Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:20])([C:16](OC)=[O:17])[C:12](OC)=[O:13].[BH4-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:20])([CH2:16][OH:17])[CH2:12][OH:13]
Reactant: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
To a stirred solution of dimethyl 2-(2-fluoro-4-nitrophenyl)-2-methylmalonate (1.0 g, 3.50 mmol, 1.0 eq) in methanol (20 mL) was added NaBH4 (0.67 gm, 17.63 mmol, 5.0 eq) at 0° C. and stirred at RT for 16 h. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was vaporated under reduced pressure. The crude product obtained was purified by CC using EtOAc/PE (2:3) to get 2-(2-fluoro-4-nitrophenyl)-2-methylpropane-1,3-diol (400 mg, 50%; TLC system: EtOAc/PE (1:1), Rf: 0.3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[N:27][C:28]#[N:29])[C:6]=2[CH:30]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1>[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[N:27][C:28]#[N:29])[C:6]=2[CH:30]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(OC)[C@@]1(C)Oc2ccc(N)cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(OC)[C@@]1(C)Oc2ccc(NC(=O)c3ccccc3)cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
100 mg (0.24 mmol) of the compound obtained in example 5 was dissolved in 1 ml of THF, then 28 μl (0.24 mmol) of benzoyl chloride and 51 μl (0.37 mmol) of triethylamine were added thereto. The reaction was stirred at room temperature for 2 hours, 10 ml of saturated NaHCO3 solution was added, and aqueous layer was extracted with 20 ml of ethyl acetate. Organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2), to give 68 mg (yield: 54%) of the target compound.
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]=[C:10]([NH:17][CH:18]3[CH2:20][CH2:19]3)[C:9]=2[N+:21]([O-])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].N>O1CCOCC1.O.C(OCC)(=O)C>[N:1]1([C:8]2[N:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]=[C:10]([NH:17][CH:18]3[CH2:19][CH2:20]3)[C:9]=2[NH2:21])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 3 %

Procedure:
To a suspension of 6-(1-azepanyl)-N,2-dicyclopropyl-5-nitro-4-pyrimidinamine 197 (0.5 g, 16 mmol) in 1,4-dioxane (35 ml) and water (35 ml) is added sodium hydrosulfite (2.19 g, 13 mmol) and ammonia (25% solution, 1.2 ml). The mixture is stirred at room temperature for 10 h then diluted with ethyl acetate and washed three times with water. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford a yellow oil. The crude oil is purified by column chromatography (dichloromethane/ethanol/ammonia: 95/5/0.5) to give pure 6-(1-azepanyl)-N4,2-dicyclopropyl-4,5-pyrimidinediamine 63 (137 mg, 30%) as a reddish solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc(Nn2cnnc2)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.23 Gram of 4-[(4-trifluoromethylphenyl)-amino]-4H-1,2,4-triazole, 0.28 g of 4-bromobenzyl bromide and 0.17 g of anhydrous potassium carbonate were added to 5 ml of acetonitrile and the mixture was stirred for 3 hours at room temperature. The solvent was removed by distillation and water was added to the residue, which was then extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to give crude crystals from the chloroform eluate. The crude crystals were recrystallized from a mixed solvent of ethyl acetate/ether to give 0.22 g of 4-[N-(4-bromobenzyl)-N-(4-trifluoromethylphenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([F:11])=[C:9]([F:12])[C:6]([CH2:7][OH:8])=[C:5]([F:13])[C:4]=1[F:14].[C:15]([C:17]([CH3:27])=[CH:18][C@@H:19]1[C@@H:21]([C:22](O)=[O:23])[C:20]1([CH3:26])[CH3:25])#[N:16]>CN(C)C1C=CN=CC=1.ClCCl>[C:15]([C:17]([CH3:27])=[CH:18][C@@H:19]1[C@@H:21]([C:22]([O:8][CH2:7][C:6]2[C:5]([F:13])=[C:4]([F:14])[C:3]([O:2][CH3:1])=[C:10]([F:11])[C:9]=2[F:12])=[O:23])[C:20]1([CH3:26])[CH3:25])#[N:16]
