Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[Cl:39]C1C=CC(CC(=O)C(OCC)=O)=CC=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][C:25]([Cl:39])=[CH:24][CH:23]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)C(=O)Cc1ccc(Cl)cc1
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1ccc(Cl)cc1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 66 %

Procedure:
This was prepared as described for C4 using ethyl 3-(4-chlorophenyl)-2-oxopropanoate B7 (100 mg, 0.441 mmol), sodium hydride (11.65 mg, 0.485 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (181 mg, 0.441 mmol). The resulting compound was isolated in the form of white solid in 66% yield.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].S(=O)(=O)(O)O>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:4][C@@H:3]([C@H:5]2[O:6][C@@H:11]3[O:12][C:9]([CH3:11])([CH3:7])[O:10][C@@H:9]3[C@H:7]2[OH:8])[CH2:2][O:1]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In this example, 125 g of powdered D-glucose is added to a stirred solution of 120 ml of concentrated 96 wt.% sulfuric acid in 3 liters of acetone and the mixture is stirred vigorously at room temperature overnight. The reaction mixture is cooled to 10° C. and gaseous ammonia is bubbled keeping the temperature below 25° C. Solids are filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with 1 liter of water and extracted three times with 300 ml of methylene chloride. The methylene chloride extracts are combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated to give a white crystalline residue of crude 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.C(O)C>O>[O:15]1[CH2:14][CH:13]1[CH2:11][NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: N#CCc1ccc(N)cc1
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(NCC2CO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
A mixture of 4-aminobenzylcyanide (10 g, 75.7 mmol), epichlorohydrine (7.9 ml, 9.25 g, 100 mmol), ethanol (15 ml) and water (10 ml) was heated under reflux for 2 hours. After cooling the reaction mixture was poured into 100 ml of water and extracted with ether (3×50 ml). The organic extracts were combined and stirred with 50 ml of 10N NaOH at room temperature for 3 hours. The organic layer was separated, washed with water until neutral, dried over MgSO4 and concentrated. The residue was chromatographed over a silica gel column eluting with a 3:1 mixture of benzene and ethyl acetate to afford 7.24 g of the title compound as an oil, yield: 51.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:61][N:62]1[CH2:66][CH2:65][CH2:64][C@@H:63]1[CH:67]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:67]/[C@H:63]4[CH2:64][CH2:65][CH2:66][N:62]4[CH3:61])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Reactant: CN1CCC[C@@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@H]1CCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (250 mg, 0.40 mmol) was dissolved in 10 mL of dry tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (440 μL, 0.44 mmol). The reaction mixture was stirred for 30 minutes, added dropwise with a solution of (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (90 mg, 0.80 mmol) in 5 mL of tetrahydrofuran, and stirred for 30 minutes, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 5 (46 mg, yield 19.7%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1.S(OC)(O[CH3:31])(=O)=O>>[CH3:31][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Reactant: COS(=O)(=O)OC
Product: COC(=O)COc1cccc(C=CC(=O)c2c(OC)cc(C)n(C)c2=O)c1

Procedure:
According to the same manner as that of Example a-25 except that 0.71 g of 4-hydroxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone was used in place of 4-hydroxy-3-[3-[3-(2-hydroxyethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone, and 0.28 ml of dimethyl sulfate was used in place of iodomethane, 0.37 g of 4-methoxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (60a)] was obtained as a pale yellow crystal.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH:11][N:12]=[CH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:9][C:8](=[O:24])[N:7]([CH3:25])[C:6]1=[O:26])[CH:2]([CH3:4])[CH3:3].[C:27]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O)#[N:28].C(N(CC)CC)C>CN(C=O)C.CCOCC>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[C:32]([C:31]3[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=3)[C:27]#[N:28])=[C:9]2[C:8](=[O:24])[N:7]([CH3:25])[C:6]1=[O:26])[CH:2]([CH3:4])[CH3:3]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(C)Cn1c(NN=Cc2cccc3ccccc23)cc(=O)n(C)c1=O
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C#N)c3)n(Cc3cccc4ccccc34)nc21
Yield: 69.7 %

Procedure:
A solution of 100 mg (0.26 mmol) of l-naphthaldehyde (3-isobutyl-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone, 36 mg (0.27 mmol) of 3-cyano benzaldehyde and 20 uL of triethylamine in 20 mL DMF was heated at 85° C. for 20 h. The mixture was diluted with ether and washed 4 times with water. The ether was dried (MgSO4) and concentrated to give a yellow solid which was recrystallized from ethanol to give 84 mg of the subtitle product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[C:5]([F:15])[CH:4]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>O1CCCC1.C1C(=O)[N-]C(=O)C1.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.Br[Pd+]>[F:15][C:5]1[CH:4]=[C:3]([CH2:2][C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)[CH:8]=[CH:7][C:6]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C)c1ccc(CBr)cc1F
Reactant: OB(O)c1ccco1
Agent: Br[Pd+]
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)[N-]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(Cc2ccco2)cc1F
Temperature: 25 °C
Yield: 45.3 %

