Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(C(O)(CC2OC(C)(C)OC(=O)C=2)CCC2C=CC(C(CC)(CC)C#N)=C(F)C=2)CCC[CH2:2]1.[CH:34]1([C:39]([OH:64])([CH2:54][C:55]2[O:56]C(C)(C)O[C:59](=[O:61])[CH:60]=2)[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3([C:51]#[N:52])[CH2:50][CH2:49]3)=[C:44]([F:53])[CH:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([C:39]2([CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]([CH2:1][CH3:2])([CH2:50][CH3:49])[C:51]#[N:52])=[C:44]([F:53])[CH:43]=3)[CH2:54][C:55](=[O:56])[CH2:60][C:59](=[O:61])[O:64]2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCC(C#N)(CC)c1ccc(CCC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Reactant: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Product: CCC(C#N)(CC)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F

Procedure:
The desired product was prepared analogously to Example A(86) step 5, substituting 2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile (0.84 g, 1.8 mmol) from step 3 below in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. Yield: 0.393 g, 54%. 1H NMR (CDCl3) δ: 1.01 (t, J=7.45 Hz, 6H), 1.62-1.90 (br, 8H), 2.03-2.17 (br, 4H), 2.20-2.29 (br, 2H), 2.37 (p, J=9.35 Hz, 1H), 2.75-2.82 (m, 2H), 2.86 (d, J=7.58 Hz, 2H), 3.53 (d, J=2.02 Hz, 2H), 6.94 (dd, J1 =13.01 Hz, J2=1.64 Hz, 1H), 7.04 (dd, J1=7.83 Hz, J2=1.77 Hz, 1H), 7.57 (t, J=8.21 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cc1cccc(-c2cccc(CO)c2)c1
Temperature: 90 °C
Yield: 104.9 %

Procedure:
3-Hydroxymethylbenzeneboronic acid (1.8 g, 11.8 mmol), 3-bromophenylacetic acid (2.55 g, 11.8 mmol), tribasic potassium phosphate, (7.54 g, 35.5 mmol), DMF (55 ml), and water (20 ml) were degassed under nitrogen in a 250 ml flask fitted with a reflux condenser. Bis[triphenylphosphine]palladium(II) chloride (0.17 g, 0.24 mmol) was added. The mixture was degassed under nitrogen, and heated at 90° C. overnight, then acidified with 2N HCl, mixed with brine (15 ml), and extracted with methylene chloride (3×15 ml). The organic materials were combined, dried (MgSO4), then concentrated under reduced pressure which gave 3.0 g of 3-(3-hydroxymethylphenyl)phenyl acetic acid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[S:13][C:14]4[CH2:18][CH2:17][CH2:16][C:15]=4[C:10]3=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:8]=2[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:41]1[CH2:45]OC[CH2:42]1.ICCC>CN(C=O)C>[C:1]1([C:7]2[N:12]=[C:11]3[S:13][C:14]4[CH2:18][CH2:17][CH2:16][C:15]=4[C:10]3=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[C:8]=2[CH:26]([CH2:42][CH2:41][CH3:45])[C:27]([O:29][CH3:30])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1c(-c2ccccc2)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(-c2ccccc2)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 94.6 %

Procedure:
This compound was prepared according to the procedure C from Methyl [2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.185 g; 0.45 mmol), LHMDS 1N in THF (0.495 mL; 0.495 mmol), 1-iodopropane (0.066 mL; 0.675 mmol) in DMF (1.3 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.194 g (95%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:10](B(O)O)=[CH:9][CH:8]=1)=[O:5].I[C:37]1[N:41]2[CH:42]=[CH:43][C:44]([CH3:46])=[CH:45][C:40]2=[N:39][C:38]=1[C:47]1[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]([O:31][C:29](=[O:30])[N:2]([CH3:1])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:37]2[N:41]3[CH:42]=[CH:43][C:44]([CH3:46])=[CH:45][C:40]3=[N:39][C:38]=2[C:47]2[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=2)=[C:11]([C:13]#[C:14][Si:15]([CH:19]([CH3:20])[CH3:21])([CH:22]([CH3:23])[CH3:24])[CH:16]([CH3:18])[CH3:17])[N:12]=1)=[O:5])([CH3:34])([CH3:33])[CH3:35]
Reactant: Cc1ccn2c(I)c(-c3ccncc3)nc2c1
Reactant: CC(C(=O)Nc1ccc(B(O)O)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccn2c(-c3ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc3C#C[Si](C(C)C)(C(C)C)C(C)C)c(-c3ccncc3)nc2c1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-[2-tri(propan-2-yl)silylethynyl]pyridin-3-yl]boronic acid D1a (1.5 g, 3.0 mmol), 3-iodo-7-methyl-2-pyridin-4-ylimidazo[1,2-a]pyridine Za (1.3 g, 3.9 mmol), Na2CO3 (0.95 g, 8.9 mmol), Dichlorobis(triphenylphosphine)palladium(II) (209 mg, 0.3 mmol), dioxane (30 ml) and water (5 ml) is stirred under argon atmosphere for 17 h at 70° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 965 mg (49%). HPLC-MS: M+H=667; tR=2.04 min (*Method—3).
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C@@H:14]([CH2:17][CH2:18][CH3:19])CO.CCN(CC)CC>C1COCC1>[CH2:17]([C@H:14]1[CH2:2][O:4][C:5](=[O:11])[NH:13]1)[CH2:18][CH3:19]
Reactant: CCC[C@H](N)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC[C@H]1COC(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 185.8 %

