:4])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:11]
Reactant: COCOc1cccc(OCOC)c1-c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1cccc(O)c1-c1ccccc1
Yield: 98.9 %

Procedure:
A solution of 16 (400 mg, 1.46 mmol) in MeOH (12.0 mL) at room temperature was treated dropwise with 3 M HCl (430 μL, 11.7 mmol), then heated to reflux for one hour. Water (15 mL) was added and the solution was extracted with EtOAc (3×20 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 17 as an orange amorphous solid (269 mg, 99%): 1H NMR (CDCl3, 400 MHz) 7.60 (d, J=7.6 Hz, 2H), 7.53-7.49 (m, 1H), 7.46-7.44 (m, 2H), 7.18 (t, J=8.2 Hz, 1H), 6.62 (d, J=8.2 Hz, 2H), 4.84 (s, 1H), 4.83 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:33]([O:37][C:38](=[O:46])[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:33]([O:37][C:38]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:46])([CH3:36])([CH3:35])[CH3:34]
Reactant: Brc1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)NCCCCCN
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCCNc1cccc2cnccc12
Temperature: 70 °C
Yield: 84.3 %

Procedure:
Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (245 mg), tris(dibenzylideneacetone)palladium(0) (56 mg), 2-(di-tert-butylphosphino)biphenyl (69 mg), N-(5-aminopentyl)carbamic acid tert-butyl ester (282 mg, Tokyo Kasei Kogyo) and sodium tert-butoxide (160 mg) in toluene was stirred with heating at 70° C. for 4.5 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (327 mg).
Reaction SMILES: CC(C)C(O[C@H]1[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O[C@H]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[C:35]4[C:36]([O:44][CH3:45])=[C:37]([O:42][CH3:43])[C:38]([O:40][CH3:41])=[CH:39][C:34]=4[CH2:33][CH2:32][C@H:31]([NH:46][C:47](=[O:49])[CH3:48])[C:30]=3[CH:50]=2)[C@@H]1OC(=O)C(C)C)=O.[P:58](Cl)(Cl)([O:60][CH3:61])=[O:59].[OH2:64]>C1COCC1>[P:58]([OH:59])([O:60][CH3:61])([O:25][C:26]1[CH:27]=[CH:28][C:29]2[C:35]3[C:36]([O:44][CH3:45])=[C:37]([O:42][CH3:43])[C:38]([O:40][CH3:41])=[CH:39][C:34]=3[CH2:33][CH2:32][C@H:31]([NH:46][C:47](=[O:49])[CH3:48])[C:30]=2[CH:50]=1)=[O:64]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O[C@H]3O[C@H](COC(=O)C(C)C)[C@@H](OC(=O)C(C)C)[C@H](OC(=O)C(C)C)[C@H]3OC(=O)C(C)C)cc1[C@@H](NC(C)=O)CC2
Reactant: COP(=O)(Cl)Cl
Reactant: O
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OP(=O)(O)OC)cc1[C@@H](NC(C)=O)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of N-acetyl-colchicinol (1) (0.45 g; 1.26 mmol) in THF (40 ml) under argon was cooled to 0° C. and treated with a 1.0M solution of lithiumHMDS in THF (1.39 ml; 1.39 mmol). The mixture was stirred at 0° C. for 1 hour and then added in portions over about 15 minutes to a solution of methyl dichlorophosphate (625 μl; 4.16 mmol) in THF (150 ml). The mixture was stirred at ambient temperature for 15 minutes. After addition of water (200 ml) the THF was removed by evaporation. After removal of the insoluble material by filtration, the filtrate was purified on HP20 SS resin eluting with a gradient of 0–60% methanol/water. The appropriate fractions were freeze-dried to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl methyl hydrogen phosphate as white solid (391 mg).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[FH:16].[F-].[K+]>>[F:16][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CO1
Reactant: F
Agent: [F-]
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1C[C@@H](O)CF