Procedure:
Compound 20 (0.88 g, 3.2 mmol) and 2-furan boronic acid (0.54 g, 4.8 mmol) were dissolved in tetrahydrofuran (12 mL) and a 2 M-aqueous solution (4.0 mL) of sodium carbonate. To this solution, trans-bromo(N-succinimidyl)bis(triphenylphosphine)palladium(II) [trans-PdBr(N-Succ)(PPh3)2] (25.9 mg, 1.0 mol %) was added and heated to reflux for 3 hours. After cooling to room temperature and adding ether (50 mL) to the solution, the organic layer was washed with water (30 mL) and dried (over magnesium sulfate), and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (20:1) solution followed by conventional hydrolysis with potassium hydroxide to give 0.36 g (43%) of compound (21a) of interest as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[CH:11](=O)[CH:12]([CH3:14])[CH3:13].CO>C(O)=O>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[N:4]=[CH:11][CH:12]([CH3:14])[CH3:13]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC(C)C=O
Solvent: CO
Solvent: O=CO
Product: Cc1cc(C)c(N=CC(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,4,6-Trimethylaniline (7.0 mL, 50 mmol, Aldrich) was mixed with isobutyraldehyde (4.5 mL, 50 mmol, Aldrich), methanol (20 mL), and formic acid (1 mL of a 88% aqueous solution, Fisher). The reaction mixture became reddish and was stirred at RT for 4 h. Assay by 1H-NMR showed a 2/1 mixture of product/starting materials. Additional isobutyric aldehyde (4 mL, 44 mmol) was added to the reaction mixture and it was stirred for 12 h. At this point assay by 1H-NMR showed a 5/1 mixture of product/amine. The solvent and excess aldehyde was evaporated, the residue was distilled at reduced pressure collecting three fractions: 1. 53–56° C./27 Pa, 1/1 mixture of product/amine; 2. 56–59° C., 7/1 product/amine; 3. 59–60° C., pure product (2.3 g, 24.3%). 1H NMR (CDCl3) 7.52 (d, 1H; J=4.8 Hz); 6.84 (br s, 2H); 2.70 (d of septets, 1H; J=4.8; 6.9 Hz); 2.26 (s, 3H); 2.05 (s, 6H); 1.22 (d, 6H; J=6.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[C:28]([Cl:30])[CH:29]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)cc3)c2cc1OC
Yield: 86.6 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (5 ml) with heat, 3,5-dichlorophenyl isocyanate (76 mg) was added, and the admixture was refluxed with heat for 8 minutes. The separated crystals were filtered and then washed with toluene to obtain 75 mg of the title compound (yield: 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(Cl)(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Br)cn1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-amino-5-bromopyridine (6.92 g, 40 mmol) and 6.22 g (48 mmol) of diisoproplethylamine in 50 mL of chloroform was added dropwise to a solution of 8.19 g (48 mmol) of benzyl chloroformate in 20 mL of chloroform at about 0° C., with stirring. A voluminous white precipitate formed. After about 15 minutes, the mixture was filtered and the precipitate was washed three times with chloroform and dried to give 2.70 g of the title product, mp 184° C. (dec) (recrystallization solvent=2-propanol). 1H nmr (dimethylsulfoxide-d6): δ=10.48 (br s, 1 H), 8.37 (d, 1 H), 7.98 (d of d, 1 H), 7.81 (d, 1 H), 7.40 (m, 5 H), 5.17 (s, 2 H); ms (NH3Cl): m/z=307, 309 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[Cl:7].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(C)(C)C>[Br:1][C:2]1[C:3]([CH:9]([O:15][C:3]([CH3:9])([CH3:4])[CH3:2])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[Cl:7]
Reactant: CCOC(=O)C(O)c1c(C)sc(Cl)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(Cl)c1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 165.3 %