Procedure:
A solution of triphosgene (0.431 g, 1.45 mmol) in THF (5 mL) was added dropwise to a stirred solution of (S)-2-aminopentan-1-ol (0.500 g, 4.85 mmol) and Et3N (1.49 mL, 10.7 mmol) in THF (22 mL) at 0° C. under N2. The reaction mixture was stirred at ambient temperature for 2 hours. After cooling, the suspension was filtered through GF/F paper and concentrated in vacuo. The residue was taken up in EtOAc and washed with 10% HCl, dried and concentrated to give (S)-4-propyloxazolidin-2-one (0.348 g, 55%) as a clear oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:13][CH2:14][C:15](Cl)=[O:16]>C(Cl)Cl>[C:1]([NH:5][C:15](=[O:16])[CH2:14][Cl:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a cooled (0° C.) solution of tert-butyl amine (5.25 mL, 50 mmol) in DCM (40 mL) was added triethylamine (14 mL, 101 mmol) followed by chloro acetylchloride (3.98 mL, 50.3 mmol). The reaction was warmed to RT and stirred for 2 h. The reaction mixture was concentrated, redissolved in EtOAc (20 mL) and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 5.39 g of crude product which was further purified by flash column chromatography using 7:3 Pet. Ether: EtOAc as the eluant. Pure N-tert-butyl-2-chloroacetamide (3.65 g) was isolated.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][CH2:23][CH2:24][CH2:25]I.O>O1CCCC1>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:2][C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: ClCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(=O)CCCCCl)cc1
Reaction time: 0.5 h

Procedure:
1 g (6.9 mmol) of 4-acetylbenzonitrile was dissolved in 8 ml of tetrahydrofuran. 9 ml of lithium bis(trimethylsilyl)amide (1 M solution in hexane) was gradually added to the solution at −70° C. and they were stirred for 30 minutes. 1.43 g (7 mmol) of 1-chloro-3-iodopropane dissolved in 6 ml of tetrahydrofuran was added thereto, and the resultant mixture was stirred at room temperature overnight. The reaction liquid was poured into water. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid and saturated aqueous common salt solution, and then dried over powdery magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel chromatography to obtain the title compound.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1([CH3:43])[O:30][CH:29]([CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][O:27]1.[N+](C1C=CC(C=CC2C=CC=CC=2)=CC=1)([O-])=O>O.CN(C)C=O>[CH3:25][C:26]1([CH3:43])[O:30][CH:29]([CH2:31][C:2]2[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)=[CH:4][CH:3]=2)[CH2:28][O:27]1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(C=Cc2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)cc2)O1