Procedure:
A sample of 2-[(2R)-Oxiranylmethyl]-1H-isoindole-1,3-dione (G. Alexander et al. Tetrahedron Asymmetry, 7, 1641-8, 1996) is treated with potassium hydrogen difluoride to give 2-[(2R)-3-fluoro-2-hydroxypropyl]-1H-isoindole-1,3-dione in the presence of catalyst nBu4NH2F3. The procedures and methods used in this synthesis are identical to those of Example 3, except that in step Example-3B 2-[(2R)-3-fluoro-2-hydroxypropyl]-1H-isoindole-1,3-dione is used instead of(S)-1-[(benzyloxycarbonyl)amino]-2-propanol to produce the title product.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].[OH-].[Na+].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>O.C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: Brc1ccccn1
Agent: [NH2-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phenylacetonitrile 46.8 grams (0.40 mole) was added dropwise to a stirred suspension of 31.2 g. (0.80 mole) of powdered sodium amide in 200 ml. of dry toluene in an oven-dried, 2-liter, three-neck round bottom flask, equipped with dropping funnel, thermometer, stirrer and sodium hydroxide-protected condenser. During the addition, the temperature was maintained at 30°-35°C. with ice bath cooling. Afterwards, the mixture was brought slowly to reflux and maintained there for 41/2 hours with continuous stirring. Then 63.6 grams (0.40 mole) of 2-bromopyridine in 100 ml. of toluene was added dropwise at a rate which maintained refluxing of the solution. After complete addition, stirring and refluxing was continued for 3 hours. The mixture was then cooled at 25°C. and ca. 300 ml. of water was added, at first very cautiously and then in a steady stream. The phases were separated and the toluene layer extracted with ca. 150 ml. of water, and then with several portions of cold 6 N hydrochloric acid. The acid extracts were basified with 50% sodium hydroxide with cooling and extracted with ether. The ether extract was washed with water, dried over sodium sulfate and concentrated, and the residue was distilled. Yield, 41.7 g. (54 %); b.p. 134°-136°C./0.07 mm. The distillate crystallized and after recrystallization from isopropyl ether melted at 87°-88.5°C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[I:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.CON(C)[C:18](=[O:21])[CH2:19][CH3:20]>C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.C1COCC1>[I:9][C:10]1[S:11][C:12]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:13][CH:14]=1
Reactant: CCC(=O)N(C)OC
Reactant: Ic1cccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CCC(=O)c1ccc(I)s1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
38.4 ml of a 2M solution of lithium diisopropylamide (8.2 g, 76.8 mmol) in THF-heptane-ethylbenzene was added to THF (50 ml) taken in a 500 three neck RB flask equipped with a nitrogen inlet. The mixture was cooled to −40° C. and then 2-iodothiophene (16.1 g, 76.8 mmol) taken in 50 ml of THF was added with vigorous stirring. After 10 minutes the mixture was warmed to −10° C. and stirred for 30 min. The reaction mixture was re-cooled to −40° C. and N-methoxy-N-methylpropionamide (9 g, 76.8 mmol) taken in 50 ml of THF was added in one portion. The reaction mixture was allowed to warm slowly to 0° C. and then the reaction was quenched with saturated 50 ml of NH4Cl solution. The contents were extracted with 3×100 ml of DCM, dried over MgSO4 and concentrated to give an oily residue. This was purified by flash chromatography to give the title compound (10 g, 49%).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].I[CH3:22].[H-].[Na+].Cl>CN(C)C=O.O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[O:20][CH3:22])#[N:2]
Reactant: CI
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 5-(4-cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (100 mg, 0.375 mmol) and iodomethane (0.070 mL. 1.1 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% oil dispersion, 45 mg, 1.1 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h. Water and 1 M HCl were added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with hexane/diisopropyl ether to give 5-(4-cyano-3-methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (92 mg, 87%).