Procedure:
To a suspension of ethyl 2-(4-bromo-5-chloro-2-methylthiophen-3-yl)-2-hydroxyacetate (44c) (334 mg, 1.065 mmol) in tert-butylacetate (10.9 mL) at −5° C. was added perchloric acid (70%, 0.4 mL). The mixture was stirred at −5° C. for 1 hour then at 0° C. for 30 minutes more. The mixture was stirred at room temperature for 1 hour more and was basified with a saturated aqueous solution of sodium bicarbonate until pH 8. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to afford the desired product (44d) as a colorless oil (324 mg, 0.88 mmol, 82%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][C:44](=[CH2:46])[CH2:43][N:42]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])(C)(C)C.Cl.[CH3:59][O:60][C:61]([NH:63][CH:64]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)C(O)=O)=[O:62].CCN(C(C)C)C(C)C.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1>[CH3:56][O:55][C:53](=[O:54])[NH:52][CH:48]([C:47]([N:42]1[CH2:43][C:44](=[CH2:46])[CH2:45][CH:41]1[C:38]1[NH:37][C:36]([C:31]2[CH:30]=[CH:29][C:28]3[C:33](=[CH:34][CH:35]=[C:26]([C:23]4[CH:22]=[CH:21][C:20]([C:17]5[NH:16][C:15]([CH:9]6[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][N:8]6[C:6](=[O:7])[CH:64]([NH:63][C:61]([O:60][CH3:59])=[O:62])[C:68]6[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=6)=[N:19][CH:18]=5)=[CH:25][CH:24]=4)[CH:27]=3)[CH:32]=2)=[CH:40][N:39]=1)=[O:57])[CH:49]([CH3:51])[CH3:50]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Reactant: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CC(C#N)CN7C(=O)OC(C)(C)C)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CC(C#N)CN7C(=O)C(NC(=O)OC)c7ccccc7)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Cyano-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (102.0 mg, 0.134 mmol) was stirred in DCM (2.0 mL)/HCl in dioxane (4M, 2.0 mL). After 40 minutes all volatiles were removed in vacuo. The crude material was dissolved in DMF (1.5 mL) and methoxycarbonylamino-phenyl-acetic acid (28.2 mg, 0.134 mmol), DIEA (52.2 mg, 0.4 mmol), and COMU (57.7 mg, 0.134 mmol) was added and stirring at room temperature was continued. After 15 minutes, the reaction was quenched with aqueous HCl (1N, 0.1 mL). The crude reaction mixture was purified via RP-HPLC (eluent: water/MeCN w/0.1% TFA). The product containing fractions were lyophilized to give the final compound (59.3.0 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClN1[C:26](=[O:27])[CH2:25][CH2:24]C1=O.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]3[CH2:24][CH2:25][CH2:26][O:27][C:13]=23)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(NCCN1CCCCC1)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(NCCN1CCCCC1)c1c2n(c3ccccc13)CCCO2
Yield: 29 %

Procedure:
N-[2-(1-Piperidyl)ethyl] 1 H-indole-3-carboxamide (D2) was treated initially with N-chlorosuccinimide, then with 3-bromo-1-propanol, then with potassium carbonate in acetone following the method described in Example 3. The crude product was chromatographed on silica gel eluting with chloroform/methanol (19:1) to give a pale yellow oil, which crystallised from ether to afford the title compound (E5) as a white solid (29%) mp 124°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](COCOC)=[C:7]([C:14]([CH2:18][CH3:19])=[CH:15][CH2:16][OH:17])[CH:6]=[C:5]([Si:20]([CH3:23])([CH3:22])[CH3:21])[N:4]=1.C([C@@](C([O-])=O)(O)[C@@](CC)(O)C([O-])=[O:29])C.C(OO)(C)(C)C>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@:14]1([C:7]2[CH:6]=[C:5]([Si:20]([CH3:23])([CH3:22])[CH3:21])[N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[O:29][C@@H:15]1[CH2:16][OH:17])[CH3:19]
Reactant: CCC(=CCO)c1cc([Si](C)(C)C)nc(OC)c1COCOC
Reactant: CC[C@](O)(C(=O)[O-])[C@](O)(CC)C(=O)[O-]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)(C)OO
Solvent: ClCCl
Product: CC[C@]1(c2cc(OC)nc([Si](C)(C)C)c2)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 5a (937 mg, 2.76 mmol) and activated 4 Å molecular sieves (280 mg) in CH2Cl2 (26 mL) at −20° C. was added diethyl-L(+)-tartrate (568 mg, 2.75 mmol), and Ti(OiPr)4 (629 mg, 2.2 mmol). After stirring for 1 h, tBuOOH (1.1 mL, 5.0-6.0 M in decane, predried over 4 Å molecular sieves for 1 h) was added with a syringe. The reaction mixture was kept in the freezer at −20° C. for 60 h. The solution was removed from the freezer, diluted with Et2O (5.2 mL) and quenched with a saturated Na2SO4 solution (2.6 mL). The resulting heterogeneous mixture was stirred and allowed to warm to room temperature for 2 h. Then it was filtered through a celite pad (washing with hot EtOAc several times). The combined filtrates were concentrated under vacuum. The residue was dissolved in Et2O (13 mL) at 0° C. and a 1N NaOH solution saturated with NaCl was added (8 mL). The two-phase mixture was vigorously stirred at 0° C. for 1 h and then transfered to a separatory funnel. The aqueous layer was separated and extracted 3 times with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give 651 mg (66% yield) of the crude product 6a as a clear oil with 92% ee and sufficiently pure for the subsequent reaction. Epoxide 6a was analyzed for enantiomeric purity using a Chiralcel OD-H column with 98.5:1.5 hexane:iPrOH as the eluent, using the racemate as the standard. 1H NMR (300 MHz, CDCl3) δ0.27 (s, 9H), 0.9 (t, J=7.5 Hz, 3H), 1.79 (m, 1H), 1.97 (m, 1H), 3.23 (t, J=5.8 Hz, 1H), 3.45 (s, 3H), 3.9 (m, 2H), 3.99 (s, 3H), 4.64-4.72 (m, 4H), 7.09 (s, 1H); 13C NMR (75 MHz, CDCl3) δ−1.93, 9.18, 25.63, 29.66, 53.42, 55.59, 60.64, 61.21, 63.46, 64.63, 96.44, 115.45, 121.32, 148.36, 161.89, 165.16; IR (film, NaCl, cm−1) 3463, 2945, 1562, 1451, 1345, 1041, 840; LRMS (70 eV, EI) m/z (rel int %) 355 (M+), 340, 324, 310, 294, 280, 262, 250, 89, 73, 57. HRMS m/z calcd for C17H29NO5Si (M+) 355.1815, found 355.1812, [α]23D=+28(c=0.25, CH2Cl2).
Reaction SMILES: CCO[C:4]([CH:6]1[CH2:12][CH2:11][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:5].[CH2:13](O)[CH2:14][OH:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.O.O1CCCC1.C1C=CC=CC=1>[O:10]1[C:9]2([CH2:8][CH2:7][CH:6]([CH2:4][OH:5])[CH2:12][CH2:11]2)[O:15][CH2:14][CH2:13]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 7 h
Yield: 85.1 %