Procedure:
A mixture of 120.5 g of 4-hydroxy-4'-nitrostilbene, 69 g of anhydrous potassium carbonate, 143 g of 2,2-dimethyl-4-(4-methyl phenyl sulphonyloxymethyl)-1,3-dioxolane, prepared in accordance with the specification of K. Freudenberg and H. Hess in Liebigs Annalen der Chemie Vol. 448 (1926), p. 121, and 1 l of dimethyl formamide (DMF) was boiled for 30 minutes with refluxing. After cooling the reaction mixture was poured, with vigorous stirring, into 5 l of water. The precipitated crystals were filtered off and after-washed with 5 1 of water. The crude product after drying was crystallized from 4 l of acetone. Obtained were 135 g of 4-((2,2-dimethyl)-1,3-dioxa-4-cyclopentyl)methyl)-4'nitrostilbene in the form of yellow acicular crystals having a melting point of 146°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Cl.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.5 mmol of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propionyl chloride in 10 ml of methylene chloride was added dropwise to an ice-cooled solution of 1.53 g (7.2 mmol) of 4-(trifluoromethoxy)aniline hydrochloride and 1.58 g (15.6 mmol) of triethylamine in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight and then poured into a dilute aqueous HCl solution. The organic layer was separated, washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was recrystallized from methanol to give 2.00 g (61 percent of theoretical) of the above-named product as colorless crystals which melted at 156.5°-158° C. The structure of the product was confirmed by its IR and NMR spectrum. (Compound 6)
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C(Cl)Cl>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:33]([C:32]2[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=2)=[O:34])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.125 g, 0.43 mmol) and diisopropylethylamine (0.171 g, 1.32 mmol) in methylene chloride (5.0 mL) at 0° C. was added 4-fluorobenzoyl chloride (0.080 g, 0.51 mmol) and the reaction mixture was warmed to room temperature. After 2 h the reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (silica gel, 100:0 to 95:5 dichloromethane/methanol) to provided (4-(2-tert-butylphenyl)piperazin-1-yl)(4-fluorophenyl)methanone (0.044 g, 30%) as a white solid, mp 137-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:33][CH3:34].[N:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42](=O)[O:43]C2C=CC=CC=2)=[CH:37][CH:36]=1>O1CCOCC1>[F:30][C:28]([F:31])([F:29])[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42]([NH:41][C:38]4[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=4)=[O:43])=[C:3]([O:33][CH3:34])[CH:4]=3)=[O:9])[CH2:15][CH2:14]2)=[CH:18][CH:19]=1)([OH:32])[C:24]([F:25])([F:26])[F:27]
Reactant: COc1cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)ccc1N
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)ccc1NC(=O)Nc1ccncc1
Temperature: 80 °C
Yield: 4.9 %

Procedure:
(4-Amino-3-methoxyphenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.407 mmol, 200 mg) and phenyl pyridin-4-ylcarbamate (0.610 mmol, 131 mg) were combined in dioxane (2 mL) and heated to 80° C. overnight in a reactivial. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (dichloromethane—4% methanol/dichloromethane) to afford title compound (12.2 mg). MS (ESI) m/z 612.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH:32]2[CH2:34][CH2:33]2)=[CH:24][CH:23]=1.[CH3:35][C:36]([Si:39](Cl)([CH3:41])[CH3:40])([CH3:38])[CH3:37]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:39]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH:32]4[CH2:34][CH2:33]4)=[CH:24][CH:23]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:36]([CH3:38])([CH3:37])[CH3:35])([CH3:41])[CH3:40]
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 16 h

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 1a (Prepared according to the method in WO2010022313) (3.0 g, 6.06 mmol) was dissolved in 20 mL pyridine, followed by addition of 4-dimethylamino pyridine (148 mg, 1.21 mmol) and TBSCl (1.1 g, 7.27 mmol) in turn. The reaction mixture was stirred for 16 hours, then concentrated under reduced pressure. The residue was dissolved in 100 mL ethyl acetate and 100 mL water and partitioned. The aqueous phase was extracted with ethyl acetate (100 mL), and the organic layer was washed with water (50 mL), combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 1b (3.0 g, yellow solid), yield: 81.1%. 1H NMR (400 MHz, CD3OD): δ 7.50 (dd, 1H), 7.38 (m, 2H), 7.08 (d, 2H), 6.82 (d, 2H), 4.04 (m, 5H), 3.88 (m, 1H), 3.82 (m, 2H), 3.75 (m, 1H), 3.59 (m, 1H), 3.40 (m, 2H), 3.07 (m, 1H), 3.06 (s, 3H), 0.90 (s, 9H), 0.53 (m, 4H), 0.10 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:2]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>O1CCOCC1.C(O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:17])=[CH:2][CH:3]=3)=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:27]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(C)cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccc(C)cc2)n(-c2ccc(F)cc2)n1
Yield: 41.5 %