Reactant: CC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: COc1c(F)c(F)c(CO)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=C(C)C#N)C2(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Under a nitrogen atmosphere, 0.49 g of N,N-dicyclohexylcarbodiimide was added to a mixture of 0.50 g of 4-methoxy-2,3,5,6-tetrafluorobenzyl alcohol, 0.43 g of (1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid, 0.087 g of 4-dimethylaminopyridine and 7 ml of anhydrous dichloromethane, and the mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.62 g of 4-methoxy-2,3,5,6-tetrafluorobenzyl(1R)trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate represented by the following formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:30][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=3)[CH:5]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCC1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NC2CCCC2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and cyclopentylamine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:28]1[N:29]=[CH:30][S:31][CH:32]=1)[C:12]([NH:14][CH:15]1[C:26](=[O:27])[N:17]2[C:18]([C:23]([OH:25])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])(C)(C)C.C(OC(C)C)(C)C.CCCCCC>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:6]([CH2:8][O:9][N:10]=[C:11]([C:28]1[N:29]=[CH:30][S:31][CH:32]=1)[C:12]([NH:14][CH:15]1[C:26](=[O:27])[N:17]2[C:18]([C:23]([OH:25])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]12)=[O:13])([OH:7])=[O:5]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cscn3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3cscn3)[C@H]2SC1
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
Trifluoroacetic aid (8.4 ml) was added to a suspension of 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer) (2.1 g) in methylene chloride (4.2 ml) and anisole (2.1 ml) at ambient temperature and the mixture was stirred for 1.5 hours at the same temperature. To the resultant solution was added diisopropyl ether (50 ml) and n-hexane (30 ml) and the mixture was stirred. The precipitates were collected by filtration, washed with a solution of diisopropyl ether and n-hexane (1:1). The precipitates were added to a mixture of ethyl acetate and water, and the mixture was adjusted to pH 7.0 with saturated aqueous solution of potassium carbonate. The separated aqueous layer was adjusted to pH 4 with 10% hydrochloric acid and the solution was washed with ethyl acetate. The aqueous layer was adjusted to pH 1.8 with 10% hydrochloric acid and saturated with sodium chloride. The acidic solution was extracted with ethyl acetate and tetrahydrofuran (1:1). The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 7-[2-carboxymethoxyimino-2-(4-thiazolyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer) (1.0 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]([C:20]1[CH:33]=[CH:32][C:23]2[C@@H:24]3[C@H:29]([CH2:30][CH2:31][C:22]=2[CH:21]=1)[NH:28][CH2:27][CH2:26][CH2:25]3)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(CC2C=CC3[C@@H]4[C@H](CCC=3C=2)NCCC4)CCCCC1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:28]3[C@@H:29]4[C@@H:24]([C:23]5[CH:32]=[CH:33][C:20]([CH2:13][C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)=[CH:21][C:22]=5[CH2:31][CH2:30]4)[CH2:25][CH2:26][CH2:27]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: c1ccc(Cc2ccc3c(c2)CC[C@@H]2NCCC[C@H]32)cc1
Agent: c1cc2c(cc1CC1CCCCC1)CC[C@@H]1NCCC[C@H]21
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccc(Cc4ccccc4)cc3CC[C@@H]21
Yield: 12 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and a mixture of cis-8-benzyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline and cis-8-cyclohexylmethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline (ca. 30:70) following a procedure analogous to that described in Example 1 and separated from the also formed Example 83 by HPLC on reversed phase (MeOH/H2O/NH4OH). Yield: 12% of theory; LC (method 1): tR=3.35 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH2:49][OH:50])[CH3:48])C1C=CC=CC=1>CO.Cl.[Pd]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@@H:12]2[O:11][C:10]([CH2:49][OH:50])([CH3:48])[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@H:13]2[OH:23])=[CH:32][C:33]=1[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(C)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3OC(C)(CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