Procedure:
A reflux condenser equipped with a Dean-Stark water separator was attached to a round bottom flask containing ethyl 4-cyclohexanonecarboxylate (5 ml, 31.4 mmol), ethylene glycol (1.93 ml, 34.5 mmol), p-toluenesulfonic acid monohydrate (200 mg, 1.05 mmol), and benzene (30 ml). The mixture was heated under reflux for 3 hours. To the reaction mixture, triethylamine (181 μl, 1.3 mmol) was added and the mixture was concentrated. A tetrahydrofuran solution of the resultant crude substance was added to a tetrahydrofuran (30 ml) suspension of lithium aluminum hydride (1.31 g, 34.5 mmol) at 0° C. After the mixture was stirred at room temperature for 7 hours, water (1.3 ml), a 5N aqueous sodium hydroxide solution (1.3 ml), and water (3.9 ml) were sequentially added to the mixture at 0° C. After dried over sodium sulfate, the mixture was filtrated. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane=1/2, 1/1, 2/1) to obtain the title compound (4.6 g, yield: 85.1%) as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1>C(Cl)Cl>[CH3:27][O:26][C:25]1[CH:24]=[C:23]2[C:18](=[CH:17][C:16]=1[O:15][CH3:14])[CH:19]=[C:20]([C:5](=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:21]=[CH:22]2
Reactant: COc1cc2ccccc2cc1OC
Reactant: CCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCC(=O)c1ccc2cc(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (2.66 g) was added to a solution of: heptanoylchloride (3.1 ml) and 2,3-dimethoxynaphthalene (3.76 g) in methylene chloride (50 ml) at 0° C. The reaction mixture was stirred at room temperature overnight and then worked up as described in example 3(a). The crude product was recrystallized from ethanol. Yield: 2.8 g, melting point 77-78° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH2:17].CCN(CC)CC>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:17][CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: NC1Cc2ccccc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Temperature: 25 °C
Yield: 82 %

Procedure:
Under N2 at −75° C., trifluoroacetic acid was added to a stirring solution of 2,3-dihydro-1H-inden-2-amine (HCl salt, 8.0 g, 47.2 mmol), Et3N (14.9 ml, 106.7 mmol) and THF (160 ml). After the solution was allowed to warm up to rt, it was partitioned between H2O and DCM. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was triturated with hexanes: Et2O (1:1) to obtain the product as a white solid (8.9 g, 82% yield). 1H-NMR (400 MHz, CDCl3) δ 7.28-7.20 (m, 4H), 6.50 (s, 1H), 4.81-4.74 (m, 1H), 3.38 (dd, J=16.4, 7.1 Hz, 2H), 2.89 (dd, J=16.3, 4.2 Hz, 2H).