Procedure:
A mixture of ethyl 4-(4-tolyl)-2,4-dioxobutanoate (4.7 g) and 4-fluorophenylhydrazine hydrochloride (3.6 g) in dioxane (35 ml) and ethanol (35 ml) was refluxed for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The oily residue (8 g) was purified.by column chromatography on silica gel (130 g) eluting with chloroform to give an oil of ethyl 1-(4-fluorophenyl)-5-(4-tolyl)pyrazole-3-carboxylate (2.7 g).
Reaction SMILES: C([O:3][P:4](Cl)[O:5]CC)C.[CH2:9]([Mg]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl>C(OCC)C>[CH2:9]([PH:4](=[O:3])[OH:5])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CCOP(Cl)OCC
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=[PH](O)CCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Diethylchlorophosphite (15.6 g, 0.1 mol) in 100 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenethylmagnesium chloride (100 mL, 0.1 mol, 1.0 M in THF) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and stirred at room temperature overnight. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. The liquid was stirred as 15 mL of water was added followed by 0.5 mL of concentrated hydrochloric acid. An exothermic reaction was observed and stirring continued for 15 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. The clear liquid was brought up in sodium hydroxide (40 mL, 2.0 M NaOH), stirred for 1 hour and washed once with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give phenethylphosphinic acid (1,R=CH2CH2Ph, R1=H) (9.8 g, 58%) as a clear light yellow oil.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:35][CH2:34]3)=C(C(OC)=O)N=1)CC2)=O.S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCCI)=C(C(OCC)=O)N=1)CC2)=[O:64].C1C=CC(N2CCNCC2)=CC=1.N1(C2C=CC(O)=CC=2)CCNCC1>>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([OH:64])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CN1CCN(c2ccccc2)CC1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCCI
Agent: Oc1ccc(N2CCNCC2)cc1
Agent: c1ccc(N2CCNCC2)cc1
Product: CN1CCN(c2ccc(O)cc2)CC1

Procedure:
Compound 82A was prepared in a similar manner to the synthesis of compound 62A by substituting compound 42C and phenylpiperazine with paraformahyde and 4-(piperazin-1-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 6.74-6.78 (m, 2H), 6.61-6.65 (m, 2H), 2.93-2.95 (m, 4H), 2.41-2.44 (m, 4H), 2.22 (s, 3H). ESI (+)/MS: 193 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH3:9][C@H:10]1[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][O:11]1>>[OH:16][C@:14]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=2)[CH2:13][CH2:12][O:11][C@@H:10]([CH3:9])[CH2:15]1
Reactant: Brc1cccc(Br)c1
Reactant: C[C@H]1CC(=O)CCO1
Product: C[C@H]1C[C@@](O)(c2cccc(Br)c2)CCO1
Yield: 66 %

Procedure:
Using an analogous procedure to that described in the portion of Example 6 which is concerned with the preparation of starting materials, 1,3-dibromobenzene was reacted with (2S)-2-methyltetrahydropyran-4-one to give (2S,4R)-4-hydroxy-4-(3-bromophenyl)-2-methyltetrahydropyran in 66% yield as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:15]1([C:24]([O-])=[O:25])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[Cl:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][C:24]([C:15]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]1)=[O:25]
Reactant: CCOC(=O)C1(C(=O)[O-])CCC1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)CCC1

Procedure:
23.1 g of 5-chlorotryptamine hydrochloride, 17.3 g of monoethyl cyclobutanedicarboxylate, 36 ml of diisopropylethylamine and 33.7 g of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate are stirred for 20 hours at ambient temperature in 200 ml of dichloromethane. After washing with water, drying over sodium sulphate and filtering off the organic phase over Celite, evaporation under reduced pressure enables the expected product to be isolated.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[Cl:13].[Cu][C:15]#[N:16].O>CN(C)C=O>[Cl:13][C:3]1[C:4]([F:12])=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][C:2]=1[C:15]#[N:16]
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1F
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C#N)c(Cl)c1F
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-bromo-3-chloro-2-fluorophenyl)acetamide (17.0 g) and copper(I) cyanide (5.88 g) in N,N-dimethylformamide was stirred at 150° C. overnight. After warming to room temperature, water was added, and the mixture was extracted with methyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give N-(3-chloro-4-cyano-2-fluorophenyl)acetamide. Ethanol (250 mL)-concentrated hydrogen chloride (26.6 mL) was added to N-(3-chloro-4-cyano-2-fluorophenyl)acetamide, and the mixture was refluxed overnight. The mixture was ice-cooled, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column, and the obtained solid was washed with hexane to give the title compound as a pale-yellow solid (yield: 7.0 g, 64%).