To a stirred solution of {(3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-methyl-tetrahydro-pyran-2-yl}-methanol (150 mg, 0.21 mmol) in methanol (10 mL) was added 10% Pd/C (70 mg) and 2 drops of conc. HCl. The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 18 hours. The reaction mixture was filtered through cetlie bed, washed with methanol, filtrate was concentrated and purified by preparative chiral HPLC to furnish 35 mg of (3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-hydroxymethyl-2-methyl-tetrahydro-pyran-3,4,5-triol.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([C:15]([O:17]C)=[O:16])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:19])[CH2:2][CH3:3].[OH-].[Na+]>CO>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:19])[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cccc(C(=O)OC)c2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(CCC)C1Cc2cccc(C(=O)O)c2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A mixture of methyl 3-(dipropylamino)-1,2,3,4-tetrahydro-2-oxo-8-quinolinecarboxylate (1.0 g), methanol (15 mL) and 4.0 N sodium hydroxide solution (3.3 mL) was stirred at room temperature for 30 minutes. The methanol was removed and the residue was reconstituted in water (5 mL) and neutralized by addition of 4.0 N hydrochloric acid (3.3 mL). The precipitate was filtered off, washed with water and air dried to give 0.67 g of 3-(dipropylamino)-1,2, 3,4-tetrahydro-2-oxo-8-quinolinecarboxylic acid, mp 214-217° C. Anal Calcd for C16H22N2O3 : C, 66.18; H, 7.64; N, 9.65. Found: C, 65.99; H, 7.67; N, 9.62.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.Cl.[CH2:23]([NH:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C>[CH2:23]([N:30]1[C:15](=[O:17])[C:14]2[C:13](=[O:19])[C:12]3[CH:11]=[CH:10][C:9]([Cl:20])=[CH:8][C:7]=3[NH:6][C:5]=2[C:3]([OH:4])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (5.00 g, 16.90 mM) and benzylhydrazine dihydrochloride (46.15 g, 236.50 mM) in ethanol (100 mL) was added triethylamine (75.8 mL, 541.0 mM). The mixture was heated to give a brown solution which was refluxed for 40 hours during which time a precipitate formed. The suspension was cooled to room temperature and filtered to give the benzylhydrazine salt of the title compound as an impure yellow solid. Multiple crystallizations from ethanolic hydrogen chloride and methanol gave the title compound (0.370 g, 6%) as a white powder, mp 347-350° C.; MS(CI): 354 (M+H).
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.[CH2:12]([C@H:14]1[O:16][CH2:15]1)Cl.C(=O)([O-])[O-].[Na+].[Na+].CC(C)([O-])C.[K+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)C>[CH2:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@@H:14]1[O:16][CH2:15]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC[C@@H]1CO1
Agent: CC(C)(C)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: O=C1NC(=O)c2c(C[C@H]3CO3)cccc21
Temperature: 15 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Into a reaction vessel were put phthalimide (200.0 g, 1.36 mol), (S)-epichlorohydrin (226.4 g, 2.45 mol), anhydrous sodium carbonate (14.40 g, 0.136 mol), benzyltrimethylammonium chloride (25.24 g, 0.136 mol) and isopropanol (1.2 L) and the mixture was reacted at 25° C. for 22 hours to give crude N-(3-chloro-2-hydroxypropyl)phthalimide. The reaction mixture is cooled to 15° C. and then thereto was dropped a mixture of potassium tert-butoxide (183.0 g, 1.63 mol) and isopropanol (0.8 L) over a two hours period and the mixture was stirred for 2 hours at the same temperature. The solvent was removed and to the residue was added ethyl acetate (1.3 L). The mixture was washed with water (0.65 L), and then ethyl acetate was removed to give crude (S)-glycidylphthalimide. The crude product was crystallized from ethyl acetate-hexane to give the object (S)-glycidylphthalimide (206.3 g, yield: 75%, optical purity: 98% e.e.) as white crystals. mp 99–101° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[Cl:38][C:39]1[CH:44]=[C:43]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]3)=[N:22][CH:23]=2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]
Reactant: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 42 %

Procedure:
Following general procedure II, (R)-tert-butyl (1-(5-((6-chloro-3-isobutyryl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (225 mg, 0.63 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (175 mg, 0.66 mmol) to afford the desired product (168 mg, 62%) as a solid: ESI MS m/z 635 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>CN1CCCC1=O>[C:6]1(/[CH:5]=[CH:4]/[CH2:3][CH2:2][O:18][N:19]2[C:20](=[O:29])[C:21]3=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]3[C:23]2=[O:24])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCC/C=C/c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1OCC/C=C/c1ccccc1
Yield: 56 %

Procedure:
Example 1 was repeated to react 67 g (0.32 mol) of E-4-bromo-1-phenyl-1-butene with 29 g of potassium carbonate (0.21 mol) and 51.9 g of N-hydroxyphthalimide (0.32 mol) in 320 ml of N-methylpyrrolidone. The crude product, precipitated by means of ice-water, was taken up in dichloromethane and washed twice with dilute sodium hydroxide solution. A customary working up gives the product in a 56% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>>[CH3:11][N:12]([CH3:14])/[CH:13]=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: COC(OC)N(C)C
Product: Cc1ccc(C(=O)/C=C/N(C)C)cc1
Yield: 74 %

Procedure:
A solution of 1-(4-methylphenyl)ethanone (1.34 g, 10 mmol) in DMF-DMA (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (PE/EA=4:1˜2:1) to give the title compound (1.40 g, 74%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.37 (3H, s), 2.95-3.11 (6H, m), 6.72 (1H, d, J=12.0 Hz), 7.21 (2H, d, J=8.0 Hz), 7.78-7.82 (m, 3H).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C>CO>[CH3:20][O:19][C:17]([C:16]1[NH:7][C:1]2[C:6]([C:15]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:18]
Reactant: COC(=O)CCC(=O)C(=O)OC
Reactant: NNc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1c(C(=O)OC)[nH]c2ccccc12
Temperature: 75 °C

Procedure:
Phenyl hydrazine (5.7 ml), dimethyl 2-oxoglutarate (10 g) and acetic acid (1.0 ml) in methanol (100 ml) were heated at reflux for 1 hour, then concentrated in in vacuo. The crude hydrazone (13 g) was dissolved in saturated methanolic hydrochloric acid (350 ml) and heated to 75° C. for 16 hours with continual stirring. The reaction was diluted with water (200 ml) and extracted with dichloromethane. Combined organic extracts were washed with saturated aqueous sodium hydrogencarbonate solution, water, saturated aqueous sodium chloride solution and dried (MgSO4). The solvent was removed in vacuo to give a yellow crystalline solid (7.0 g); NMR d (CD3SOCD3) 3.59 (s, 3H), 3.83 (s, 3H), 4.12 (s, 2H), 7.06 (t, 1H), 7.26 (t, 1H), 7.41 (d, 1H), 7.63 (d, 1H), 11.76 (brs, 1H); M/z (−) 246 (M−H+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH2:3]1.CN1CCCC1=O.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>ClCCl>[Si:25]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CN1C=CC(c2c[nH]c3ccc(O)cc23)=CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN1CCC(c2c[nH]c3ccc(O[Si](C)(C)C(C)(C)C)cc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3-(1-methyl-pyridin-4-yl)-5-hydroxy-1H-indole (8.0 g, 34.7 mmol) and 1-methyl-2-pyrrolidinone (10 mL) in dichloromethane (90 mL) stirring at 0° C., was added tert-butyldimethylsilyl chloride in small portions (5.50 g, 36.5 mmol), followed by imidazole also in small portions (2.48 g, 36.5 mmol). The reaction mixture was stirred for 1 hour at 0° C., then overnight at room temperature. The mixture was concentrated in vacuo to a solid residue, which was directly purified on silica gel. Elution with a 9:1 mixture of dichloromethane and methanol provided 7.60 g (63%) of the title compound as a white solid: mp=191-195° C.; 1H NMR (400 MHz, dmso-d6): 10.46 (s, 1H), 7.02 (d, 1H, J=8.4 Hz), 6.87 (d, 1H, J=2.4 Hz), 6.74 (d, 1H, J=2.4 Hz), 6.45 (dd, 1H, J=8.6, 2.6 Hz), 2.69 (br d, 2H, J=11.2 Hz), 2.46 (tt, 1H, J=11.8, 3.6 Hz), 2.04 (s, 3H), 1.92-1.80 (m, 2H), 1.75-1.67 (m, 2H), 1.50 (qd, 2H, J=12.4, 3.6 Hz), 0.81 (s, 9H), 0.00 (s, 6H); MS (APCI): m/e 345 0.2 (M+1).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH:12]([CH2:26][OH:27])[CH2:13][C:14]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[OH:17])[CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:27][CH2:26][CH:12]1[CH2:11][CH:10]2[CH:15]([CH2:16][NH:8][CH2:9]2)[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])([OH:17])[CH2:13]1
Reactant: COc1ccccc1C1(O)CC(CO)CC2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1C1(O)CC(CO)CC2CNCC21
Reaction time: 3 h
Yield: 128.2 %

Procedure:
A suspension of 3.1 g of (3aRS,4RS,6SR,7aSR)-2-benzyl-6-hydroxymethyl-4-(2-methoxyphenyl) perhydroisoindol-4-ol and 0.5 g of 20% palladium hydroxide on carbon black in 75 cm3 of ethanol is hydrogenated under atmospheric pressure at 60° C. for 3 hours. The reaction mixture is subsequently filtered and concentrated to dryness under reduced pressure (2.7 kPa). 3.0 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol are obtained in the form of a thick white foam.